Paradoxical inhibition of autonomic output following cortical suppression: When inhibiting an inhibitor results in more (not less) inhibition.

Paradoxical effects in brain stimulation, where inhibition of a putative inhibitory region leads to stronger (not weaker) downstream suppression, challenge overly simplistic classical assumptions about excitation-inhibition interactions. Joshi et al. (2024) demonstrated that optimised inhibitory multi-channel transcranial direct current stimulation (MtDCS) over the right ventrolateral prefrontal cortex (rVLPFC) enhanced suppression of autonomic skin conductance responses (SCRs). However, this only occurred in individuals with signs of elevated cortical hyperexcitability and only in the cathodal condition. This inhibitory effect challenges simplistic polarity-based single-node functional models that assume fixed excitatory or inhibitory outcomes. We propose that such paradoxical inhibition may be understood through systems-level (network) accounts such as precision predictive coding and cortical gain control. We further examine how microcircuit models such as Inhibition-Stabilised Networks (ISNs) might be scaled up to explain these paradoxical outcomes. Together, these frameworks suggest that suppression of excitatory drive, under conditions of heightened salience and trait vulnerability, may paradoxically trigger enhanced inhibitory output as a stabilising response. This challenges simple cause-effect models of neuromodulation and highlights the need for theories to incorporate emergent network dynamics. As a novel entry point into paradoxical dynamics, these findings require careful replication and extensions to probe how suppressed excitation may trigger stabilising inhibition across distributed neural systems.