Palpitations and dyspnea are fundamental to the human experience of panic anxiety, but it remains unclear how the brain dynamically represents changes in these interoceptive sensations. We used isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline, to induce sensations of palpitation and dyspnea in healthy individuals (n=23) during arterial spin labeling functional magnetic resonance imaging (fMRI). We hypothesized that the right mid-insular cortex, a central recipient of viscerosensory input, would preferentially respond during the peak period of cardiorespiratory stimulation. Bolus infusions of saline and isoproterenol (1 or 2 μg) were administered in a blinded manner while participants continuously rated the intensity of their cardiorespiratory sensation using a dial. Isoproterenol elicited dose-dependent increases in cardiorespiratory sensation, with all participants reporting palpitations and dyspnea at the 2 μg dose. Consistent with our hypothesis, the right mid-insula was maximally responsive during the peak period of sympathetic arousal, heart rate increase, and cardiorespiratory sensation. Furthermore, a shift in insula activity occurred during the recovery period, after the heart rate had largely returned to baseline levels, with an expansion of activation into anterior and posterior sectors of the right insula, as well as bilateral regions of the mid-insula. These results confirm the right mid-insula is a key node in the interoceptive network, and inform computational models proposing specific processing roles for insula subregions during homeostatic inference. The combination of isoproterenol and fMRI offers a powerful approach for evaluating insula function, and could be a useful probe for examining interoceptive dysfunction in psychiatric disorders.

Conflict of interest: KP and MAK are named on patent applications for AAV variants used in this paper. MAK has equity interests in LogicBio Therapeutics. MG has equity interests in Yecuris Corp., Ambys Medicines, and LogicBio Therapeutics. MH owns stock in Encellin and Viacyte Inc., receives research support from Eli Lily, and holds roles as consultant and member of the scientific advisory board for Semma Therapeutics and Encellin.

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Contradictory results from the efforts for detecting evoked neuronal currents have left the feasibility of neuronal current MRI (ncMRI) an open question. Most of the previous ncMRI studies in human subjects are suspect due to their inability to separate or eliminate the hemodynamic effects. In this study, we used a bloodless turtle brain that eliminates hemodynamic effects, to explore the feasibility of detecting visual-evoked ncMRI signals at 9.4T. The turtle brain, with its eyes attached, was dissected from the cranium and placed in artificial cerebral spinal fluid. Light flashes were delivered to the eyes, which produced visual-evoked neuronal activity in the brain. Local field potential (LFP) and MRI signals in the turtle brain were measured in an interleave fashion. Although robust neuronal responses to the visual stimulation were observed in the LFP signals, no significant signal changes synchronized with neuronal currents were found in the MRI images. Analysis of the temporal stability of the MRI time courses indicated that the detectable effect sizes are 0.11% and 0.09° for the magnitude and phase, respectively, and the visual-evoked ncMRI signals in the turtle brain are below these levels.