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 detectible 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.

Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity we used voxel-based morphometry (VBM) to investigate the relationship between grey matter density across the whole brain and inter-individual differences in pain sensitivity in 116 healthy volunteers (62 females, 54 males). Structural MRI and psychophysical data from 10 previous fMRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49°C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions exhibited a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure.

Pain is a uniquely individual experience that is heavily shaped by evaluation and judgments about afferent sensory information. In visual, auditory, and tactile sensory modalities, evaluation of afferent information engages brain regions outside of the primary sensory cortices. In contrast, evaluation of sensory features of noxious information has long been thought to be accomplished by the primary somatosensory cortex and other structures associated with the lateral pain system. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that the prefrontal cortex, anterior cingulate cortex, posterior parietal cortex, thalamus, and caudate are engaged during evaluation of the spatial locations of noxious stimuli. Thus, brain mechanisms supporting discrimination of sensory features of pain extend far beyond the somatosensory cortices and involve frontal regions traditionally associated with affective processing and the medial pain system. These frontoparietal interactions are similar to those involved in the processing of innocuous information and may be critically involved in placing afferent sensory information into a personal historical context.

Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.

In many sensory modalities, afferent processing is dynamically modulated by attention and this modulation produces altered sensory experiences. Attention is able to alter perceived pain, but the mechanisms involved in this modulation have not been elucidated. To determine whether attention alters spatial integration of nociceptive information, subjects were recruited to evaluate pain from pairs of noxious/innocuous thermal stimuli during different spatial attentional tasks. Divided attention was able to abolish spatial summation and produce inhibition of pain. In contrast, directed attention enhanced pain intensity by partially integrating both stimuli. This dynamic modulation of spatial integration indicates that attention alters spatial dimensions of afferent nociceptive processing to optimize the perceptual response to input from a particular body region or stimulus feature. This dynamic spatial tuning of nociceptive processing provides a new conceptual insight into the functional significance of endogenous pain inhibitory and facilitatory mechanisms.