Pain is a sensory and affective experience that serves a critical adaptive function, inspiring the organism to enact protective behaviors. While it is often a response to sensory input, it does not have a direct, linear relationship to such input. Rather, individuals report a transition where sensory input goes from being relatively innocuous to painful at a particular temperature or range of temperatures (commonly referred to as the pain threshold).
In order to examine the neural mechanisms underlying this transition, we measured BOLD responses to thermal stimuli varying from 44 °C to 49 °C, and fit the BOLD response profile with a non-linear function designed to capture neural activation reflecting perceptual as distinct from sensory processing. We predicted that neural regions supporting the perception of pain, as opposed to the stimulus property of heat, would show a non-linear, sigmoidal-shaped increase in BOLD response magnitude across temperatures. The sigmoid function has been extensively used to model thresholded responses in different types of nonlinear systems including neuronal responses to pain (Neugebauer and Li, 2003
), and prior data suggested a sigmoidal shape in both BOLD responses to thermal stimuli (Timmermann et al., 2001
), as well as corresponding subjective reports (Bornhovd et al., 2002
; Buchel et al., 2002
Consistent with this prediction, the sigmoid fit was found to account for significantly more of the variance in the BOLD signal than a more simple linear function in a number of brain regions previously associated with the neural pain response. Activations of the insula and dorsal anterior cingulate in the present study are consistent with previously reported activation of these regions in neuroimaging studies of pain (Farrell et al., 2005
; Peyron et al., 2000
) and, more specifically, studies examining the transition from innocuous to painful sensation (Bornhovd et al., 2002
; Buchel et al., 2002
; though see Oertel et al., n.d.). The insula has been implicated in the integration of incoming information on the state of the body and corresponding subjective states (Craig, 2009
) as well as with estimation of the magnitude of pain intensity (Baliki et al., 2009
; Coghill et al., 1999
); but see also Moayedi and Weissman-Fogel (2009)
. Cingulate has been implicated in facilitation of pain-related motor responses (Shackman et al., 2011
). Both are thought to be regions where cognitive and emotional information relevant to pain are processed and integrated with sensory information (Brooks and Tracey, 2007
; Ploner et al., 2011
; Wiech et al., 2010
), reinforcing the multi-faceted nature of the pain experience.
As mentioned previously, activation of dorsal cingulate and both anterior and posterior regions of insula are consistent with similar activations in studies examining the transition from innocuous to painful sensation (Bornhovd et al., 2002
; Buchel et al., 2002
). The present study found a more extensive network of activations, however.
Of particular note is the preponderance of activations in regions associated with motor responses. The observed thalamic activations were in the area of the ventral lateral nucleus, known to be a projection site for spinothalamic afferents commonly associated with pain and thermal information (Craig and Dostrovsky, 2001
). While this region receives nociceptive input, it also receives projections from motor regions including the globus pallidus (Borsook, 2007
), which was significantly associated with the transition from innocuous to painful sensation in this study. Ventral lateral nuclei also project to the premotor cortex, consistent with activations observed in that region. Within this context, it is noteworthy that the periacquductal gray which was also activated has not only been associated with descending modulation of pain (Fields and Basbaum, 1999
), but has been implicated in the instantiation of fight or flight responses (Bandler and Keay, 1996
). Taken together these findings strongly demonstrate the prioritization of neural processing associated with preparation for action as stimuli move from being innocuous to affectively salient. Studies examining neural activation associated with perceived intensity of pain (Coghill et al., 1999
; Derbyshire et al., 1997
) have observed similar patterns of activation, leading to a question for future study, namely which of the activations associated with the transition from innocuous to painful sensation in the present study increase with graded increases in temperature above the pain threshold.
A key finding of this study is the corroboration of measures of self-reported pain by sigmoid-fitted BOLD response profiles in a network of pain processing regions derived totally independently from the self-reports. We found that sigmoid-fitted activation in these neural regions accounted for up to 85% of the variance in individual warmth and pain ratings (significantly more than the raw BOLD response magnitudes). Furthermore, the point of inflection in the fit neural response profile showed tight correspondence to the temperature at which subjects reported maximum increases in their subjective experience of pain and the point at which button presses indicating pain became consistent.
The fact that the neural and self-report data corroborate each other confirms that the observed shift in activation levels corresponds to the perceptual switch from innocuous to painful levels of stimulation. Importantly, it also provides a further validation of self-reports of pain (Coghill et al., 2003
). This convergent validity is particularly important given variability observed across individuals in the degree to which a given point on the stimulus continuum reliably divides innocuous from painful experiences (Gracely, 1999
). While such variance could be disregarded as idiosyncratic pain reporting behavior rather than a true reflection of perceptual experience, the correspondence between the profiles of sigmoid fitted brain activation in a distinct set of brain regions and subjective ratings strongly supports the notion that individuals differ not only in the level of stimulation required to consistently elicit pain, but the degree to which this threshold is a discrete point rather than a graded range of temperatures.
One central feature of pain that remains to be thoroughly tested is the extent to which such transitions from innocuous to painful experience vary across individuals and with the experimental or clinical context. Our pain ratings indicate that at least in the current experimental context there is great individual variability, not necessarily in the temperature at which individuals show the steepest rise in pain ratings, but in the steepness of the rise. In addition, there is variability in the extent to which participants rate low temperatures as 0 or 1 on an interval pain scale, despite indicating with a categorical decision that such temperatures are not painful. This would suggest that the idea of a single well-defined temperature at which a stimulus becomes painful is not always justified. One of the motivations of the current study was to determine whether such variability in pain rating slopes could be accounted for by corresponding differences in BOLD response profiles. Our results show this to be the case. A strength of our analysis approach is that the formula used for non-linear curve fitting provides separate variables for the point of maximum inflection in the curve (which can be used as an index of the pain threshold) and slope of the curve (corresponding to the degree that the pain threshold is a discrete point or occurs over a range of temperatures for a given individual). By allowing for quantification of these variables, this methodology may provide clinically important insight into the mechanisms underlying individual differences in pain sensitivity. It also provides a means for determining the profile of pain in different experimental contexts and with different groups of individuals.
We note that although a sigmoid function provides flexibility in this regard, it still imposes theoretically-motivated constraints on the broad class of response profiles that will be fit. We further restricted our sigmoidal analysis to voxels that showed an increase from the lowest to the highest temperatures. It is quite possible that other networks in the brain that support different aspects of pain processing have a response profile that cannot be modeled with a sigmoid. For example, regions showing a uniform response across temperatures (which might be encoding the presence of a nociceptive stimulus), a decrease across temperatures (perhaps reflecting a switch away from background processing as is often the case with the “default” network) or other types of response would not have been captured. In addition, a number of brain regions in the current study showed no obvious plateau in the group average BOLD response at the highest temperatures, perhaps due to the limited range of painful temperatures available for use in the study (see Methods). In such cases, a polynomial could offer an equally good fit with fewer estimated parameters, though one would have to know that were the case for all individual subjects beforehand. Using a sigmoid function in this case allows a more flexible fit on the basis of fewer apriori assumptions at the expense of a single extra parameter to estimate. In sum, the function we describe here was not intended to give a comprehensive view of all the stages in pain processing, but rather was a way of testing a specific hypothesis in a focused manner. The general technique of using nonlinear fitting to response profiles could, however, be applied to test for other types of response depending on the theoretical question being asked.
One aspect of this study that was not explicitly addressed was the affective response of participants to the stimuli. Because participants were not aware of temperature they were about to experience on any given trial, it is possible that responses at lower temperatures included an element of relief and a reduction in anxiety when they realized the hottest stimulus was not being applied. Indeed, the neural processes by which ascending nociceptive signals are imbued with affective/hedonic salience is of vital importance to furthering our understanding of how the experience of pain varies across contexts, individuals, and the lifespan. The neural circuits that detect and assign affective salience to other sensory modalities such as vision (Ghashghaei et al., 2007
; Rolls, 2004
) reflect a hierarchy of processing, in which early, fairly rudimentary and inflexible processes are modulated by later, more elaborate and flexible processes. Though this study did not directly address the neural process by which nociceptive signals become affectively salient, it complements studies of how this salience is modified under various cognitive and affective conditions (Ploner et al., 2011
; Wiech et al., 2010
). Such information is vital to our understanding of both pain and affective disorders, as well as their frequent comorbidity.