Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome

Abstract

Aims: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction often triggered by emotional or physical stress. Severe activation of the sympathetic nervous system with catecholamine release caused by a dysfunctional limbic system has been proposed as a potential mechanism. We hypothesize that brain regions responsible for autonomic integration and/or limbic processing might be involved in the development of TTS. Here, we investigated alterations in resting state functional connectivity in TTS patients compared with healthy controls.

Methods and results: Using brain functional magnetic resonance imaging (fMRI), resting state functional connectivity has been assessed in 15 subjects with TTS and 39 healthy controls. Network-based statistical analyses were conducted to identify subnetworks with altered resting state functional connectivity. Sympathetic and parasympathetic networks have been constructed in addition to the default mode network and whole-brain network. We found parasympathetic- and sympathetic-associated subnetworks both showing reduced resting state functional connectivity in TTS patients compared with controls. Important brain regions constituting parasympathetic- and sympathetic-associated subnetworks included the amygdala, hippocampus, and insula as well as cingulate, parietal, temporal, and cerebellar regions. Additionally, the default mode network as well as limbic regions in the whole-brain analysis demonstrated reduced resting state functional connectivity in TTS, including the hippocampus, parahippocampal, and medial prefrontal regions.

Conclusion: For the first time, we demonstrate hypoconnectivity of central brain regions associated with autonomic functions and regulation of the limbic system in patients with TTS. These findings suggest that autonomic-limbic integration might play an important role in the pathophysiology and contribute to the understanding of TTS.

Keywords: Sympathetic; Autonomic-limbic integration; Brain–heart connection; Parasympathetic; Resting state fMRI; Takotsubo syndrome.

Figure 1

Takotsubo syndrome-related hypoconnectivity among central nervous brain structures controlling para- and sympathetic functions as well as regions associated with the default mode network and limbic system. Shown are the more conservatively thresholded subnetworks with reduced resting state functional connectivity in Takotsubo syndrome patients compared with healthy control women. Colour bars represent the set t-value of the connections between which the two groups differ in connectivity strength. The more liberally thresholded subnetworks and detailed information of the nodes and connections involved are shown in the Supplementary materials online. (A) At the higher set threshold (t = 2.30), the Takotsubo syndrome-related parasympathetic-associated hypoconnected subnetwork is composed of seven edges distributed over eight nodes (P = 0.003, FWE-corrected, 5000 permutations). A detailed description of the nodes constituting the subnetworks can be found in Supplementary material online, Table S3. Among these nodes are the right amygdala, left and right hippocampus, left and right middle and superior temporal gyrus, left primary motor cortex and the left supramarginal/angular gyrus, and the left cerebellum. (B) At the higher set threshold (t = 2.25), the Takotsubo syndrome-related sympathetic-associated hypoconnected subnetwork is composed of five edges distributed over six nodes (P = 0.044, FWE-corrected, 5000 permutations). A detailed description of the nodes constituting the subnetworks can be found in Supplementary material online, Table S4. Among these nodes are the left and right amygdala, left and right middle cingulate gyrus, left dorsolateral prefrontal cortex, left anterior insular cortex, left and right cerebellum, and left and right supramarginal gyrus and superior parietal lobule. (C) At the higher set threshold (t = 2.15), the Takotsubo syndrome-related hypoconnected default mode network is composed of 15 edges distributed over 15 nodes (P = 0.033, FWE-corrected, 5000 permutations). A detailed description of the nodes constituting the subnetworks is depicted in Supplementary material online, Table S5. Among these nodes are the left and right hippocampus, left parahippocampal gyrus, left and right dorsal and ventral medial prefrontal cortex, left posterior cingulate cortex, left temporal pole, left and right inferior parietal lobule, and the left and right temporoparietal junction. (D) At the higher set threshold (t = 2.80), the Takotsubo syndrome-related hypoconnected subnetwork is composed of 13 edges distributed over 13 nodes (P = 0.023, FWE-corrected, 5000 permutations). A detailed description of the nodes constituting the subnetworks is depicted in Supplementary material online, Table S6. Among these nodes are the left anterior insular cortex, left posterior cingulate cortex, left and right medial orbitofrontal cortex, left middle temporal gyrus, right pallidum, and the cerebellum.