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Out-of-step: brain-heart desynchronization in anxiety disorders


Imaging studies in anxiety disorders (AD) show abnormal functional connectivity primarily in the salience network (SN), somatomotor network (SMN), and default mode network (DMN). However, it is not clear how precisely these network changes occur including their relation to psychopathological symptoms. Here, we show that the functional networks affected in AD overlap with cortical regions that receive visceral inputs (the so-called central/visceral autonomic network). Focusing on cardiac afferents, we suggest that network changes in AD may be due to reduced phase synchronization between ongoing neural and cardiac activity. This neuro-cardiac desynchronization occurs due to the abnormal phase resetting of neural activity at the onset of each heartbeat, as measured by a lower intertrial coherence and heartbeat-evoked potential. Biochemically, cardiac afferents reach subcortical serotonergic raphe nuclei and noradrenergic locus coeruleus (among others) which, in turn, are known to reciprocally modulate the DMN and SMN/SN on the cortical level. Consistent with the network changes in AD, decreases in serotonergic and noradrenergic activity are known to increase connectivity in both SMN and SN while, at the same time, they decrease DMN connectivity. SMN and SN increases, in turn, lead to increased emotional arousal/anxiety and bodily awareness whereas decreased DMN connectivity leads to an unstable sense-of-self in AD. Finally, we integrate our proposal with interoceptive predictive processing models suggesting neuro-cardiac desynchronization as a mechanism for “noisy” bottom-up information leading to a persistently uncertain bodily state in top-down models. In sum, integrating theories on active interference and hyperarousal, we propose a precise neuro-cardiac and biochemically -driven mechanisms for key psychopathological symptoms of AD.

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Fig. 1: Altered resting state functional connectivity (RSFC) in different neural networks in anxiety disorders.
Fig. 2: Overlap in regions processing cardiac activity and regions affected in anxiety disorders.
Fig. 3: Neuro-cardiac desynchronization, functional networks, and symptoms of anxiety disorders.
Fig. 4: Abnormal neuro-cardiac synchronization in an interoceptive predictive coding framework.


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Tumati, S., Paulus, M.P. & Northoff, G. Out-of-step: brain-heart desynchronization in anxiety disorders. Mol Psychiatry 26, 1726–1737 (2021).

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