Roles of the insular cortex in the modulation of pain: insights from brain lesions

Abstract

Subjective sensory experiences are constructed by the integration of afferent sensory information with information about the uniquely personal internal cognitive state. The insular cortex is anatomically positioned to serve as one potential interface between afferent processing mechanisms and more cognitively oriented modulatory systems. However, the role of the insular cortex in such modulatory processes remains poorly understood. Two individuals with extensive lesions to the insula were examined to better understand the contribution of this brain region to the generation of subjective sensory experiences. Despite substantial differences in the extent of the damage to the insular cortex, three findings were common to both individuals. First, both subjects had substantially higher pain intensity ratings of acute experimental noxious stimuli than age-matched control subjects. Second, when pain-related activation of the primary somatosensory cortex was examined during left- and right-sided stimulation, both individuals exhibited dramatically elevated activity of the primary somatosensory cortex ipsilateral to the lesioned insula in relation to healthy control subjects. Finally, both individuals retained the ability to evaluate pain despite substantial insular damage and no evidence of detectable insular activity. Together, these results indicate that the insula may be importantly involved in tuning cortical regions to appropriately use previous cognitive information during afferent processing. Finally, these data suggest that a subjectively available experience of pain can be instantiated by brain mechanisms that do not require the insular cortex.

Figures

Figure 1.

High-resolution T1 images showing the extent of the lesions. Both patients had large left MCA ischemic strokes with lesions encompassing the insular cortex. Patient 1's lesions involved large portions of the insula, parts of SII, basal ganglia, and white matter. Patient 2's lesions were more extensive than patient 1's and involved large portions of the insula and SII, parts of basal ganglia, and white matter. Patient 2 also suffered from hemorrhagic transformation of the ischemic stroke.

Figure 2.

Thermal thresholds (means ± SEM). Disturbances in temperature sensations seen in patients are consistent with lesions to the insula. In patient 1, although the heat pain threshold of the affected side was normal, the threshold of the unaffected side was in the range of the innocuous warm detection threshold and is consistent with allodynia. In patient 2, the innocuous cool detection threshold of the affected side was markedly lower than that of the unaffected side and controls and was in the range of the cold pain threshold. In addition, patient reported feeling no cold pain even at 0°C (*). The innocuous warm detection threshold of the affected side was markedly elevated when compared with the unaffected side and controls and was in the range of the heat pain threshold. Both innocuous warm and cool detection thresholds were asymmetric between sides. For each patient, only the average of six measurements per thermal threshold was recorded, so SEM could not be calculated.

Figure 3.

Pain intensity and unpleasantness VAS ratings during the graded noxious stimulation (means ± SEM). Both patients retained ability to discriminate noxious stimuli of graded intensities. Both exhibited monotonic increases in VAS ratings of pain intensity and unpleasantness as stimulus temperature increased.

Figure 4.

Pain intensity and unpleasantness VAS ratings during the long-duration noxious stimulation (means ± SEM). The solid squares indicate individual control's data. The solid triangles indicate 90th percentile of the control's data. Both patients exhibited significantly elevated pain intensity ratings compared with those of the control group (A). However, the effect of lesion on pain unpleasantness was not statistically significant, although patient 2 displayed a trend toward elevated pain unpleasantness on the affected side (B). Additionally, each patient responded differently. Whereas patient 2 had asymmetric pain ratings between sides without much disparity between the two pain dimensions, patient 1 had elevated pain intensity ratings across sides with normal pain unpleasantness.

Figure 5.

Pain-related activation of the insula. Stimulation of the unaffected (left) leg in patients activated similar brain areas as in controls. However, in the patients only the right (contralateral) insula was activated since the left insula was damaged by the lesions. In the controls, insular activation was detected bilaterally. In contrast, painful stimulation of the affected (right) leg in patients did not produce any detectable right (ipsilateral) insular activation. This suggests that insular activation may not be necessary for a conscious experience of pain and that contralateral insular activation appears to be necessary to produce ipsilateral insular activation. The structures named at the bottom are for both controls and patients. VMPFC, Ventromedial prefrontal cortex; PCC, posterior cingulate cortex; dACC, dorsal anterior cingulate cortex.

Figure 6.

SI activation during pain. Stimulation of the unaffected (left) side did not generate any SI activation in both patients. Interestingly, stimulation of the affected (right) body side produced robust contralateral SI activations in both patients. It appears that SI activations in patients may only be reliably detected during stimulation of the affected side when insular activation was not present (Fig. 5). These results suggest SI may be recruited to help with processing of nociceptive information after insular damage.

Figure 7.

Left/right SI ROI activation ratio. The solid squares indicate individual control's data. The solid triangles indicate 90th percentile of the control's data. In both patients, the left/right SI ROI activation ratios were significantly greater than those of the controls. Thus, contralateral SI activation during stimulation of the affected (right) side relative to contralateral SI activation during stimulation of the unaffected (left) side was significantly greater in patients than the controls. This suggests that, in the absence of insula, brain areas such as SI may be recruited to help with the processing of nociceptive information.

Figure 8.

DLPFC activation during pain. Right DLPFC activations during painful stimulation were detected in both patients, but not in the controls. Painful stimulation of the unaffected (left) side activated the right DLPFC in both patients but not in the controls. However, stimulation of the affected (right) body side activated the right DLPFC in patient 1, but not in patient 2 and controls. Right DLPFC activations may represent recruitment of additional brain areas to help with processing nociceptive information in the face of insular damage.