Am J Physiol Regul Integr Comp Physiol 289: R319 –R325, 2005.
First published March 31, 2005; doi:10.1152/ajpregu.00123.2005.
CALL FOR PAPERS
Physiology and Pharmacology of Temperature Regulation
Anteroposterior somatotopy of innocuous cooling activation focus in human
dorsal posterior insular cortex
Le H. Hua,1 Irina A. Strigo,1 Leslie C. Baxter,2 Sterling C. Johnson,3 and A. D. (Bud) Craig1
1
Atkinson Research Laboratory and 2Neuropsychology Neuroimaging Laboratory, Barrow
Neurological Institute, Phoenix, Arizona; and 3University of Wisconsin Medical School,
William S. Middleton Memorial Veterans Affairs Hospital, Madison, Wisconsin
Submitted 17 February 2005; accepted in final form 29 March 2005
the somatosensory cortices but, rather, is located in the insula,
which is associated with autonomic control (14). This site is
the terminus of a spinothalamocortical pathway, phylogenetically distinct to primates and highly developed in humans, that
is an expansion of a homeostatic afferent system representing
the physiological condition of the body (16). These new
findings fundamentally revise our understanding of the neural
representation of feelings from the body (16).
To verify and extend these findings, we used functional
magnetic resonance imaging (fMRI) to examine thermosensory
activation sites in the dorsal posterior insula (dpIns). Our
central hypothesis is that if the thermosensory representation in
the dpIns participates in the haptic function of localization as
well as discrimination, then it should be somatotopically organized. In this initial study, we used cooling stimulation at two
body sites. On the basis of the tract-tracing data in the monkey
(11), we anticipated finding a somatotopic gradient organized
in the anteroposterior direction.
MATERIALS AND METHODS
(i.e., sensations of cool, warm,
cold, and hot) are important for tactile recognition of objects
and for homeostatic control of body temperature, functions that
are traditionally differentiated as exteroceptive and interoceptive, respectively (28). The exteroceptive aspect of (innocuous
and noxious) thermal sensibility has been regarded as a capacity of the somatosensory system, allied with the sense of touch.
Specifically, it has been thought that the haptic abilities to
discriminate different temperatures and to localize thermal
stimuli on the body must involve the somatotopically wellorganized system that represents discriminative cutaneous
mechanoreception (23, 43). This has been an explicit presumption at least since Weber’s analysis of somatic sensation in
1846 (47).
However, recent findings indicate that the cortical substrate
for discriminative innocuous thermal sensation is not part of
The data were obtained from 15 healthy, right-handed subjects (6
men and 9 women) between 19 and 41 (mean 27.3) yr of age. All
subjects signed consent forms approved by the Barrow Neurological
Institute’s institutional review board. Before imaging, each subject
was screened for the ability to discriminate different innocuous cool
temperatures (28, 25, and 22°C).
Imaging procedures. For fMRI data acquisition, subjects lay supine
in the 3.0-T magnetic resonance scanner (Signa, General Electric)
with eyes closed, ears plugged, and head held firmly in place by foam
pads and tape straps. A fiducial was applied to the left forehead.
Blankets and scarves were used to minimize thermosensory contamination by the ventilation inside the scanner. During the fMRI session,
each subject received stimulation from a large Peltier-type thermode
(30 ⫻ 30 mm; model TSA-II, Medoc, Ramat-Yishai, Israel) situated
on the right thenar hand and with a different thermode (16 ⫻ 16 mm)
situated on the right lateral neck. Both thermodes were fixed in place
with tape.
A single functional scan was collected using hand stimulation,
followed by one using neck stimulation. The stimulus sequence
during each functional scan consisted of six presentations of an
innocuous cooling stimulus that ramped linearly from 33 to
23.25°C at 0.25°C/s (39-s duration, or 13 functional image volumes at TR ⫽ 3 s) and then a return to the baseline temperature of
33°C (⬃1°C/s, 18-s total duration), interleaved with 30-s periods at
Address for reprint requests and other correspondence: A. D. Craig, Atkinson Research Laboratory, Barrow Neurological Institute, 350 West Thomas
Rd., Phoenix, AZ 85013 (E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
temperature; homeostasis; interoception; thermoregulation; functional
imaging
THERMAL SENSATIONS IN HUMANS
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Hua, Le H., Irina A. Strigo, Leslie C. Baxter, Sterling C. Johnson,
and A. D. (Bud) Craig. Anteroposterior somatotopy of innocuous
cooling activation focus in human dorsal posterior insular cortex. Am J
Physiol Regul Integr Comp Physiol 289: R319 –R325, 2005. First published March 31, 2005; doi:10.1152/ajpregu.00123.2005.—Prior data
indicate that graded activation by innocuous thermal stimuli occurs in the
dorsal posterior insular (dpIns) cortex of humans, rather than the parietal
somatosensory regions traditionally thought necessary for discriminative
somatic sensations. We hypothesized that if the dpIns subserves the
haptic capacity of localization in addition to discrimination, then it should
be somatotopically organized. Using functional magnetic resonance imaging to detect activation in the dpIns by graded cooling stimuli applied
to the hand and neck, we found unimodal foci arranged in an anteroposterior somatotopographic pattern, consistent with participation of the
dpIns in localization as well as discrimination. This gradient is orthogonal
to the mediolateral somatotopy of parietal somatosensory regions, which
supports the fundamental conceptual differentiation of the interoceptive
somatic representation in the dpIns from the parietal exteroceptive representations. These data also support the suggestion that the poststroke
central pain syndrome associated with lesions of the dpIns is a thermoregulatory dysfunction. Finally, another focus of strongly graded activation, which we interpret to represent thermoregulatory behavioral motivation elicited by dynamic cooling, was observed in the dorsal medial
cortex.
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DPINS
Fig. 1. Time course of cooling stimulus. Six stimuli were
presented in each functional scan.
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RESULTS
Figure 3 presents the global activation map from the group
regressor analysis for hand stimulation, displayed at a threshold of P ⬍ 0.001 (t ⫽ 3.79, cluster size ⱖ10). All peaks are
described in Table 1. The glass brain clearly shows two strong
activation sites: the dpIns (highlighted in the three-dimensional
display in Fig. 3, bottom left; t ⫽ 6.51, P ⬍ 0.0001; centered
at MNI ⫺38, ⫺24, 14) and the dorsal medial cortex (highlighted in the three-dimensional display in Fig. 3, bottom right;
t ⫽ 8.58, P ⬍ 0.0001; centered at MNI ⫺8, 18, 58). Smaller,
weaker activation clusters were also noted in the right dorsolateral prefrontal cortex and the right anterior insula.
By contrast, the boxcar analysis (not shown) revealed
strong activation mainly in the posterior parietal cortex
Fig. 2. Top: user-specified linear regressor. Bottom: linear regressor convolved
with the standard hemodynamic response function (blue) compared with the
time course of the aggregate blood oxygenation level-dependent signal in the
dorsal posterior insula (dpIns) region of interest (ROI; green) during stimulation of the hand.
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baseline (Fig. 1). A single functional scan using foot brush (block
paradigm, 15 s on-15 s off) was collected between the two cooling
scans to provide an interval between cooling scans and as an
internal control. To ensure that the subjects were attentive to the
thermal stimuli, they were verbally alerted 5–10 s before the onset
of each cooling stimulus, and they were asked to rate the intensity
of each stimulus on a standard scale of 0 –10. The ratings were
collected at the end of each functional run. In two subjects, the
thermode on the neck did not maintain the correct position, and the
cooling stimuli were not perceived; those two subjects were
excluded from the analysis of neck stimulation.
Functional magnetic resonance scans using blood oxygenation
level-dependent (BOLD) contrast were obtained with a T2*-weighted
single-shot gradient echo echo-planar pulse sequence (TR ⫽ 3 s,
TE ⫽ 30 ms, flip angle ⫽ 90°, 64 ⫻ 64 matrix, field of view ⫽ 240
mm, native voxel size ⫽ 3.75 ⫻ 3.75 mm in plane). Thirty-two
contiguous 4-mm-thick slices were acquired in the axial plane, parallel to the anterior-posterior commissure line, covering the whole
brain volume. This produced 78 (i.e., 13 ⫻ 6) BOLD image volumes
during cooling of each body site for each subject. A T1-weighted
anatomic (structural) scan with 92 axial slices covering the whole
head was obtained at the end of the scanning session.
Analysis methods. The functional images were analyzed using
SPM2 (25, 26). The first two frames were discarded to allow for field
stabilization. Each series of functional images was corrected for
motion and realigned to the first volume in each scan sequence. The
series was then spatially coregistered to the echo-planar image (EPI)
template in SPM2 in standard Montreal Neurological Institute (MNI)
space (24), resampled at 2 ⫻ 2 ⫻ 2 mm, and smoothed with an
8-mm full-width half-maximum isotropic Gaussian kernel. Signal
intensity was globally normalized across each series, high-pass
filtered at 128 s, and corrected for serial correlations using the
autoregressive model (1).
Statistical analyses were carried out using the general linear model
(25). The time series of each voxel was fitted to the stimulus temperature function using 1) a boxcar and 2) a user-specified regressor,
convolved with the standard hemodynamic response function (hrf)
provided by SPM2. The ON period used in the boxcar analysis was
identical to the period of the cooling ramp (excluding the rewarming
period), and the OFF period was the asymmetric baseline period. The
user-specified regressor was a linearly increasing ramp designed to
model the temperature gradation of the cooling ramp on the basis of
the hypothesis that this causes a linearly increasing BOLD signal (Fig.
2, top). The results of the regression analysis from the individual
subjects were subsequently combined in a second-order randomeffects model (1-sample t-test) for group analysis.
To compare directly the somatotopography of loci activated by
stimulation of the two different body sites, i.e., hand and neck, we
performed directed region-of-interest (ROI) analyses. On the basis of
previous imaging results (14), the ROI was defined, using the MarsBar toolbox for SPM2 (4), as a sphere centered in the dpIns (at MNI
⫺38, ⫺24, 14) with a 15.0-mm radius. The results from the ROI
analyses for each body locus were superimposed on a single subject
anatomic volume to create a somatotopographic image.
Peaks with P ⬍ 0.05 and a minimum cluster size of 2 voxels for
ROI small-volume analyses were regarded as significant. Exploratory
whole brain analyses used a significance threshold of P ⬍ 0.001
(uncorrected) and a minimum cluster size of 10 voxels. All significant
peaks are reported.
TOPOGRAPHY OF FMRI COOLING ACTIVATION IN
DPINS
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bilaterally (which has been associated with spatial attention)
(14) and the cerebellum. Activation in the dpIns and dorsal
medial cortex was below statistical threshold. Because a
boxcar model does not fully account for dynamic change
within epochs of cooling, the contrast between this result
and the result from the regressor analysis underscores the
Table 1. Activation loci correlated with dynamic
hand cooling regressor
Brain Region
L dorsal medial
L posterior insula
R dorsolateral prefrontal
(BA46)
R anterior insula
R orbitofrontal (BA10)
L temporal lobe (BA22)
L anterior insula
R middle insula
R inferior parietal
(BA40)
R caudate
Talaraich
Coordinate
t-Statistic
Cluster
Size
⫺8, 20, 52
⫺8, 18, 58
⫺38, ⫺22, 14 ⫺38, ⫺24, 14
8.28
6.51
235
137
55, 32, 21
56, 32, 24
38, 17, ⫺8
38, 18, ⫺8
44, 51, 5
44, 52, 8
⫺63, ⫺9, 6
⫺64, ⫺10, 6
⫺42, 13, ⫺14 ⫺42, 14, ⫺14
44, ⫺6, ⫺5
44, ⫺6, ⫺6
4.45
4.35
4.52
5.19
4.76
4.60
94
93
59
32
27
22
4.34
4.31
12
10
63, ⫺22, 23
10, 8, 3
MNI Coordinate
64, ⫺24, 24
10, 8, 4
L, left; R, right, MNI, Montreal Neurological Institute.
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direct, linear relation between decreasing cool temperature
and increasing BOLD activation in the dpIns and dorsal
medial cortex revealed by the regressor analysis.
The time course of the aggregate BOLD signal in the dpIns
ROI (defined below) is shown in Fig. 2, bottom, plotted over
the convolution product of the linear regressor and the hrf
model; these are clearly parallel. In other words, the BOLD
signal in the dpIns activation focus showed linearly increasing
activation that directly corresponded to the linearly decreasing
(cool) stimulus temperature.
Figure 4 presents the global result of the group regressor
analysis for neck stimulation in 13 subjects (2 were excluded). Neck stimulation resulted in graded activation of
the dpIns (t ⫽ 2.44, P ⬃ 0.015, centered at MNI ⫺38, ⫺16,
14). The neck activation data show considerable noise,
presumably due to movement-related artifact. The contrast
between these data and the hand cooling data emphasizes
the benefits obtained with use of a larger thermode and a
larger sample size in the hand data. (We do not suspect that
the reduced activation in the dpIns was due to the fixed order
of presentation, because in preliminary trials, serially repeated scans with hand stimulation at comparable intertrial
intervals produced similar results.) Notably, graded activation was not observed in the sensorimotor cortices in the
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Fig. 3. Statistical parametric mapping (SPM) plots showing activation foci in the dpIns and dorsal medial cortex by graded hand cooling.
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DPINS
Fig. 4. Left: SPM plots showing activation in the
dpIns and other sites by graded neck cooling.
Right: ROI plotted on a standard anatomic
volume.
cooling data within the dpIns ROI survives the significance
cutoff of P ⬍ 0.05 used for small-volume corrections.
By masking the neck and the hand cooling statistical parametric mapping data with the same dpIns ROI and simultaneously superimposing the results on a standard single subject
anatomic volume, the composite image shown in Fig. 5 was
obtained. The neck cooling focus is shown in green and the
Fig. 5. Somatotopographical organization of
hand (red) and neck (green) activation foci in
the dpIns superimposed on a standard anatomic volume.
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Rolandic area (S1/M1) or parietal operculum (S2/PV) in the
global analyses using hand or neck stimulation.
The neck cooling data can be didactically masked with an
ROI over the dpIns, because a directed search in the dpIns is
justified by the evidence from the previous PET imaging study
(14). The ROI mask used a 15-mm-radius sphere centered at
MNI ⫺38, ⫺24, 14 (Fig. 4, right). The activation in the neck
TOPOGRAPHY OF FMRI COOLING ACTIVATION IN
hand cooling focus in red. Clearly, these are arranged in a
contiguous anteroposterior relation, with the neck focus centered ⬃8 mm anterior to the center of the hand focus. The
spatial relation of the hand and neck cooling sites revealed by
these data is valid and reliable, because the data were obtained
in the same subjects in single scanning sessions. Foci separated
by at least the width of the Hanning window can be regarded
as statistically distinct (35). In addition, a paired t-test comparison of the hand and neck data showed that the activation in
the more posterior dpIns focus was significantly higher during
hand than during neck stimulation (t ⫽ 4.89, P ⬍ 0.001, n ⫽ 13).
DISCUSSION
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psychophysical measurements of human thermosensory capacities. These lamina I neurons are distinct morphologically as
well as functionally and biochemically, so they can be viewed
as a virtual “labeled line” for thermal sensation (17).
The thermoreceptive-specific lamina I STT neurons project
by way of the lateral STT, and lesions of this pathway in cats
and humans selectively eliminate contralateral thermal sensation (17, 33, 37). In monkeys, anatomic and physiological
findings indicate that thermoreceptive-specific lamina I neurons project to the posterior part of the ventral medial (VMpo)
nucleus in the posterolateral thalamus with an anteroposterior
(head-to-foot) topography (13, 17, 22). Recordings of thermoreceptive-specific VMpo units in monkeys confirm these observations (10, 13). Furthermore, similar units have been recorded in the region of the human VMpo (also called the
“posterior-inferior region of the ventral caudal nucleus), and
graded microstimulation at such recording sites produced
graded, well-localized specific thermal sensations in awake
humans (19, 34, 38). Notably, thermoreceptive-specific neurons have not been identified in any other portion of monkey or
human thalamus.
Anterograde tracing data in the monkey indicate that the
VMpo nucleus projects to the dpIns cortex with an anteroposterior topography (11). The available lesion, stimulation, and
functional imaging data in humans are consistent with this
cortical projection. Thus only lesions of this region reduce or
eliminate contralateral thermal sensation in humans (2, 27, 45).
Electrical stimulation of the dpIns in awake humans can result
in specific thermal sensations (39). A laser-evoked potential
study provided evidence that selective warming specifically
activates the dpIns (29), and recent fMRI studies provided
supplemental data supporting activation of the insular cortex
by cooling and “paradoxical heat” (3, 18, 20). Notably, imaging evidence also indicates strong activation of the human
dpIns by noxious cold (8, 12, 36).
Direct evidence indicating that discriminative thermal sensation is represented in the dpIns was first provided by our
earlier PET imaging study in humans (14), in which a graded
series of tonic cool stimuli was presented on the right hand and
a global regression analysis across these temperatures was
performed. The dpIns was the only site in the contralateral
cortex in which graded activation that correlated directly with
the stimulus temperature was observed. The present data confirm that activity in the dpIns is directly correlated with cooling
stimuli, and when combined with the preceding functional,
anatomic, and clinical evidence on the ascending thermosensory pathway, this finding strongly supports the unique ability
of the dpIns to participate in discriminative cooling sensation.
The recognition that the discriminative thermosensory cortex
lies in the dpIns is striking because of the association of the
insular cortex with autonomic control, rather than somatosensation. Yet, this finding is consistent with the emerging view
that ascending lamina I projections serve as a general homeostatic afferent pathway conveying activity that represents numerous aspects of the physiological condition of the body (16).
This finding is consistent also with accumulating functional
imaging data indicating that the dorsal insular cortex is activated by several interoceptive modalities, including exercise,
cardiorespiratory activation, itch, sensual touch, hunger, thirst,
taste, and “air hunger” (16), as well as muscle pain (32), heat
pain (5), and cold pain.
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The present data provide significant support for our hypothesis that the innocuous thermosensory representation in the
dpIns is somatotopographically organized with an anteroposterior gradient. These data indicate that this cortical thermosensory representation can subserve localization as well as discrimination.
The haptic capacities of discrimination and localization that
are such perceptually obvious aspects of human thermal sensation have traditionally been regarded as its primary characteristics; therefore, thermal sensation has been categorized
conceptually with the discriminative sense of cutaneous touch
and has been thought to involve the somatosensory cortices. By
contrast, the homeostatic functions of thermal sensibility have
traditionally been relegated to “lower” portions of the central
nervous system, e.g., the hypothalamus and brain stem. However, the primal role of temperature sensation throughout
evolution (to enable adaptive responses to the effects of temperature on metabolism) is an essential capacity for all animals.
Amoebas, worms, fish, and reptiles thermoregulate. In mammals, the maintenance of core temperature is absolutely critical
for homeostasis and survival. The deep significance of this
evolutionary perspective is substantiated by the finding that the
neural representation of discriminative thermal sensation in the
human cortex is located in the insula, the limbic sensory
cortical region classically associated with autonomic control
and homeostasis, rather than in the parietal somatosensory
cortical regions (14, 29). The present data underscore the
fundamental distinction that thermal sensation is represented in
the central nervous system as one aspect of the physiological
condition of the body.
Central representation of discriminative thermal sensation.
Whereas considerable evidence on the precise coding properties of specific cutaneous thermoreceptors was gathered in the
1960s and 1970s (28), investigators who sought thermosensory
neurons in portions of the lemniscal somatosensory system
found only neurons with convergent properties (so-called “T ⫹
M” cells) that showed discharges with a nonlinear relation to
temperature that originated from slowly adapting mechanoreceptors (6, 7, 42). Specific thermoreceptive neurons in the
central nervous system were first discovered by Christensen
and Perl (9) in lamina I of the spinal dorsal horn. Thermoreceptive lamina I trigeminothalamic and spinothalamic tract
(STT) neurons that are specifically responsive to cooling or
warming have subsequently been well characterized in cats and
monkeys (1, 13, 15, 22). These neurons appear to constitute the
only ascending pathway for discriminative thermosensory activity. Their linear responses to temperature directly parallel
DPINS
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used dynamic cooling stimuli, there was very strong correlative
activation in the dorsal medial cortex. Our interpretation that
this activity represents the homeostatic motivation associated
with thermoregulatory behavior is supported by the observation that thermoregulatory behavior is not blocked by lesions of
the hypothalamus (44), whereas motivation by painful stimuli
(i.e., aversive conditioning) is blocked by lesions of the anterior cingulate (30). The identification of thermosensory activation in this region of the dorsal medial cortex [which many
reviewers nevertheless view as associated with “cognitive,”
rather than “emotional,” behavior (40)] is a second major result
of this study. Direct examinations of thermoregulatory processing by other physiologists have not yet identified this region,
but further work is clearly needed (31).
Role of the dpIns in central pain. Finally, these studies also
impact our understanding of the effects of lesions of the dpIns,
which have been directly associated with the central pain
syndrome (45). Our earlier PET identification of the dpIns as
the site of the discriminative thermosensory cortex was interpreted as support for the hypothesis that thermosensory dysfunction might be the cause of the ongoing burning pain in this
syndrome by disinhibition. That is, thermosensory dysfunction
would impair the normal inhibition of pain by cooling, resulting in pain by the release of ongoing inhibition. This hypothesis thus suggests that central pain is actually a thermoregulatory dysfunction (14). It incorporates anatomic findings indicating that the dpIns has a major role in the control of
homeostatic integration, including direct projections to critical
sites in the brain stem. A cardinal (and nearly universal) feature
of this syndrome is that such burning pain occurs in the region
of the body where the thermosensory dysfunction is most
profound (3, 16). In order for this cross-modal topographic
correspondence to occur, the thermosensory representation in
the dpIns (and its forebrain and descending connections) must
be somatotopically organized. The present study provides direct evidence supporting this organization.
ACKNOWLEDGMENTS
We thank M. Auldridge, L. Brady, A. Godinez, K. Krout, and P. Puppe for
technical assistance.
A preliminary report of this work was presented at the 2004 Meeting of the
Society for Neuroscience.
GRANTS
This work was supported by National Institute of Neurological Disorders
and Stroke Grant NS-40413 and the Barrow Neurological Foundation.
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However, this finding contrasts with the traditional view that
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