Parsing Pain Perception Between Nociceptive Representation and Magnitude Estimation

1 Department of Physiology, 2 Department of Anesthesia, and 3 Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois Submitted 1 October 2008; accepted in final form 2 December 2008 Assessing the size of objects rapidly and accurately clearly has survival value. A central multisensory module for subjective magnitude assessment is therefore highly likely, suggested by psychophysical studies, and proposed on theoretical grounds. Given that pain perception is fundamentally an assessment of stimulus intensity, it must necessarily engage such a central module. Accordingly, we compared functional magnetic resonance imaging (fMRI) activity of pain magnitude ratings to matched visual magnitude ratings in 14 subjects. We show that brain activations segregate into two groups, one preferentially activated for pain and another equally activated for both visual and pain magnitude ratings. The properties of regions in the first group were consistent with encoding nociception, whereas those in the second group with attention and task control. Insular cortex responses similarly segregated to a pain-specific area and an area (extending to the lateral prefrontal cortex) conjointly representing perceived magnitudes for pain and vision. These two insular areas were differentiated by their relationship to task variance, ability to encode perceived magnitudes for each stimulus epoch, temporal delay differences, and brain intrinsic functional connectivity. In a second group of subjects ( n = 11) we contrasted diffusion tensor imaging–based white matter connectivity for these two insular areas and observed anatomical connectivity closely corresponding to the functional connectivity identified with fMRI. These results demonstrate that pain perception is due to the transformation of nociceptive representation into subjective magnitude assessment within the insula. Moreover, we argue that we have identified a multisensory cortical area for "how much" complementary and analogous to the "where" and "what" as described for central visual processing. Address for reprint requests and other correspondence: A. V. Apkarian, Department of Physiology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611 (E-mail: a-apkarian{at}northwestern.edu )