![Prolonged periods of cold result in (a) positive BOLD responses in the orbitofrontal cortex but (b) negative BOLD responses in the parietal cortex (arrows). These effects can be distinguished from fMRI correlates of cooling and warming (Figs. 2, 3, 4, and 6). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]](https://www.researchgate.net/profile/Otto-Muzik-2/publication/323106660/figure/fig5/AS:599585214967811@1519963663648/Prolonged-periods-of-cold-result-in-a-positive-BOLD-responses-in-the-orbitofrontal_Q320.jpg)
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In Vivo Correlates of Thermoregulatory Defense
in Humans: Temporal Course of Sub-Cortical and
Cortical Responses Assessed With fMRI
Otto Muzik
1,2
*and Vaibhav A. Diwadkar
3
1
Department of Pediatrics, Wayne State University School of Medicine, Detroit,
Michigan 48201
2
Department of Radiology, Wayne State University School of Medicine, Detroit,
Michigan 48201
3
Department of Psychiatry and Behavioral Neurosciences, Wayne State University
School of Medicine, Detroit, Michigan 48201
r r
Abstract: Extensive studies in rodents have established the role of neural pathways that are activated
during thermoregulation. However, few studies have been conducted in humans to assess the com-
plex, hierarchically organized thermoregulatory network in the CNS that maintains thermal homeosta-
sis, especially as it pertains to cold exposure. To study the human thermoregulatory network during
whole body cold exposure, we have used functional MRI to characterize changes in the BOLD signal
within the constituents of the thermoregulatory network in 20 young adult controls during non-
noxious cooling and rewarming of the skin by a water-perfused body suit. Our results indicate signifi-
cant decreases of BOLD signal during innocuous whole body cooling stimuli in the midbrain, the right
anterior insula, the right anterior cingulate, and the right inferior parietal lobe. Whereas brain activa-
tion in these areas decreased during cold exposure, brain activation increased significantly in the bilat-
eral orbitofrontal cortex during this period. The BOLD signal time series derived from significant
activation sites in the orbitofrontal cortex showed opposed phase to those observed in the other brain
regions, suggesting complementary processing mechanisms during mild hypothermia. The significance
of our findings lies in the recognition that whole body cooling evokes a response in a hierarchically
organized thermoregulatory network that distinguishes between cold and warm stimuli. This network
seems to generate a highly resolved interoceptive representation of the body’s condition that provides
input to the orbitofrontal cortex, where higher-order integration takes place and invests internal states
with emotional significance that motivate behavior. Hum Brain Mapp 37:3188–3202, 2016.V
C2016 Wiley
Periodicals, Inc.
Key words: thermoregulation; cold stress; midbrain; insula; orbitofrontal cortex; fMRI
r r
Additional Supporting Information may be found in the online
version of this article.
Contract grant sponsors: NIDDK R01DK102455, WSU MRGI Pro-
gram 2013, a Jack Ryan Award for Collaborative Research Excel-
lence from the WSU School of Medicine, the Lyckaki Young Fund
from the State of Michigan, the Children’s Hospital of Michigan
Foundation, and the Cohen Neuroscience Endowment
*Correspondence to: Otto Muzik, PhD, PET Center, Children’s
Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201.
E-mail: otto@pet.wayne.edu
Received for publication 21 September 2015; Revised 18 April
2016; Accepted 18 April 2016.
DOI: 10.1002/hbm.23233
Published online 24 May 2016 in Wiley Online Library (wileyonli-
nelibrary.com).
rHuman Brain Mapping 37:3188–3202 (2016) r
V
C2016 Wiley Periodicals, Inc.
INTRODUCTION
Thermoregulation is an essential autonomic response
preserved across all genera [Terrien et al., 2011], but par-
ticularly in mammalian species who have extensive and
dynamic homeothermic requirements. Detailed work in
mammalian (and particularly rodent) models suggests that
the hierarchically organized spinobrachiopreoptic pathway
is essential in sub-serving thermoregulatory autonomic
defenses [Cerri et al., 2013; Morrison, 2011], which exist in
parallel with the spinothalamocortical somatosensory path-
way that mediates temperature perception [Nakamura and
Morrison, 2008]. With respect to autonomic sympathetic
thermoregulation, lateral parabrachial neurons in the mid-
brain region receive afferents from spinal neurons, in turn
transmitting thermosensory signals to control regions of
the hypothalamus including the preoptic area [Morrison
et al., 2008; Nakamura and Morrison, 2008] mediating both
heat- and cold-related thermoregulatory defenses [Naka-
mura and Morrison, 2011].
Because thermoregulatory requirements are closely
shaped by evolutionary pressures (that differ across spe-
cies) [Angilletta, 2009], extension of animal studies to
humans is essential. Limited in vivo neuroimaging studies
exist, but the few conducted suggest that some of the
same autonomous reflex arcs form a central facet of the
human brain’s thermoregulatory system. For example,
during endogenous heat challenges, such as in menopau-
sal hot flashes [Diwadkar et al., 2014], brain stem
responses are closely associated with the onset of hot
flashes. In comparison, responses in regions such as the
prefrontal cortex, cingulate cortex and insula trail increases
in body temperature. These latter interoceptive responses
appear to reflect neural responses to changes in physiolog-
ical states [Craig, 2002]. As such, interoceptive responses
are general, resulting not only from endogenous thermal
events such as hot flashes but also during the application
of exogenously applied temperature sensation, including
heat [Davis et al., 1998; Kubina et al., 2010; Kwan et al.,
2000] and cold [Kwan et al., 2000; McAllen et al., 2006].
Processes associated with whole body skin cooling engage
thermoregulatory defense mechanisms, associated with
both responses to cooling and responses to (relatively) pro-
longed exposure to cold; however, these have rarely been
studied with fMRI. fMRI is an invaluable method for esti-
mating task-induced hemodynamic changes in a priori
identified brain regions [Logothetis, 2008]. Recent sugges-
tions have advocated the value of fMRI in elucidating
responses within (or connectivity between) theoretically
constrained networks of brain regions: the choice of these
regions are motivated by aspects of task- or paradigm-
relevant processing [Diwadkar, 2015; Friston, 2011; Ste-
phan and Roebroeck, 2012] and follows the principle of
relative specialization of brain function [Friston, 2005], an
organizing tenet of the brain. Thus, just as behavioral/cog-
nitive domains are characterized by specific distributed
architectures [Mesulam, 1998; Park and Friston, 2013],
thermoregulatory mechanisms within the mammalian cen-
tral nervous system (CNS) are characterized by distributed
architectures. Small diameter primary afferents from the
periphery converge first on homeostatic nuclei within the
brainstem that mediate CNS responses to these peripheral
inputs [Satinoff, 1978]. The afferents from the periphery
induce autonomous thermoregulatory responses in medul-
lary nuclei that are relayed to autonomic control centers in
the preoptic area of the hypothalamus [Terrien et al.,
2011], but in the case of human thermoregulation, these
signals are also forwarded to multiple cortical areas,
including the insular cortex, the anterior cingulate, the
posterior parietal somatosensory cortex and the orbitofron-
tal cortex, where they give rise to subjective feelings. Mul-
tiple lines of evidence across mammalian studies imply
that these subcortical and cortical regions constitute a
value-generating network of regions that collectively rep-
resent sub-processes associated with thermoregulatory
defenses that subsequently guides behavior. These subpro-
cess include autonomous homeostatic responses (midbrain,
hypothalamus, and insula) [Satinoff, 1978], top–down
modulation of thermoregulatory control (parietal lobe)
[Gallace et al., 2014], interoceptive assessment of internal
physiological states (insula and anterior cingulate cortex)
[Craig, 2002; Diwadkar et al., 2014] and affective codes
associated with the pleasantness or the unpleasantness of
those states (orbitofrontal cortex) [Rolls, 2010]. This
hypothesized network was entered as the a priori focus of
effect discovery in this inquiry.
To elucidate responses in these network constituents, we
concurrently acquired body temperature and fMRI signals
while normal healthy volunteers were exposed to a care-
fully manipulated oscillating whole body temperature chal-
lenge. The challenge was designed to induce periods of
mild hypothermia interspersed by periods of return to basal
core body temperature. A notable feature of our analyses
was the focus on multiple temporal windows within the
paradigm: (1) First, we identified fMRI correlates associated
with skin temperature gradients, both cooling (i.e., as tem-
perature decreased) and warming (i.e., as temperature
returned toward basal levels), and (2) Second, we also
explored fMRI correlates associated with (relatively) pro-
longed exposure to cold, relative to prolonged states of
basal temperature. These analyses within the same study
explored potentially separable or overlapping CNS corre-
lates of cooling (or warming) and cold (or warmth).
Hypothermia is the condition that results when the
body’s core body temperature falls below a value that can
be metabolically sustained. Mild hypothermia engages
sympathetic physiologic responses, with the aim of effi-
ciently preserving body heat; these include shivering,
tachychardia, vasoconstricton as well as potential activa-
tion of brown adipose tissue via sympathetic innervation
[Gonzalez-Alonso, 2012]. Without intervention, mild hypo-
thermia transitions to a severe stage resulting in failure of
critical physiologic systems. Despite the putative complexity
rResponse of the Human Thermoregulatory Network to Cold r
r3189 r
of CNS mechanisms in thermoregulatory defenses to mild
hypothermia and the accepted clinical benefits of the latter
in preserving brain function following trauma, the neural
correlates of mild hypothermia in humans remain obscure.
Therefore, our results provide evidence that the process of
inducing controlled mild-hypothermia (using a whole-body
temperature challenge) induces a complex and heterogene-
ous pattern of both positive and negative fMRI-estimated
neuronal responses. We show that these neuronal responses
exhibit systematic linear relationships to contemporaneously
monitored skin temperature (itself related to core body tem-
perature [Xu et al., 2013]). Moreover, we also show that
changes in temperature, but not prolonged stable periods of
cold and warm temperature, are more predictive of CNS
responses. This evidence implies that CNS responses are
most sensitive to dynamic thermoregulatory defense, rather
than adaptation to a new and transient temperature follow-
ing thermoregulatory challenge. This contemporaneous
application of experimentally induced skin temperature
challenges provides an effective framework for investigat-
ing differential neural correlates of mild hypothermia
within a network of regions that includes the anterior
insula, midbrain and the orbitofrontal cortex.
MATERIALS AND METHODS
Subjects
MRI studies were performed in 20 young adults (10M/
10F, mean age 25.1 63.4 years, age range 20–31 years) with
a BMI in the normal range (22.712.1 kg/m
2
) and a body
fat percentage of 24.0 64.3%. Participants were not taking
any medication, and had no history of neurological or psy-
chiatric disorder. All subjects had a normal structural MRI
scan. The Human Investigation Committee of Wayne State
University authorized the study and informed written con-
sent was obtained from all participants.
MRI Procedure
Gradient echo EPI fMRI data acquisition was conducted
on a 3T Siemens Verio system using a 12-channel volume
head coil (TR: 2.6 s, TE: 29 ms, FOV: 256 3256 mm
2
,
acquisition matrix: 128 3128, 36 axial slices, voxel dimen-
sions: 2 3233 mm
3
). In addition, a 3D T1-weighted ana-
tomical MRI image was acquired (TR: 2,200 ms, TI: 778
ms, TE: 3 ms, flip-angle 5138, FOV: 256 3256 mm
2
, 256
axial slices of thickness 51.0 mm, matrix 5256 3256,
scan-time 55 min 22 s). These parameters allow acquisi-
tion of fMRI data with high in vivo spatial resolution. The
total study time was approximately 1 h.
fMRI Cold Exposure Paradigm
Thermoregulatory challenge was applied using a speci-
alized whole-body garment through which subjects were
exposed to either a neutral or cold temperature stimulus.
The garment incorporates a network of small-diameter
plastic tubing (Allen Vangard, Ottawa, CA) (Fig. 1A)
through which temperature-controlled neutral (31–348C) or
cold water (2–48C) was circulated from two separate water
reservoirs located outside the scanner room. The effects of
these exogenous temperature stressors on body tempera-
ture was monitored using an MRI-compatible GaAs crystal
sensor located at the tip of an optical fiber cable (OpSense,
Quebec City, CA). This approach relies on the temperature
dependence of the energy band gap of a GaAs semicon-
ductor crystal. The GaAs sensor is opaque for wavelengths
below the bandgap and transparent for wavelengths above
the energy band gap. The sensor was taped to the skin at
the location of the left rib cage, the location selected on the
basis of proximity to important anatomical features (close
to the pulmonary blood vessels which are possibly the
most representative sites for core body temperature) and
the ability to consistently place the sensors based on those
anatomical landmarks. Previous studies [Xu et al., 2013;
Yamakage and Namiki, 2003] have shown a strong correla-
tion (R
2
50.70) between this location and core body tem-
perature. The skin temperature was recorded (30-s
intervals) during the experimental paradigm that was
blocked into five 5-min epochs alternating between the
neutral and cold stimulus (Fig. 1B).
As seen, the alternating stimulus induced skin tempera-
ture oscillations in an approximate 48C(!78F) range, and
this decrease from baseline (which was determined as 34 6
1.38CduringthetimewhenthestructuralT1-weighted
image was acquired and prior to water being circulated
through the tube suit), is notable given the relatively short
duration of cold exposure (5 min). Moreover, the tempera-
ture curve can be classified into two broadly distinct
regimes: (a) A dynamic gradient associated with cooling and
re-warming (or return to neutral) reflecting high rates of skin
temperature change in response to the stimulus and (b) peri-
ods when skin temperature remains relatively stable (cold or
neutral) plausibly reflecting adaptation. The temporal width
of these is denoted in Figure 1B, and the temperature ranges
within each of the windows are depicted in Figure 1C.
These distinct regimes constituted separable physiologi-
cal predictors of the BOLD response and were used to
construct epochs of interest for fMRI analyses. Each epoch
was modeled with a temporal radius of 1.5 min centered
at either (a) points of the highest rates of skin temperature
change (in the negative or positive direction) or (b) at the
points of relatively skin temperature (at both neutral and
cold condition). Thus, in each participant these first level
models estimate neuronal responses during (relatively)
rapid skin temperature transitions when thermoregulatory
demands are maximal separately from periods of rela-
tively stable skin temperature, presumably reflecting adap-
tation following temporary relaxation of the stimulus.
We specifically avoided collecting subjective ratings of
unpleasantness during the fMRI scan to eliminate conscious
rMuzik and Diwadkar r
r3190 r
deliberation of changes in internal body states. However,
post-experimental debriefing indicated that all subjects per-
ceived the maximum stimulus as “very cold,” although all
participants denied pain or substantial discomfort.
Statistical Analysis
The fMRI images were analyzed using SPM8 (Wellcome
Department of Cognitive Neurology, Institute of Neurol-
ogy, London, UK). In all analyses, the first four images
were discarded to account for EPI equilibration effects.
The remaining images in the sequence were realigned to
correct for head movements, corrected for slice timing,
and subsequently spatially normalized according to the
transformation matrix derived between the coregistered
(to the mean EPI sequence image) T1-weighted image vol-
ume and the MNI template brain. The images were then
smoothed spatially with a 3D Gaussian kernel of 6 mm
Figure 1.
(A) Subject dressed in the tube suit covering the arms to the
wrists, the legs to the ankles and the torso. (B) The bar at the
base of the graph depicts the stimulus (study paradigm) consisting
of two 5-min cooling periods (blue/dark) interspersed between
neutral temperature background (orange/light), resulting in aver-
age skin temperature oscillations (error bars 6s.d.). From the
temperature curve, we derived two classes of epoch windows
(horizontal arrows). The filled arrows depict temporal windows
characterized by warming (orange/light) or cooling (blue/dark).
Complementary temporal windows (open arrows) assessed fMRI
responses for neutral (orange/light) or cold (blue/dark) periods.
These periods were characterized by different ranges of skin tem-
perature. (C) The vertical arrows depict the range (and direction
of change) of skin temperature during warming or cooling, and
neutral or cold temporal windows. Color/Shading conventions
are maintained from (B). The figure clearly indicates that periods
of warming and cooling were associated with more dynamic
changes in skin temperature than periods of neutral or cold.
[Color figure can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
rResponse of the Human Thermoregulatory Network to Cold r
r3191 r
FWHM and re-sampled (2 3232 mm
3
). A high-pass fil-
ter (cutoff 1/128 s) was used to remove low-frequency sig-
nal drifts. The data were modeled voxel-wise, applying a
general linear model based on a boxcar waveform (based
on the previously described epochs modeled from skin
temperature data) and convolved with the canonical
hemodynamic response function. The confounding effect
of global signal intensity was removed using proportional
scaling. The first-level analysis included correction for
within-scanner motion by means of 6 realignment parame-
ters as regressors, which were derived from the initial
realignment step.
Variations in fMRI responses under the different
regimes from the skin temperature curve were modeled at
the first level using pair-wise directional contrasts. Sepa-
rate contrasts identified fMRI responses associated with
cooling relative to warming, and periods of cold relative
to periods of neutral skin temperature (explicitly defined
in Fig. 1B,C).
These individual contrast images were submitted to a
second-level random-effects analysis [Turner et al., 1998],
to assess group-based activation during the temporal win-
dows of interest. All analyses were constrained respecting
the relative homogeneity of function within regions of
interest that constitute our hypothesized a priori thermo-
regulatory network, introduced above (Table I). Significant
clusters within each region were subsequently identified
using AlphaSim [Ward, 2000], by estimating the minimum
cluster extent for activated clusters to be rejected as false
positive (noise-only) clusters.
This chosen approach performs a Monte Carlo alpha
probability simulation, thus computing the probability of a
random field of noise (after taking into account the spatial
correlations of voxels based on the image smoothness
within each region of interest estimated directly from the
data set) to produce a cluster of a given size, after the noise
is thresholded at a given level. Thus, instead of using the
individual voxel probability threshold alone in achieving
the desired overall significance level, the method uses a
combination of both probability thresholding and minimum
cluster size thresholding. The underlying principle is that
true regions of activation will tend to occur over contiguous
voxels within a region of relative functional homogeneity,
whereas noise has much less of a tendency to form clusters
of activated voxels. Activations were assessed in the previ-
ously motivated thermoregulatory-interoceptive network
that included the brainstem, insula, anterior cingulate cor-
tex, orbitofrontal cortex, posterior parietal cortex, and the
hypothalamus. To report activation peaks, voxel coordinates
in MNI space were transformed into Talairach space using
a previously established algorithm [Lancaster et al., 2007],
and Brodmann areas were reported where appropriate
[Lancaster et al., 2000].
RESULTS
Skin Temperature
Cold water from a reservoir filled with ice slush was cir-
culated through the tube suit for two 5-min periods, dur-
ing which the skin temperature fell from !348C to !308C
(P<0.001 between cold and neutral stimulus blocks, see
Fig. 1C). The relatively short time duration of cold expo-
sure (5 min) allows the perception of a “cold” stimulus in
the absence of pain. In post-experimental interviews, all
subjects perceived the maximum stimulus as “very cold,”
although none considered it “painful,” and all denied
shivering.
fMRI Analysis
Bidirectional contrasts identified multiple clusters in
core thermoregulatory and interoceptive regions. These
clusters revealed complementary responses to body tem-
perature changes during cooling and warming. Cooling
resulted in significant decreases in fMRI measured neuro-
nal responses in core thermoregulatory regions including
the midbrain (Fig. 2). These decreases generalized to the
anterior insula (Fig. 3), the anterior cingulate cortex and
the inferior parietal cortex (see Table II). The decreases in
TABLE I. Hypothesized brain regions of the a priori network implicated in thermoregulatory control
Anatomical label Center of gravity (MNI) Region size (cm
3
/voxels) Reference
Midbrain 0/9/42 39.2/4878 Tzourio-Mazoyer (2002)
Insula R 243/21/20 14.2/1770 Tzourio-Mazoyer (2002)
L 43/21/20 14.2/1770 Tzourio-Mazoyer (2002)
ACC 0/53/12 21.7/2713 Tzourio-Mazoyer (2002)
InfPariet R 252/218/217 23.6/2953 Tzourio-Mazoyer (2002)
L 52/218/217 23.6/2953 Tzourio-Mazoyer (2002)
OFC R 231/60/32 29.8/3719 Tzourio-Mazoyer (2002)
L 31/60/32 29.8/3719 Tzourio-Mazoyer (2002)
See [Tzourio-Mazoyer, 2002]. See also Supporting Information Figure 1.
SPM analysis was constrained to these constituents.
ACC: anterior cingulate cortex; OFC: orbito-frontal cortex; InfPariet: inferior parietal lobule.
rMuzik and Diwadkar r
r3192 r
fMRI activity during cooling were complemented by sig-
nificantly increased activity in only one structure: the bilat-
eral orbitofrontal cortex (Fig. 4).
The signatures of cooling were far more widespread
than those seen associated with prolonged experience of
cold skin temperature. Prolonged periods of cold skin tem-
perature resulted in only two significant clusters of brain
activations. First, we observed significant deactivation in
the right inferior parietal cortex, but significant activation
of the bilateral orbitofrontal cortex during the warm phase
(see Table II, Fig. 5). Both these activation loci were simi-
larly positioned to those observed during the dynamic
process of cooling.
The temporal course of the responses to cooling, and
their statistical relationship to changes in body tempera-
ture were investigated in further analyses.
Regional Time Series Analysis
Additional analyses were performed to relate changes in
the fMRI estimated neuronal signal with dynamic changes
in body temperature (resulting from thermoregulatory
challenge). After significant activation clusters were identi-
fied in the second-level analysis, these activation clusters
were subsequently used as masks to extract the fMRI
Figure 2.
Negative BOLD responses to cold stress in the midbrain are
depicted on coronal, axial and sagittal views (arrows). The
adjoining graph depicts the BOLD response (no symbols)
derived as the eigenvariate at the location of the midbrain acti-
vation juxtaposed against fluctuations in skin temperature
(circles) in response to cold stress. Error bars are 6s.d. The
BOLD response in the midbrain is proximate in phase to skin
temperature responses. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
rResponse of the Human Thermoregulatory Network to Cold r
r3193 r
responses at each sampled time point across the whole
study in each subject. For each activation mask and sub-
ject, the first eigenvariate from the modeled fMRI
responses time sequence was extracted and then averaged
over the sample. In further analyses, these values were
correlated with the contemporaneously acquired skin tem-
perature values. In these analyses, the skin temperature
values were normalized to fluctuations from the subjects’
mean across the experiment. The resulting correlation coef-
ficients were tested for significance using t-tests; moreover
Fisher’s test was used to determine significant differences
between correlations obtained from the various brain
regions. A two-sided Pvalue of less than 0.05 was consid-
ered as significant.
The correlation analyses further elaborated the activa-
tion effects (Fig. 6). Significant positive relationships
between the normalized skin temperature and the BOLD
response were observed in the midbrain, right insula, right
anterior cingulate, and the right inferior parietal cortex.
In contrast, a significant negative relationship was
observed with the orbitofrontal cortex (Table III). The
absolute values of the correlation coefficients ranged from
0.88 to 0.92 and all correlation coefficients were highly sig-
nificant (P<0.001). Finally, no significant difference was
Figure 3.
Negative BOLD responses to cold stress in the insula are
depicted on coronal, axial, and sagittal views (arrows). The
adjoining graph depicts the BOLD response (no symbols)
derived as the eigenvariate at the location of the insula activa-
tion juxtaposed against fluctuations in skin temperature (circles)
in response to cold stress. Error bars are 6s.d. As with the
midbrain, the insula BOLD response is approximately phase
locked to the fluctuations in skin temperature induced by cold
stress. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
rMuzik and Diwadkar r
r3194 r
determined among the positive correlation coefficients and
among the negative correlation coefficients.
DISCUSSION
Here, we probed the neuronal correlates of mild hypo-
thermia through the contemporaneous acquisition of skin
temperature and fMRI data during an oscillatory thermo-
regulatory challenge. The challenge induced skin tempera-
ture changes that were characterized by dynamic
oscillations in cooling and warming interspersed with
periods when skin temperature remained relatively stable
for more prolonged periods (as the applied paradigm
shifted from cold to neutral temperature water).
Complementary phase patterns of decreasing and
increasing BOLD signal in response to skin temperature
changes induced by the mild hypothermic challenge were
observed, segregated by region. Cooling was associated
with (a) Significant decreases in BOLD in the midbrain,
the right anterior insula, the right anterior cingulate, and
the right inferior parietal lobe but (b) significant increase
in BOLD that was confined to the bilateral orbitofrontal
cortex. Moreover, these fMRI estimated neuronal changes
were tightly and intricately coupled with observed
changes in skin temperature: In each of the midbrain,
insula, anterior cingulate, and inferior parietal lobe,
decreases in skin temperature predicted decreases in fMRI
responses. In comparison, in the orbitofrontal cortex,
decreases in skin temperature predicted increases in fMRI
responses. Our cumulative results suggest that thermoreg-
ulatory and interoceptive structures may be more sensitive
to temperature dynamics, than to adaptation/habituation
to prolonged periods of skin temperature in narrow tem-
perature bands.
Plausible Neurophysiological Correlates of
Observed Deactivation
Co-localization of fMRI and electrophysiological data
has related deactivation in the fMRI signal to decreases in
neuronal activity [Shmuel et al., 2006]; in turn neurometa-
bolic coupling has been closely linked to synaptic activity
[Viswanathan and Freeman, 2007]. Therefore, the observed
decreases in fMRI responses in the mid-brain and other
putative interoceptive targets, may reflect a “turning
down” of metabolic load as body temperature changes sig-
nal the onset of mild hypothermia. A logical speculation is
that this reduction reflects efficient neuronal principles of
energy conservation that are early signatures of CNS
responses to non-threatening core-body temperature
decreases. Moreover, the observed decrease of the fMRI
signal in interoceptive brain regions (that is contemporane-
ous with skin cooling) in the right insula corresponds well
with previous reports that postulate that this structure
contains a sensory representation of small-diameter affer-
ent activity that relates to the physiological condition of
the entire body, making discriminative thermal sensation
possible [Craig et al., 2000; Craig, 2002]. The discrimina-
tory thermal function of the insula is also supported by
our previous findings that showed, during endogenous
thermal events such as menopausal hot flash episodes, an
increase of the fMRI signal in the bilateral insula [Diwad-
kar et al., 2014].
The complementary response of the OFC is notable both
for its functional significance, and for its distinct positive
pattern. This distinction suggests that efficient neuronal
responses may be specific to thermoregulatory and intero-
ceptive systems. The OFC is the principle exteroceptive
region of the brain [Bechara et al., 2000; Petrides, 2007].
Extent theories imply that the OFC receives interoceptive
TABLE II. Brain areas displaying significantly increased/decreased brain activation pattern during the cold exposure
paradigm in the whole study group (N520)
Anatomical ROI
Critical
cluster extent
Individual
cluster extent
Uncorrected
P-value (T-value) Voxel peak (Tal)
Cooling <Warming (Figs. 2–4)
Midbrain 260 350 <0.001 (4.38) (2, 230, 28)
Insula R 160 480 0.002 (3.74) (38,15,6; BA13)
ACC R 191 543 0.002 (3.26) (6, 27, 19; BA24)
InfPariet R 165 176 0.003 (3.47) (46,228,30; BA40)
Cooling >Warming (Figs. 2–4)
OFC R 119 379 0.003 (3.20) (16,45,215;BA11)
OFC L 119 227 0.006 (2.80) (236,30,223,BA47)
Cold <Neutral (Fig. 5)
InfPariet R 99 141 0.002 (3.08) (44,240,33; BA40)
Cold >Neutral (Fig. 5)
OFC R 171 240 0.001 (3.28) (34,21,217;BA47)
OFC L 171 347 <0.001 (4.35) (220,32,214,BA11)
Abbreviations: ACC, anterior cingulate cortex; OFC, orbito-frontal cortex; InfPariet, inferior parietal lobule; R, right; L, left.
rResponse of the Human Thermoregulatory Network to Cold r
r3195 r
“images” of internal process, and is highly responsive to
the noxiousness elicited by the image. The OFC has been
shown to correlate strongly with subjective thermal per-
ception and is associated with the discrimination of posi-
tive and negative rewards, or hedonic valence [Craig
et al., 2000; Rolls et al., 2003, 2008]. Thus, in our experi-
ment, temperature-sensitive representations (i.e., mildly
noxious changes in body temperature) may be forwarded,
via the colossal pathway, from the insula to the OFC
where hedonic valence is attached to the subjective feeling
of distress. It has been speculated that energy-efficient
maintenance of the body state (i.e., homeostasis) is
achieved through an ordered set of neural constructs that
are re-represented at various integration levels, starting in
the midbrain and then progressing to the posterior, middle
and finally anterior insula [Craig, 2009]. During this pro-
cess, the mid-insula integrates these homeostatic re-repre-
sentations with activity that is associated with emotionally
salient environmental stimuli. In this sense, the opposite
phase of the insular and orbitofrontal activations observed
in this study can be regarded as a temperature differentia-
tion process that is subsequently converted into a subjec-
tive evaluation of the stimulus.
Of particular interest is the observation that periods of
dynamic skin temperature are more evocative of pro-
nounced responses in thermoregulatory brain regions
Figure 4.
Positive BOLD responses to cold stress in the orbitofrontal cor-
tex are depicted on coronal, axial, and sagittal views (arrows).
The adjoining graph depicts the BOLD response (no symbols)
derived as the eigenvariate at the location of the orbitofrontal
cortex activation juxtaposed against fluctuations in skin tempera-
ture (circles). Error bars are 6s.d. Unlike the midbrain and the
insula, OFC responses are in phase opposition to fluctuations in
skin temperature induced by cold stress. [Color figure can be
viewed in the online issue, which is available at wileyonlineli-
brary.com.]
rMuzik and Diwadkar r
r3196 r
than periods of relatively stable skin temperature. Our
analyses of time series confirmed that the activation/
deactivation of brain areas was closely predicted by the
skin temperature gradient, that is, with the time when
the change in skin temperature is maximal. As noted ear-
lier, this suggests that thermoregulatory brain centers are
highly sensitive to the degree of heat loss and less sensi-
tive to states when skin temperature remains nearly con-
stant, independent from the absolute temperature level.
Although the exact mechanisms are unknown, this obser-
vation may constitute CNS correlates of peripheral
systems. For example, temperature-activated transient
receptor potential (TRP) ion channels are expressed in
free nerve endings in all layers of the skin [Patapoutian
et al., 2003] and function as versatile polymodal cellular
sensors that sense and are modulated by a wide array of
inputs, including temperature, pressure, pH, voltage,
chemicals, lipids, and other proteins. Several classes have
been identified (TRPv1 – TRPv8), with channel activities
dependent on specific temperature ranges. TRPM8 is the
primary cold sensor in higher organisms, and several
studies have shown that TRPM8 regulates body tempera-
ture [Almeida et al., 2012; Gavva et al., 2012], although it
is also implicated in a wide variety of other physiologi-
cally important roles [Hilton et al., 2015]. As a result, it is
conceivable that the activity of this channel is most sensi-
tive to rapid changes in skin temperature and less so to
relatively stable temperature, an inference that our obser-
vations conform to.
In addition to core thermoregulatory brain regions, we
observed de-activations in the area of the inferior parietal
cortex. This finding is consistent with a recent model that
suggests that a network of brain areas, including the pos-
terior parietal and the insular cortices, might play a crucial
role in maintaining the integrity of the body at both the
homeostatic (i.e., thermoregulation) and psychological (i.e.,
in terms of perception and the sense of body ownership)
levels [Moseley et al., 2012]. Within this structure, named
the “body matrix,” multisensory information regarding the
body and the space around it, is constantly integrated.
This notion is based on recent reports showing that a
reversible functional interference of the general area of the
posterior parietal cortex via regional transcranial stimula-
tion is able to disrupt thermoregulatory control [Gallace
et al., 2014]. Our data extends these results and suggests
that the inferior parietal cortex might also contribute to a
top–down modulation of thermoregulatory control. In this
sense, the inferior parietal cortex might be involved in
both processing incoming signals regarding a variation of
body temperature, as well as in affecting the functioning
of those efferent systems responsible for modulating such
homeostatic variable. These mechanisms appear to be in
play during both types of skin temperature regimes that
we addressed.
Relationship to Previous Findings
The involvement of the insula in the interoception of
thermoregulatory processes has been extensively demon-
strated in the literature [Craig et al., 2000; Fechir et al.,
2010; James et al., 2013], yet to our knowledge, this is the
first study to specifically assessing cooling, and therefore,
the first report of de-activation in this region during
cooling-related body temperature decreases. Previous
imaging studies have typically applied short thermal
Figure 5.
Prolonged periods of cold result in (a) positive BOLD responses
in the orbitofrontal cortex but (b) negative BOLD responses in
the parietal cortex (arrows). These effects can be distinguished
from fMRI correlates of cooling and warming (Figs. 2, 3, 4, and
6). [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
rResponse of the Human Thermoregulatory Network to Cold r
r3197 r
stimuli to small skin areas and have focused on thermal
sensory responses that are inextricably associated with
pain perception [Rolls et al., 2008]. The only other previ-
ous study that applied similar methodology to ours was
by McAllen et al. [2006]. They focused on, and elegantly
demonstrated highly specific medullary raphe activations
on a rostral slice of the medullary system, chosen for being
closest in comparative anatomy to the rodent. Our study
complements this work: Our fMRI acquisition was moti-
vated by focus on a wider thermoregulatory and thermor-
eceptive network. Such a focus demanded more extensive
sub-cortical and cortical fMRI coverage from the mid-brain
to superior brain regions. Thus, our resultant slice pre-
scriptions did not consistently capture fMRI responses in
the rostral portions of the brain stem identified by
McAllen et al. However, the loci of fMRI deactivation in
the mid-brain reported here are highly consistent with our
recently reported evidence of increased activations during
endogenously generated hyper-thermic events [Diwadkar
et al., 2014]. Specifically, mid-brain regions (and regions
across the interoceptive network including the insula and
anterior cingulate) are positively activated when sympto-
matic menopausal women experience hot flashes, that is,
intense heat surges in the body. Thus, mid-brain loci
Figure 6.
The three panels represent BOLD as a function of decreases in
skin temperature that results from our cold stress paradigm.
Changes in skin temperature are represented relative to
decreases from the peak (x-axis: left to right), and the BOLD
data are summarized in 0.58C bin widths. Adjoining each graph
is an image of the cluster peaks from which the BOLD
responses were derived (arrows). These images are for negative
BOLD in the (a) midbrain (coronal slice), (b) insula (axial slice)
and for positive BOLD in the (c) orbitofrontal cortex (OFC,
sagittal slice). The significant decreases in BOLD in the midbrain
(a) and the insula (b) as a function of decreases in skin tempera-
ture are clearly seen (R
2
50.82 and R
2
50.83, respectively). In
comparison, the OFC shows a significant increase in BOLD as a
function of decreases in skin temperature (R
2
50.85). [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
rMuzik and Diwadkar r
r3198 r
appear to respond differently in response to hypo- and
hyper-thermic challenges.
The response of the thermoregulatory network to cold
exposure has also been studied using positron emission
tomography (PET) imaging, a method that uses F18-
labeled deoxyglucose (FDG) to measure cerebral glucose
metabolism during brain activation. Because glucose
uptake is a relatively slow process (glucose uptake is 90%
complete 30 min after injection of the FDG tracer), FDG
PET imaging represents the average glucose metabolism
over an extended time period (30–45min) and provides
complementary information to the faster blood flow
changes measured with BOLD fMRI. Nevertheless, FDG
PET studies using a similar methodology as ours showed
right insular deactivation during whole body cooling
[Fechir et al., 2010], in agreement with our findings. The
authors interpreted this result as a release of inhibitory
control by higher-order brain regions on autonomic centers
located in the brainstem. Such a mechanism might provide
a reasonable explanation for sympathetic hyperactivity,
which occurs after hemispheric stroke [Pellecchia et al.,
2003; Riedl et al., 2001].
In addition to the anterior insula, areas in both the ante-
rior cingulate cortex and midbrain were co-activated dur-
ing cold exposure with similar valence exhibiting
temperature discriminatory function. Activation of the
anterior cingulate cortex is observed in imaging studies of
emotion [Gressens et al., 2008; Gunn et al., 1997] consistent
with the fact that an emotion is both a feeling and a moti-
vation. For example, an imaging study of placebo analge-
sia found concomitant activation of both the anterior
cingulate cortex and the right anterior insula [Xie et al.,
2007], supporting the notion that the feeling associated
with the internal homeostatic representation is accompa-
nied by activation in brain areas that modulate behavior.
Moreover, co-activations observed in the midbrain areas
are likely associated with low-level control of homeostasis
including cardiovascular and cardiorespiratory regulation.
The similarity of the observed activation pattern in the
insula, anterior cingulate cortex and midbrain points
toward a vertically integrated system ranging from sub-
conscious homeostatic regulatory mechanisms to abstract
meta-representations of the physiological state of the body
that triggers a conscious behavioral response.
Further Considerations and Limitations
In the absence of direct measurements of temperature
from within the body itself, we are careful to note that our
CNS effects can only be related to the skin temperature
changes that we directly measured, and it is unclear how
the relatively short cooling periods (2 35min) might have
affected (if at all) core body temperature. It has been
argued that skin temperature represents only an auxiliary
feedback signal to the main thermoregulatory system,
reducing the system’s response time and making core
body temperature more stable [Romanovsky, 2007, 2014].
Consistent with this model is the observation that skin
temperature is relatively more important for driving most
(but not all) thermoregulatory behaviors [Roberts, 1988],
whereas core body temperature is relatively more impor-
tant for triggering autonomic responses [Jessen, 1981;
Sakurada et al., 1993]. Such an organization reflects the
fact that behavioral responses are often aimed at escaping
impeding thermal insults.
We also note that our observed fMRI patterns were in
evidence despite potential challenges to sensitivity as tem-
poral changes in the temperature stressor overlapped with
the phase of scanner drift. As a result, portions of the
BOLD signals in regions of interest might have been
removed by the applied high-pass filter potentially
decreasing the statistical power of our results. Neverthe-
less, the observation of low-frequency oscillations of
regional BOLD signal with both opposite phase and simi-
lar amplitude suggests that scanner drift corrections were
almost exclusively driven by global changes in BOLD sig-
nal, thus preserving local oscillations. Moreover, mild
hypothermia is associated with physiological reactions like
shivering, tachycardia, and vasoconstriction. Although
skin temperature was monitored throughout the study
and the observed skin temperature oscillations were found
to be comparable across subjects, there might potentially
exist differences in both temperature perception as well as
in physiological responses to the periodic cooling and
warming paradigm, even in the studied highly homoge-
nous group of young lean subjects (age range 20–31 years,
BMI 20–25 kg/m
2
). Thus, these effects on activation cannot
be excluded, despite the fact that post-experimental
debriefing indicated that subjects perceived the maximum
stimulus as “very cold.”
Our study’s generalizability may be restricted by some
temporal and spatial limitations inherent in fMRI.
Although our spatial resolution was high relative to many
studies (2 32 mm in-plane) precise anatomical location
TABLE III. Correlation analysis between skin
temperature and regional BOLD fMRI time series
Anatomical ROI Correlation coeff. R P-value
Cooling <Warming (Fig. 6)
Midbrain 0.90 <0.001
Insula R 0.91 <0.001
ACC R 0.89 <0.001
InfPariet R 0.89 <0.001
Cooling >Warming (Fig. 6)
OFC R 1L20.92 <0.001
Cold <Neutral
InfPariet R 0.88 <0.001
Cold >Neutral
OFC R1L20.90 <0.001
Abbreviations: ACC, anterior cingulate cortex; InfPariet, inferior
parietal lobule; OFC, orbito-frontal cortex; R, right; L, left.
rResponse of the Human Thermoregulatory Network to Cold r
r3199 r
remains challenging because of variations in the intrinsic
spatial resolution of cortical regions and sub-cortical
nuclei. Cellular differences in midbrain nuclei are not eas-
ily distinguishable using conventional imaging methods
(explaining the absence of well resolved anatomical
masks). Thus, the designation of the exact anatomical loca-
tion with respect to the observed significant deactivation
in the midbrain region is challenging and one can only
speculate with respect to the underlying mechanisms. One
possibility is that our loci represent a subpopulation of
neurons in the dorsal raphe nucleus, based on the work
by Lowry et al. [Lowry et al., 2009]. According to this
model, neurons within lamina I of the spinal cord project
(via fiber tracts in the ventrolateral funiculus) to the mid-
line raphe magnus nucleus, from where ascending projec-
tions innervate the medial reticular formation and strongly
innervate the region lateral and ventral to the medial lon-
gitudinal fasciculi in the interfascicular part of the dorsal
raphe nucleus [Bobillier et al., 1976]. This is in line with
observations indicating that the interfascicular part of the
dorsal raphe region is a critical part of afferent pathways
regulating thermoregulatory function [Consolazione et al.,
1984; Gottschlich and Werner, 1985; Werner and Bienek,
1985, 1990], but serotonergic neurons in the dorsal raphe
nucleus also project to forebrain limbic structures regulat-
ing emotional behavior [Lowry et al., 2008].
A region that was notably silent was the hypothalamus,
which has been shown to be heavily implicated in thermo-
regulatory control based on rodent literature. However,
the hypothalamus has been only infrequently identified in
human fMRI studies of thermoregulation (Freedman et al.
2006; Diwadkar et al. 2014). This absence [Diwadkar et al.,
2014; Kochanek and Safar, 2003] may be attributed to par-
tial volume effects associated with the small structure of
the hypothalamic nuclei and/or cross-species distinctions
in evolutionary endowed thermoregulatory mechanisms of
the structure. This is an open question, itself worthy of
systematic inquiry.
Finally, application of fMRI to investigate brainstem
responses is beset by several methodological challenges. In
addition to magnetic susceptibility artifacts associated
with signal originating from regions close to the brain-CSF
interfaces, there is mixing of signal as a consequence of
voxel resampling during image preprocessing, such as
motion correction and spatial normalization. Moreover, no
suitable neuroimaging brainstem atlas exists to aid in the
registration and warping to a common template. As a
result the alignment of brainstem structures might be sub-
optimal, decreasing the statistical power of the analysis,
especially given the small size of the underlying nuclei.
The process of functional brain network discovery using
neuroimaging data is fundamentally challenging [Friston
et al., 2012]. These challenges relate in part to lack of spe-
cific representation of neuronal events in fMRI signals, the
hemodynamic bases of which agglomerate neural events
across multiple spatial and temporal scales [Logothetis,
2008; Singh, 2012]. Moreover, the generative neuronal driv-
ers of the fMRI signal can only be estimated from the
overt signals themselves [Stephan, 2004]. These collective
considerations exercise limits on the interpretive possibil-
ities of fMRI data regardless of the conditions under which
they are acquired and we acknowledge our inability with
this paradigm to clearly isolate specific functional differen-
ces. Moreover, the current iteration of our work does not
delineate patterns of functional integration across net-
works. This remains an important future extension of our
work, given that integration of diverse functional modules
(as opposed to the relative specialization of such modules
assessed here) is a parallel organizing principle of brain
function [Friston, 2005].
CONCLUSION
Whole body skin cooling clearly evokes systematic
responses in a hierarchically organized thermoregulatory
network. This network seems to generate a highly resolved
interoceptive representation of the body’s condition that
provides input to the orbitofrontal cortex, where higher-
order integration may invest emotional significance to
external stimuli to the body, subsequently motivating
behavior [Rolls, 2010]. These novel results begin to eluci-
date cortical and sub-cortical responses to thermoregula-
tory challenge. A validated framework for assessing CNS
effects of thermoregulatory challenge in vivo is valuable as
impaired thermoregulation has been implicated in a host
of metabolic and endocrine syndromes. We hope that our
work can contribute to the creation of a putative frame-
work for linking peripheral and CNS measures in large
cohort-based studies.
ACKNOWLEDGMENT
We thank Dalal Khatib for assistance in collecting the
data. The authors declare no competing financial interests.
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