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1Center for Functional Pain Neuroimaging and Therapy Research, Massachusetts General Hospital—Nuclear Magnetic Resonance Center, Department of Radiology, Charlestown, Massachusetts 02129-2060; and 2Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892
Submitted 2 April 2003; accepted in final form 16 August 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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). Recent work has demonstrated that the response to noxious stimuli has several components (Apkarian et al. 1999; Becerra et al. 1999, 2001; Kern et al. 1998).
After our initial report of more than one hemodynamic response to thermal pain (Becerra et al. 1999), we subsequently evaluated in another study the two main components (phases) and demonstrated a temporal segregation of responses in the CNS pathways involved in primary sensory processing (classic pain pathways) and emotional processing (reward/aversion pathways) (Becerra et al. 2001). Specifically, regions involved in emotion processing such as the sublenticular extended amygdala, the prefrontal cortex, and the ventral tegmentum, all activated during the first/early phase while regions such as the thalamus, primary sensory cortex, and insula involved in classic pain pathways were observed to activate during the second/late phase.
The present experiment was designed to further evaluate the multiphasic nature of the CNS response to noxious stimuli. For sensory/discriminative activation (classic pain pathways), represented by the late phase response, we predicted that the response should be segregated both spatially and temporally based on the location of the stimulation site (e.g., dorsum of the hand versus dorsum of the foot). Such a notion would seem obvious given the difference in distance between the two sites. Noxious heat activates C-fiber and A
-fiber nociceptors (Iggo and Ogawa 1971; Magerl et al. 1999; Naka and Kakigi 1998; Opsommer et al. 1999; Treede 1999; Yarnitsky et al. 1992). These fibers conduct at speeds of 1-10 m/s. The relative distance between the hand and the foot may result in a relative delay of the CNS response of the foot with respect to the hand.
Reward/aversion circuitry has been reported to be activated across a number of different experimental conditions including drugs (Becerra et al. 2001), taste (Blood and Zatorre 2001; O'Doherty et al. 2002; Small et al. 2001), facial expression (Aharon et al. 2001; Elliott et al. 2000), and pain conditions including acupuncture (Hui et al. 2000) and noxious heat (Becerra et al. 2001). It has been suggested that this circuitry is important in survival because it prepares the individual for specific actions. Because there is no somatotopic information in these substrates (no spatial segregation), we wished to determine if activation in reward/aversion circuitry is site-independent. The possible mechanism for this is unclear and may be dependent on activation of separate pathways from the spinothalamic tract (conveying predominantly C and A information) such as the spino-hypothalamic and -parabrachialamygdaloid tracts (Bernard and Besson 1990; Burstein et al. 1996) or via fast feedback loops from cortical regions. No significant differences in temporal response (even within the limits of the fMRI signal) would support the notion of another process including one that emotional processing may indeed precede sensory processing as previously been proposed (see Zajonc 1980).
Here, using fMRI of the effects of a 46°C applied to the dorsum of the left hand and foot, we report on early and late phase activations observed in sensory/discriminative and motivational/affective circuitry.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Nine right-handed male subjects were recruited into the study [27.0 ± 3.8 (SD) yr old]. The Human Subjects Committee on experimentation approved the study, and the study conformed to the Helsinki agreement on experimentation in human volunteers. Experiments were performed at the same time of day to control for circadian variation (Strian et al. 1989). Full consent was obtained from subjects prior to the study, and subjects were remunerated for their participation.
Imaging
Scanning was performed using a 1.5 Tesla scanner (General Electric, Milwaukee, WI). A conventional three-dimensional sagittal, T1-weighted, SPOILED/GRASS gradient echo sequence was acquired (in-plane resolution: 1.2 mm, slice thickness: 2.8 mm, 60 slices) for registration to the Talairach Atlas (Talairach and Tournoux 1988). Twenty contiguous slices (7-mm thick) were prescribed perpendicular to the anterior/posterior commisure line, extending from the anterior frontal lobe to part of the cerebellum. A T1-weighted echoplanar inversion recovery sequence (TI = 1,100 ms, in-plane resolution: 1.57 mm) was acquired for high-resolution structural images to be used in preliminary statistical maps. Functional scans consisted of an asymmetric spin echo, T2*-weighted sequence (TR/TE = 2,500/70 ms, flip angle: 90, in-plane resolution: 3.125 mm) performed on the same 20-slice prescription. One hundred volumes were acquired per functional scan resulting in a scan time of 4 min 10 s.
Paradigm
Two functional scans were performed on each subject. Each functional scan consisted of three thermal (46°C) stimuli for 29 s interspersed with 36 s at 35°C. The stimuli were applied to the dorsum of the left foot or the dorsum of the left hand. To avoid order effects, five subjects received the stimuli on the hand first followed by the foot, whereas the other four subjects received the stimuli to the foot first then the hand. Stimuli were produced using a Peltier thermode, 3 x 3 cm in size (Medoc, Haifa, Israel). After each scan, subjects rated their pain on a visual analogue scale (0 = no pain and 10 = max pain imaginable).
fMRI analysis
Functional data were motion corrected, globally normalized, and transformed into the Talairach space (Talairach and Tournoux 1988). Functional data were averaged across time. A 5-mm Gaussian filter was used to smooth the data and prewhitening was performed using FEAT (Image Analysis Group, FMRIB, Oxford, UK) (Woolrich 2000).
Temporal delays calculation
Several fMRI analysis tools based on a generalized linear model (GLM), such as FSL, add the first derivative of the hemodynamic response to correct for small delays of the actual brain response with respect to the model (Image Analysis Group, FMRIB, Oxford, UK). However, for longer delays, this approach fails. Fourier analysis allows the calculation of temporal delays of a function with respect to another regardless of the length of the delay. A description of this approach follows:
The definition of the Fourier transform F(
) of a function f(t) is
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The Fourier transform is a complex function (i.e., real and imaginary components)
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) is a real function of positive values and A() is a function in radians (angle). The relationship between Eqs. 2 and 3 can be seen in Fig. 1.
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) will be
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Which can be rewritten as
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Hence, the delay only affects the angle of the Fourier transform (Eq. 7), not its magnitude (Eq. 6), it imposes a linear component on it: -t0.
If the hemodynamic model for the response (HR) has an angle H() and a voxel showing significant activation has an angle A(), then the delay D can be estimated from
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It is important to note that the temporal delay D is a measure of the displacement of the response in time, it does not necessarily measure delay in onset of activation or delay in peak activation. In our case, the measurement of the delay refers to the delay the HR has to experience to match the time course of a voxel. Figure 2 depicts two hemodynamic responses, one delayed with respect to the other by 10 s and their corresponding magnitude of their Fourier transforms. For these two HRs, the magnitude of the Fourier transform are identical. Figure 3 displays their angle function and the difference. The slope corresponds to the delay and comes to 10 s.
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is the error, assumed to be normally distributed. The Fourier transform of Eq. 9 is
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The remaining question is if the noise characteristics are the same, FSL corrects for autocorrelation of the data assuring that the noise is normally distributed, the Fourier transform of a normal distribution is another normal distribution, therefore the noise in the Fourier transform remains normally distributed and allows for parametric statistics to be applied.
The activations maps determined from the magnitude data can in turn be used to determine delays based on areas of significant activation. Subtracting the angle function data of the foot from the hand results in a data set (the relative angle) containing information about the relative delay in brain responses. To calculate the delay, a linear fit of the relative angle data set yields a map of "slopes." Significantly activated areas are used as a mask for the slope map to identify delays across different structures. This approach gives voxel-by-voxel delay results. For primary somatosensory activation, however, this is not accurate because hand and foot are spatially represented at different locations; therefore to determine the delay, we need to extract the angle function corresponding to the hand and the foot from each data set to calculate the relative angle.
Functional data and the HR were Fourier transformed using Matlab (MathWorks, Natick, MA). The HR was obtained from convoluting a standard gamma function with a temporal function resembling the stimuli. To increase frequency resolution, data and HR were demeaned and zero-padded to 256 data points. Statistical analysis was carried out using FEAT, the FMRIB Easy Analysis Tool, and FILM with local autocorrelation correction (Woolrich et al. 2001). z statistic images were thresholded using clusters determined by z > 2.3 and a cluster significance threshold of P = 0.05 (Forman et al. 1995; Friston et al. 1992; Worsley et al. 1992). Figure 4 depicts the process followed in this report to obtain statistical and delay maps. Hand and foot statistical maps were compared with determine regions of interest (ROIs) of common activation. These ROIs were further used to extract the delays when comparing hand with foot.
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RESULTS |
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Table 1 summarizes activation detected in different structures after noxious thermal stimulation of the hand and the foot. Structures are arranged in Table 1 according to their function in pain processing (Iadarola et al. 1998). The table lists significance of activation (z score) for each structure as well as its Talairach coordinates. Consistent with our previous study (Becerra et al. 2001), the response to the noxious thermal stimulus was biphasic for the foot as well as the hand with regions associated with emotion circuitry responding in the early phase and regions of sensory pain processing responding in the late phase. The delays quoted in Table 1 were calculated for the hand and foot using Eq. 8 as described in METHODS. For all the structures except the primary somatosensory area (S1; see METHODS for an explanation), delays were calculated from common ROIs as determined from an overlap map of hand and foot activation. For structures involved in sensory/discriminative processing of pain, an average delay of 3.6 ± 1.3 s was observed. This delay is significant (P < 0.005). For structures associated with affective/emotional processing of pain, the average delay between responses to hand versus foot stimulation was not significant (0.6 ± 2.1 s; P > 0.05). As seen in our previous study, the only structure associated with emotional processing that did not respond in the early phase is the nucleus accumbens (NAc). The NAc had a delayed activation corresponding to the late phase; furthermore, it showed a negative signal change in response to the noxious stimulus. Neither temporal nor spatial differences between the hand and foot NAc activations were observed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In this paper, we present an application of using a Fourier transform analysis for defining temporal delays. The advantage of this method, in contrast to other GLM methods, is that delays of any time may be accurately determined. Although the temporal resolution is set by the TR (2.5 s), it still allows proper sampling of the hemodynamic response. With the Fourier analysis described here, the determination of delays shorter than the specific TR is possible. Thus the observation of no temporal separation in the motivation/reward structures is not due to the lack of temporal resolution.
Response latency in somatosensory/discriminative regions is dependent on stimulation site
We previously reported that regions known to be involved in primary sensory or discriminative aspects of pain respond in the second phase of the biphasic CNS response to noxious heat (Becerra et al. 2001). The current study shows a significant difference in activation latency in all discriminative areas, including the thalamus and the primary somatosensory cortex, dependent on whether stimulation is to the left hand or left foot. Interestingly, the ipsilateral insula did not demonstrate any significant changes, whereas the contralateral insula did exhibit a latency shift. In our previous study, some regions, including the ipsilateral insula, demonstrated both early and late phase activation (Becerra et al. 2001), indicating a multifunctional response to pain which may explain the observed differences. This region has been reported to be involved both in pain (Craig et al. 2000) and other nonpain nonsensory functions (Evans et al. 2002; Feinstein et al. 2002; Winston et al. 2002).
Although an earlier fMRI study observed cortical activation after noxious heat applied to the hand and foot of normal volunteers (Berman et al. 1998), the authors did not address temporal differences. The results of this study focused on differentiating specific regional activation within the primary cortex after stimulation of the foot and hand areas. Differences in the time course of CNS activation after painful hand and foot stimulation have also been observed in vertex potentials after laser stimulation (Spiegel et al. 1996). In that study, a significant difference in electroencephalographic latency was observed dependent on whether stimulation was to the hand or the foot. The present study extends these observations and supports the notion that differences in CNS activation based on the site of stimulation can be measured using fMRI. In contrast, a magnetoencephalographic (MEG) study looking at cortical activation after laser stimulation to the hand detected early activation predominantly in S1 (Ploner et al. 2002). S2 and the anterior cingulate cortex displayed predominantly late activation. These results seem to contradict ours; however, they reported differences in brain activation that correlate with the perceptual (conscious) feeling of first and second pain after a brief (1 ms) but intense stimulation. They did not address differences in whole brain responses to prolonged pain, which may reflect complex neural pathway activations occurring early and late after the stimuli. Many of these activations are presumably subconscious. Similar MEG results were found in another study (Ninomiya et al. 2001) in which the authors found temporal segregation of activation in cortical (S1 and S2) and limbic structures (ACC). Interestingly, Maihofner et al. (2002) found insular cortex activating earlier than some cortical areas such as S2 and no activation in S1.
We provide evidence that the temporal profile of brain activation after painful sensory inputs can differentiate between stimuli applied to two regions of the body separated by 
50-70 cm. As noted in the INTRODUCTION, these differences may be explained on the basis of distance and differences in conduction velocities in pain fiber subgroups (Iggo and Ogawa 1971; Kakigi et al. 1991; LaMotte and Campbell 1978; Opsommer et al. 1999; Schmelz et al. 2000; Treede 1999; Treede et al. 1995). This may be sufficient to account for the temporal dispersion and within the temporal resolution of the fMRI signal.
Response latency in affective/emotional regions is independent of stimulation site
After noxious stimulation of the hand, activation in motivational/emotional circuitry is observed (Becerra et al. 2001). The activation pattern in this circuitry occurs rapidly prior to activation within sensory circuitry. In the present study, no significant differences in response latencies were observed when the hemodynamic responses within affective/emotional circuitry after a noxious stimulus to the hand were compared with those after the same stimulus to the foot. The reason for this is unclear, and there may be a number of proposed mechanisms.
In one formulation of the CNS response to acute pain, differences in conduction velocities and CNS response are thought to be the basis for "first" and "second" pain (Campbell and LaMotte 1983; Lewis and Pochin 1937; Price et al. 1977; Thunberg 1902). In this formulation, the faster A fibers are involved in transmitting discriminative information, and the slower conducting C fibers are involved in affective aspects of pain processing. This explanation might, however, suffer from being an oversimplification of the mechanism. Both fiber types conduct "noxious sensations" that have an aversive component. It is unlikely that fiber subtype relates to specific affective and sensory activations.
Afferent pain inputs to these brain regions have been well described in animal electrophysiology and anatomical reports (Bernard and Besson 1990; Bester et al. 1997; Burstein et al. 1996; Gear et al. 1999; Schmidt et al. 2002; Shi and Davis 1999). Early activation within affective/emotional circuitry may be the result of peripheral inputs reaching motivational/affective structures from fast-conducting central fiber systems (Treede et al. 1998). Because the temporal segregation of activation observed after hand versus foot stimulation in the sensory pathway was not observed in the emotional/affective pathway, the results indicate that central processing must account for either no difference or a difference not measured by fMRI.
The activation patterns observed may represent a more complex interaction between cognitive and subconscious processing in reward/aversion and sensory/discriminative pathways. One formulation is that the delayed processing in sensory networks reflects a very fast activation pattern not measured by the fMRI signal and the delay observed relates to further cognitive CNS processing.
Another potential reason for the early activation being observed in subcortical regions includes the possibility of anticipatory behavior. A number of studies have implicated anticipation of pain in cortical regions (Ploghaus et al. 1999; Porro et al. 2002). However, none of these studies measured changes in subcortical regions such as the NAc. This also does not rule out the contribution of anxiety to the activation patterns observed (see Ploghaus et al. 2001).
It is useful to consider the widely held interpretation that the brain's response to threat, including pain, is anticipatory and evaluative (Melzack and Casey 1967). Patrick Wall and Ronald Melzack first noted this possibility in their classic paper on the gate theory of pain (Melzack and Wall 1965). An organism's survival is dependent on determining the salience of the threat or reward associated with a given stimulus. Activation in emotional circuitry may reflect this type of evaluation [i.e., feeling before knowing (Zajonc 1980)]. The same regions that have been consistently implicated in the organization of motivational responses to rewarding stimuli (Bozarth and Wise 1986; LeDoux 1998; Robbins and Everitt 1996; Schultz et al. 1997; Wise 1998) are implicated in the motivational responses to aversive stimuli (Fenu et al. 2001; Gallagher et al. 1988) including painful stimuli (Becerra et al. 2001). Such responses probably serve to increase the animal's level of arousal in anticipation of the perceived threat and are protective. Indeed, in support of this, none of these same regions are activated by a nonnoxious thermal stimulus (Becerra et al. 2001). Furthermore, one of the regions activated in both early and late phases of our previous study, the periaqueductal gray, is known to be important in endogenous modulation including inhibition of afferent pain signals (Heinricher et al. 1987). This is an example of an apparent protective mechanism possibly tied into a circuit that is permissive to allow action/escape response rather than simply pain control.
Conclusions
The data presented suggest that differences in stimulus location do not affect the latency of activation within motivational circuitry, whereas the latency of the sensory/discriminative response to acute pain is stimulus site-dependent. An understanding of the emotional/motivational response to pain has important consequences and seems independent of conscious awareness (for a review, see Becerra et al. 2001). Such differences may have implications for future pain experiences that may produce significant behavioral manifestations [e.g., pain associated with torture (Thomsen et al. 2000) or pain inflicted on the newborn (Ruda et al. 2000) or after child abuse (Goldberg et al. 1999) or physical and sexual abuse in adults (Green et al. 1999)]. Such experiences may not only contribute to increased pain levels but also to functional illnesses associated with pain such as depression (Wilson et al. 2001).
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work was funded by National Institutes of Health Grants 012581 and 12650, from the Kaneb, Goldfarb, and Slifka families and from the MayDay Foundation (D. Borsook), and 41290 (L. Becerra).
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. Borsook, Descartes Therapeutics, Inc., 790 Memorial Dr., Suite 104, Cambridge, MA 02139 (E-mail: dborsook{at}dtrx.com).
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
|---|
Apkarian AV, Darbar A, Krauss BR, Gelnar PA, and Szeverenyi NM. Differentiating cortical areas related to pain perception from stimulus identification: temporal analysis of fMRI activity. J Neurophysiol 81: 2956-3963, 1999.
Becerra LR, Breiter HC, Stojanovic M, Fishman S, Edwards A, Comite AR, Gonzalez RG, and Borsook D. Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study. Magn Reson Med 41: 1044-1057, 1999.[CrossRef][ISI][Medline]
Becerra L, Breiter HC, Wise R, Gonazlez RG, and Borsook D. Reward circuitry activation by noxious thermal stimuli. Neuron 32: 927-946, 2001.[CrossRef][ISI][Medline]
Berman HH, Kim KH, Talati A, and Hirsch J. Representation of nociceptive stimuli in primary sensory cortex. Neuroreport 9: 4179-4187, 1998.[ISI][Medline]
Bernard JF and Besson JM. The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J Neurophysiol 63: 473-490, 1990.
Bester H, Besson JM, and Bernard JF. Organization of efferent projections from the parabrachial area to the hypothalamus: a phaseolus vulgarisleucoagglutinin study in the rat. J Comp Neuro 383: 245-281, 1997.[CrossRef][ISI][Medline]
Blood AJ and Zattore RJ. Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci USA 98: 11818-11823, 2001.
Bozarth MA and Wise A. Involvement of the ventral tegmental dopamine system in opioid and psychomotor stimulant reinforcement. NIDA Res Monogr 67: 190-196, 1986.[Medline]
Burstein R, Falkowsky O, Borsook D, and Strassman A. Distinct lateral and medial projections of the spinohypothalamic tract of the rat. J Comp Neurol 373: 549-574, 1996.[CrossRef][ISI][Medline]
Campbell JN and LaMotte RH. Latency to detection of first pain. Brain Res 266: 203-208, 1983.[CrossRef][ISI][Medline]
Craig AD, Chen K, Bandy D, and Reiman EM. Thermosensory activation of insular cortex. Nat Neurosci 3: 184-190, 2000.[CrossRef][ISI][Medline]
Elliott R, Friston KJ, and Dolan RJ. Dissociable neural responses in human reward systems. J Neurosci 20: 6159-6165, 2000.
Evans KC, Banzett RB, Adams L, McKay L, Frackowiak RS, and Corfield DR. BOLD fMRI identifies limbic, paralimbic, and crebellar activation during air hunger. J Neurophysiol 88: 1500-1511, 2002.
Feinstein JS, Goldin PR, Stein MB, Brown GG, and Paulus MP. Habituation of attentional networks during emotion processing. Neuroreport 13: 1255-1258, 2002.[CrossRef][ISI][Medline]
Fenu S, Bassareo V, and Di Chiara G. A role for dopamine D1 receptors of the nucleus accumbens shell in conditioned taste aversion learning. J Neurosci 21: 6897-6904, 2001.
Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, and Noll DC. Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 33: 636-647, 1995.[ISI][Medline]
Fowler CJ, Sitzoglou K, Ali Z, and Halonen P. The conduction velocities of peripheral nerve fibers conveying sensations of warming and cooling. J Neurol Neurosurg Psychiatry 51: 1164-1170, 1988.[Abstract]
Friston KJ, Worsley KJ, Frakowiak RSJ, Mazziotta JC, and Evans AC. Assessing the significance of focal activations using their spatial extent. Hum Brain Map 1: 214-220, 1992.
Gallagher M, McMahan RW, and Schoenbaum G. Orbitofrontal cortex and representation of incentive value in associative learning. J Neurosci 19: 6610-6614, 1988.
Gear RW, Aley KO, and Levine JD. Pain-induced analgesia mediated by mesolimbic reward circuits. J Neurosci 19: 7175-7181, 1999.
Goldberg RT, Pachas WN, and Keith D. Relationship between traumatic events in childhood and chronic pain. Disabil Rehabil 21: 23-30, 1999.[CrossRef][ISI][Medline]
Green CR, Flowe-Valencia H, Rosenblum L, and Tait AR. Do physical and sexual abuse differentially affect chronic pain states in women? J Pain Symptom Manage 18: 420-426, 1999.[CrossRef][ISI][Medline]
Hagander LG, Midani HA, Kuskowski MA, and Parry GJ. Quantitative sensory testing: effect of site and skin temperature on thermal thresholds. Clin Neurophysiol 111: 17-22, 2000.[CrossRef][ISI][Medline]
Heinricher MM, Cheng ZF, and Fields HL. Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray. J Neurosci 7: 271-278, 1987.[Abstract]
Hui KK, Liu J, Makris N, Gollub RL, Chen AJ, Moore CI, Kennedy DN, Rosen BR, and Kwong KK. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects. Hum Brain Map 9: 13-25, 2000.[CrossRef][ISI][Medline]
Iadarola MJ, Berman KF, Zeffiro TA, Byas-Smith MG, Gracely RH, Max MB, and Bennett GJ. Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain 121: 931-947, 1998.
Iggo A and Ogawa H. Primate cutaneous thermal nociceptors. J Physiol 216: 77P-78P, 1971.[Medline]
Kakigi R, Endo C, Neshige R, Kuroda Y, and Shibasaki H. Estimation of conduction velocity of A delta fibers in humans. Muscle Nerve 14: 1193-1196, 1991.[CrossRef][ISI][Medline]
Kern MK, Birn RM, Jaradeh S, Jesmanowicz A, Cox RW, Hyde JS, and Shaker R. Identificaiton and characterization of cerebral cortical response to esophageal mucosal acid exposure and distention. Gastroenterology 115: 1353-1362, 1998.[CrossRef][ISI][Medline]
LaMotte RH and Campbell JN. Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain. J Neurophysiol 41: 509-528, 1978.
LeDoux J. The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York: Simon and Schuster, 1998.
Lewis T and Pochin EE. The double pain response of the human skin to a single stimulus. Clin Sci 3: 67-76, 1937.[ISI]
Magerl W, Ali Z, Ellrich J, Meyer RA, and Treede RD. C- and A delta-fiber components of heat-evoked cerebral potentials in healthy human subjects. Pain 82: 127-137, 1999.[CrossRef][ISI][Medline]
Maihofner C, Kaltenhauser M, Neundorfer B, and Lang E. Temporospatial analysis of cortical activation by phasic innocuous and noxious cold stimuli—a magnetoencephalographic study. Pain 100: 281-90, 2002.[CrossRef][ISI][Medline]
Melzack R and Casey KL. Localized temperature changes evoked in the brain by somatic stimulation. Exp Neurol 17: 276-292, 1967.[CrossRef][ISI][Medline]
Melzack R and Wall PD. Pain mechanisms: a new theory. Science 150: 971-979, 1965.
Naka D and Kakigi R. Simple and novel method for measuring conduction velocity of A delta fibers in humans. J Clin Neurophysiol 15: 150-153, 1998.[CrossRef][ISI][Medline]
Ninomiya Y, Kitamura Y, Yamamoto S, Okamoto M, Oka H, Yamada N, and Kuroda S. Analysis of pain-related somatosensory evoked magnetic fields using the MUSIC (multiple signal classification) algorithm for magnetoencephalography. Neuroreport 12: 1657-61, 2001.[CrossRef][ISI][Medline]
O'Doherty JP, Deichmann R, Critchley HD, and Dolan RJ. Neural responses during anticipation of a primary taste reward. Neuron 33: 815-826, 2002.[CrossRef][ISI][Medline]
Opsommer E, Masquelier E, and Plaghki L. Determination of nerve conduction velocity of C-fibers in humans from thermal thresholds to contact heat (thermode) and from evoked brain potentials to radiant heat (CO2 laser). Neurophysiol Clin 29: 411-422, 1999.[ISI][Medline]
Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JN, and Tracey I. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci 21: 9896-903, 2001.
Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, and Rawlins JN. Dissociating pain from its anticipation in the human brain. Science 284: 1979-1981, 1999.
Ploner M, Gross J, and Timmermann L. Schnitzler cortical representation of first and second pain sensation in humans. Proc Natl Acad Sci USA 99: 12444-12448, 2002.
Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P, Maieron M, and Nichelli P. Does anticipation of pain affect cortical nociceptive systems? J Neurosci 22: 3206-3214, 2002.
Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 288: 1769-1772, 2000.
Price DD, Hu JW, Dubner R, and Gracely RH. Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3: 57-68, 1977.[CrossRef][ISI][Medline]
Robbins TW and Everitt BJ. Neurobehavioural mechanisms of reward and motivation. Curr Opin Neurobiol 6: 228-236, 1996.[CrossRef][ISI][Medline]
Ruda MA, Ling QD, Hohmann AG, Peng YB, and Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 289: 628-631, 2000.
Schmelz M, Schmid R, Handwerker HO, and Torebjork HE. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibers. Brain 123: 560-571, 2000.
Schmidt BL, Tambeli CH, Barletta J, Luo L, Green P, Levine JD, and Gear RW. Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats. J Neurosci 22: 6773-6780, 2002.
Schultz W, Dayan P, and Montague PR. A neural substrate of prediction and reward. Science 275: 1593-1599, 1997.
Shi C and Davis M. Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J Neurosci 19: 420-430, 1999.
Small DM, Zatorre RJ, Dagher A, Evans AC, and Jones-Gotman M. Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain 124: 1720-1733, 2001.
Spiegel J, Hansen C, and Treede RD. Laser-evoked potentials after painful hand and foot stimulation in humans: evidence for generation of the middle-latency component in the secondary somatosensory cortex. Neurosci Lett 216: 179-182, 1996.[CrossRef][ISI][Medline]
Strian F, Lautenbacher S, Galfe G, and Holzl R. Diurnal variations in pain perception and thermal sensitivity. Pain 36: 125-131, 1989.[CrossRef][ISI][Medline]
Talairach J and Tournoux P. Co-Planar Stereotaxic Atlas of the Human Brain. New York: Thieme Medical Publishers, 1988.
Thomsen AB, Eriksen J, and Smidt-Nielsen K. Chronic pain in torture survivors. Forensic Sci Int 108: 155-163, 2000.[CrossRef][ISI][Medline]
Thunberg T. Untersuchungen uber die bei einer einzelnen momentanen Hautreizung auftretenden zwei stechenden Empfindungen. Skand Arch Physiol 12: 394-442, 1902.
Treede RD. Transduction and transmission properties of primary nociceptive afferents. Ross Fiziol Zh Im I M Sechenova 85: 205-211, 1999.[Medline]
Treede RD, Meyer RA, and Campbell JN. Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties. J Neurophysiol 80: 1082-1093, 1998.
Treede RD, Meyer RA, Raja SN, and Campbell JN. Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin. J Physiol 483: 747-758, 1995.[ISI][Medline]
Wilson KG, Mikail SF, D'Eon JL, and Minns JE. Alternative diagnostic criteria for major depressive disorder in patients with chronic pain. Pain 91: 227-234, 2001.[CrossRef][ISI][Medline]
Winston JS, Strange BA, O'Doherty J, and Dolan RJ. Automatic and intentional brain responses during evaluation of trustworthiness of faces. Nat Neurosci 5: 277-283, 2002.[CrossRef][ISI][Medline]
Wise RA. Drug-activation of brain reward pathways. Drug Alcohol Depend 51: 13-22, 1998.[CrossRef][ISI][Medline]
Woolrich MW, Ripley BD, Brady JM, and Smith SM. Temporal autocorrelation in univariate linear modelling of FMRI data. Neuro Image 14: 1370-1386, 2001.
Worsley KJ, Evans AC, Marrett S, and Neelin P. A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab 12: 900-198, 1992.[ISI][Medline]
Yarnitsky D, Simone DA, Dotson RM, Cline MA, and Ochoa JL. Single C nociceptor responses and psychophysical parameters of evoked pain: effect of rate of rise of heat stimuli in humans. J Physiol 450: 581-592, 1992.
Zajonc RB. Feeling and thinking. Am Psychol 35: 151-175, 1980.[CrossRef]
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has been added to help visualize temporal delays.
