Adrenomedullary responses to non-invasive cortical stimulation in humans

Abstract

Abstract Introduction: The discovery of cortical adrenomedullary projections in cebus monkeys suggests that similar pathways exist in humans. Notably, the major corticoadrenomedullary projection regions have human equivalents that can be stimulated non-invasively with repetitive transcranial magnetic stimulation (rTMS). If rTMS can be used to selectively modulate adrenomedullary activity, there may be significant therapeutic benefits for stress-, affective-, or neuroimmune-related disorders. Purpose: To assess resting and stress-induced adrenomedullary neuroendocrine responses to continuous (cTBS) and intermittent (iTBS) theta burst TMS in humans. Methods: 39 healthy young adults (14W) were randomly assigned to three counterbalanced sessions of iTBS (n=19) or cTBS (n=20). Stimulation was applied to motor cortical areas that contain the majority of adrenomedullary projections in non-human primates (primary motor cortex trunk region (M1TRUNK) and presupplementary motor area (preSMA)). The M1 leg region (M1LEG) was used as a spatial control. Stimulation locations were determined based on TMS-evoked electromyographic responses in the rectus abdominus (M1TRUNK) and vastus lateralis (M1LEG) or using a combination of fMRI activity and metanalytical structural coordinates (preSMA). All TMS procedures were performed with a 96mm curved double coil and stereotactic navigation. TBS was applied as 600 biphasic TMS pulses at 80% AMT. Corticoadrenomedullary activity and corticospinal excitability (CSE) were assayed before and after TBS, immediately after maximal exercise, and 60min and 90min after TBS based on plasma epinephrine concentrations and median MEP AUC, respectively. Initial analysis of adrenomedullary responses to rTMS were made with a 2 (protocol) x 3 (visit) x 5 (time-point) mixed methods ANOVA. Results and Conclusions: As expected, exercise resulted in a large epinephrine increase (p<0.0001, 8-fold) overall. Ongoing analysis indicates that target-specific changes in adrenomedullary activity are likely, and similar to CSE, may often be paradoxical. Our preliminary results also suggest that adrenomedullary responses to subthreshold rTMS are principally stress inducible. Research Category and Technology and Methods Translational Research: 10. Transcranial Magnetic Stimulation (TMS) Keywords: Adrenal Medulla, Cortex, Sympathetic Nervous System, Non-Invasive Brain Stimulation