Directional Interactions Between Constituents of the Human Large-Scale Thermoregulatory Network

Abstract

In humans, dynamic thermoregulation is (presumably) underpinned by a complex hierarchy of functional interactions between constituents of the human thermoregulatory large-scale network. However, these interactions have not been quantified from in vivo fMRI signals acquired during the experimental delivery of whole-body thermal stress. Here, we used directed functional connectivity (dFC) analysis (based on multi-variate autoregressive models) to recover directed interactions within a single thermoregulatory network during an experimental paradigm that involved controlled exposure to whole-body cooling and warming. MRI studies were performed in 30 young adults (15M/15F, mean age 25.1 ± 3.4years). Gradient echo EPI fMRI data were acquired on a 3T Siemens Verio system. The thermoregulatory challenge was applied using a specialized whole-body garment covering the entire body. Tubes lining the innards of the suit were infused with cold (2-4°C) or neutral (31-34°C) water to induce whole-body Cooling or Warming while fMRI data were contemporaneously acquired. dFC was estimated within and between the hierarchically organized homeostatic (midbrain, pons), interoceptive (insula) and executive (anterior cingulate, orbitofrontal and superior parietal cortices) sub-networks using multi-variate autoregressive models applied to the fMRI time series data. Estimates of directed interactions (akin to Granger Causality) between nodes were analyzed to recover ascending (homeostatic sub-network "upward"), descending (executive sub-network "downward"), and lateral (within sub-network) directional ("causal") effects. Both Cooling and Warming induced complex hierarchical interactions in the thermoregulatory large-scale network. Cooling induced ascending interactions from the homeostatic (midbrain) to both the executive (OFC) and interoceptive (insula) sub-networks, particularly to the superior parietal, ACC and the anterior and posterior insulae. In comparison, descending interactions were induced from the posterior insula. Warming induced ascending interactions from the homeostatic sub-network to notably the OFC (executive) and the insulae (interoceptive). Descending interactions were induced from the ACC and the OFC. Sparser effects appear from the executive to the interoceptive sub-network during warming. Our study demonstrates a hierarchical organization of thermoregulatory function between homeostatic, interoceptive and executive sub-networks. The observed information flow between/within these is consistent with a reentrant property of the hierarchical regulatory structure, characterized by the ongoing bi-directional exchange of signals along reciprocal axonal fibers linking the various nodes.