Neurocardiology: the brain–heart connection in Takotsubo syndrome

This commentary refers to ‘Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome’, by C. Templin et al., 2019;40:1183–1187. We thank Nagai and colleagues1 for their interest in our study and for drawing attention to key findings, namely those involving the insular cortex. In our recently published study, we found decreased functional connectivity on whole-brain analysis and in three predefined subnetworks, with important nodes including, but not limited to, the amygdala, cingulate gyrus, insular cortex, temporal gyrus, and prefrontal cortex.2 Due to the length limitations of a brief communication, we could not discuss each node in detail and chose to focus on the amygdala and cingulate gyrus because of their well-established role in the limbic system and in regulating cardiac function. As the authors write, there is also compelling evidence for the role of the insula in monitoring cardiac function to support its role in Takotsubo syndrome (TTS). Additional brain structures identified in our study that lie outside of the limbic system could be discussed, such as the dorsolateral prefrontal cortex (DLPFC).2 The DLPFC has been linked to depression, stress, and threat-induced anxiety. Furthermore, DLPFC dysfunction has been associated with induced psychological stress. We believe TTS patients suffer from deficiencies in neural network activations involving multiple brain structures that ultimately might induce insufficient cardiac function. Therefore, it is not enough to examine the insula alone when investigating TTS. With regards to laterality, additional studies are needed to investigate hemispheric lateralization of cardiovascular control. As our study used whole-brain analysis, rather than comparing differences between hemispheres, we cannot draw conclusions on laterality. While there is sufficient evidence of a brain–heart axis and the central nervous system’s control over the heart, findings on hemispheric dominance over parasympathetic vs. sympathetic control remain inconsistent. Recent studies have argued that the autonomic function of the insula is lateralized so that parasympathetic regulation is localized in the left hemisphere and sympathetic in the right. However, other stroke studies have found right-sided infarcts involving the insula were associated with decreased parasympathetic activity, and therefore increased sympathetic tone relative to left-sided infarcts. This suggests that the right insula has a greater role in parasympathetic regulation of cardiac function.3 , 4 Furthermore, the proposed lateralization of autonomic function in the insula may be an oversimplification. Another study found resting muscle sympathetic nerve activity coincided with activation of the left insula while skin sympathetic activity coincided with activation of the left posterior and right anterior insula, when using concomitant fMRI and microelectrode recordings.5 Interestingly, in a previous study we observed bilaterally reduced cortical thickness of the anterior insular cortex.6 In fact, in the present study we found bilateral hypoconnectivity in the anterior insula at the lower-threshold network, only the higher-threshold network revealed hemisphere-specific hypoconnectivity. Thus, any conclusions we make on insular lateralization would be premature and beyond the scope of the present study. Additional laterality studies designed to focus specifically on the role of the insula are needed to support the claims made by the authors. Overall, we appreciate the comment by Nagai et al. and hope that our original study may continue to spark discussion and stimulate research on this interesting topic. Conflict of interest: none declared.