Alexandre S. Quevedo

Roles of the Insular Cortex in the Modulation of Pain: Insights from Brain Lesions

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.

Brain Mechanisms Supporting Spatial Discrimination of Pain

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.

The contribution of the putamen to sensory aspects of pain: insights from structural connectivity and brain lesions

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.

Brain Mechanisms Supporting Discrimination of Sensory Features of Pain: A New Model

Pain can be very intense or only mild, and can be well localized or diffuse. To date, little is known as to how such distinct sensory aspects of noxious stimuli are processed by the human brain. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that discrimination of pain intensity, a nonspatial aspect of pain, activates a ventrally directed pathway extending bilaterally from the insular cortex to the prefrontal cortex. This activation is distinct from the dorsally directed activation of the posterior parietal cortex and right dorsolateral prefrontal cortex that occurs during spatial discrimination of pain. Both intensity and spatial discrimination tasks activate highly similar aspects of the anterior cingulate cortex, suggesting that this structure contributes to common elements of the discrimination task such as the monitoring of sensory comparisons and response selection. Together, these results provide the foundation for a new model of pain in which bidirectional dorsal and ventral streams preferentially amplify and process distinct sensory features of noxious stimuli according to top-down task demands.

Attentional Modulation of Spatial Integration of Pain: Evidence for Dynamic Spatial Tuning

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.

Pain sensitivity is inversely related to regional grey matter density in the brain.

Summary Highly sensitive individuals had the least grey matter density in the bilateral precuneus, posterior cingulate cortex, posterior parietal cortex, and left primary somatosensory cortex. ABSTRACT 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 to investigate the relationship between grey matter density across the whole brain and interindividual differences in pain sensitivity in 116 healthy volunteers (62 women, 54 men). Structural magnetic resonance imaging (MRI) and psychophysical data from 10 previous functional MRI 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 showed 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.

Frontoparietal mechanisms supporting attention to location and intensity of painful stimuli

TOC summary Frontoparietal mechanisms as well as early sensory cortices contribute to directed attention to specific features of painful stimuli, such as intensity or location. ABSTRACT Attention can profoundly shape the experience of pain. However, little is known about the neural mechanisms that support directed attention to nociceptive information. In the present study, subjects were cued to attend to either the spatial location or the intensity of sequentially presented pairs of painful heat stimuli during a delayed match‐to‐sample discrimination task. We hypothesized that attention‐related brain activation would be initiated after the presentation of the attentional cue and would be sustained through the discrimination task. Conjunction analysis confirmed that bilateral portions of the posterior parietal cortex (intraparietal sulcus [IPS] and superior parietal lobule) exhibited this sustained activity during attention to spatial but not intensity features of pain. Analyses contrasting activation during spatial and intensity attention tasks revealed that the right IPS region of the posterior parietal cortex was consistently more activated across multiple phases of the spatial task. However, attention to either feature of the noxious stimulus was associated with activation of frontoparietal areas (IPS and frontal eye fields) as well as priming of the primary somatosensory cortex. Taken together, these results delineate the neural substrates that support selective amplification of different features of noxious stimuli for utilization in discriminative processes.

Filling-In, Spatial Summation, and Radiation of Pain: Evidence for a Neural Population Code in the Nociceptive System

The receptive field organization of nociceptive neurons suggests that noxious information may be encoded by population-based mechanisms. Electrophysiological evidence of population coding mechanisms has remained limited. However, psychophysical studies examining interactions between multiple noxious stimuli can provide indirect evidence that neuron population recruitment can contribute to both spatial and intensity-related percepts of pain. In the present study, pairs of thermal stimuli (35 degrees C/49 degrees C or 49 degrees C/49 degrees C) were delivered at different distances on the leg (0, 5, 10, 20, 40 cm) and abdomen (within and across dermatomes) and subjects evaluated pain intensity and perceived spatial attributes of stimuli. Reports of perceived pain spreading to involve areas that were not stimulated (radiation of pain) were most frequent at 5- and 10-cm distances (chi(2) = 34.107, P < 0.0001). Perceived connectivity between two noxious stimuli (filling-in) was influenced by the distance between stimuli (chi(2) = 16.756, P < 0.01), with the greatest connectivity reported at 5- and 10-cm separation distances. Spatial summation of pain occurred over probe separation distances as large as 40 cm and six dermatomes (P < 0.05), but was maximal at 5- and 10-cm separation distances. Taken together, all three of these phenomena suggest that interactions between recruited populations of neurons may support both spatial and intensity-related dimensions of the pain experience.

Exteroceptive aspects of nociception: insights from graphesthesia and two-point discrimination.

&NA; The exteroceptive capabilities of the nociceptive system have long been thought to be considerably more limited than those of the tactile system. However, most investigations of spatio‐temporal aspects of the nociceptive system have largely focused on intensity coding as consequence of spatial or temporal summation. Graphesthesia, the identification of numbers “written” on the skin, and assessment of the two‐point discrimination thresholds were used to compare the exteroceptive capabilities of the tactile and nociceptive systems. Numbers were “written” on the forearm and the abdomen by tactile stimulation and by painful non‐contact infrared laser heat stimulation. Subjects performed both graphesthesia tasks better than chance. The tactile graphesthesia tasks were performed with 89% (82–97%) correct responses on the forearm and 86% (79–94%) correct responses on the abdomen. Tactile graphesthesia tasks were significantly better than painful heat graphesthesia tasks that were performed with 31% (23–40%) and 44% (37–51%) correct responses on the forearm and abdomen, respectively. These findings demonstrate that the central nervous system is capable of assembling complex spatio‐temporal patterns of nociceptive information from the body surface into unified mental objects with sufficient accuracy to enable behavioral discrimination.

Effects of tongue position on mandibular muscle activity and heart rate function.

OBJECTIVES A primary goal of pain management for muscle-related pain is to reduce masticatory muscle activity. This study aimed to investigate masticatory muscle group activity and heart rate variability change when the tongue was placed on the palate or the floor of the mouth in a healthy pain-free sample. STUDY DESIGN Participants were 23 females and 18 males with a mean age of 19.6 years (standard deviation = 1.5). Muscle activity was measured using surface electromyography and heart period were measured using electrocardiography. The experimental protocol consisted of 3 periods: baseline, tongue placement on the floor of mouth, and tongue placement on palate. RESULTS Results indicated significantly more activity in the temporalis and suprahyoid muscle regions as well as a significant reduction in heart rate variability when the tongue was positioned on the palate compared with tongue position on the floor of the mouth. CONCLUSIONS Instructions to place the tongue on the roof of the mouth are not instructions that will promote reduced physiological functioning (i.e., relaxation) but rather promote small, but potentially important increases in overall activity as indexed by muscle tone and cardiac function.