In vivo correlates of thermoregulatory defense in humans: Temporal course of sub-cortical and cortical responses assessed with fMRI

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 complex, hierarchically organized thermoregulatory network in the CNS that maintains thermal homeostasis, 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 significant 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 activation in these areas decreased during cold exposure, brain activation increased significantly in the bilateral 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. © 2016 Wiley Periodicals, Inc.

Keywords: cold stress; fMRI; insula; midbrain; orbitofrontal cortex; thermoregulation.

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 average skin temperature oscillations (error bars ± s.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 temperature. (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 http://wileyonlinelibrary.com.]

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 activation juxtaposed against fluctuations in skin temperature (circles) in response to cold stress. Error bars are ± s.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 http://wileyonlinelibrary.com.]

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 activation juxtaposed against fluctuations in skin temperature (circles) in response to cold stress. Error bars are ± s.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 http://wileyonlinelibrary.com.]

Figure 4

Positive BOLD responses to cold stress in the orbitofrontal cortex 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 temperature (circles). Error bars are ± s.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 http://wileyonlinelibrary.com.]

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 http://wileyonlinelibrary.com.]

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 0.5°C 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 temperature are clearly seen (R ² = 0.82 and R ² = 0.83, respectively). In comparison, the OFC shows a significant increase in BOLD as a function of decreases in skin temperature (R ² = 0.85). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]