Discussion
TRD
CORTEX, SECONDARY, EVENT, INTERACTION
In this secondary analysis of ketamine for late-life, TRD, we investigated rapid and post-rapid changes in neural complexity following a single infusion of IV ketamine. Additionally, we studied the relationship between complexity dynamics and MADRS score change at 7 days post-infusion as a marker of non-linear foundations for optimal clinical response. Two complementary measures of non-linear neural dynamics were used to measure complexity: LZC and MSE.Rapid effects of ketamine involved increased LZC and MSE ~30 min post-initiation of infusion. Interaction modeling revealed that MSE changes were not localized to a single timescale and indicated that ketamine is associated with differential effects across the scope of functional contributors to shifting E/I balance. Post-rapid effects were restricted to MSE, with complexity reduced at 24 h across multiple timescales. However, effects reverted to baseline levels at day 7. Our findings support the hypothesis that a single sub-anesthetic ketamine infusion has time-varying effects on system-wide contributions to the evoked glutamatergic surge in individuals with LL-TRD. Further, we demonstrate that changes to complexity are observable outside of the time-window previously shown for effects on gamma oscillations. We are unable to determine the cause for differences in the post-rapid effects between LZC and MSE in our preliminary study but possibly reflect the differences in the physiological content of the two complexity measures. LZC is a measure of randomness; the complexity is equivalent to the number of patterns identifiable, and repeated, within the mixed signal. This approach treats complexity more as a blunt instrument, and is a suitable method for estimating the overall extent to which the system deviates from uniformity. We can consider this much the same as what event related potentials (ERP) represent relative to the Fourier transform. On the other hand, MSE demonstrates the regularity of information processing across different states of organization, or rather timescales. The choice to measure complexity with respect to time is inspired by the organization of oscillatory activity, where different functional processes have distinct temporal signatures. For example, top-down inhibition of the visual cortex operates at the frequency range of the alpha band [Single infusion studies have been the primary tool for mapping the clinical mechanism of action for ketamine treatment for TRD. EEG applications in this context have mainly focused on gamma oscillations as a proxy for pyramidal E/I balance [To elucidate whether complexity could provide a measure of treatment response, we investigated the relationship between both baseline and potentiated complexity and treatment outcome at 7 days. Our findings suggest that while ketamine affects the level of complexity over time in our sample, the baseline complexity and the extent to which ketamine alters complexity does not directly impact antidepressant response. This leaves open the possibility that complexity may act in some complementary capacity to gamma oscillations, but that complexity itself is not a moderator or mediator of MADRS reduction. Future study designs should consider this, giving sufficient attention to achieving the statistical power required to perform an appropriate mediation analysis.