TBS PDF

bioRxiv preprint doi: https://doi.org/10.1101/707802; this version posted July 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission....

bioRxiv preprint doi: https://doi.org/10.1101/707802; this version posted July 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TBS 1 Running head: TBS Beyond the Motor Cortex: Theta Burst Stimulation of the Anterior Midcingulate Cortex Travis E. Baker1*, Mei-Heng Lin1, Seema Parikh2, Neeta Bauer1, Carrisa Cocuzza1 1 Center for Molecular and Behavioral Neuroscience Rutgers University *Corresponding author: Center for Molecular and Behavioral Neuroscience 197 University Avenue Newark, NJ 07102 Rutgers University, Newark USA Ph: (862)-250-3351 Em: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/707802; this version posted July 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TBS 2 ABSTRACT: Intermittent Theta Burst Stimulation (TBS) applied to the left dorsolateral prefrontal cortex suppressed reward-related signaling in the anterior midcingulate cortex (aMCC), resulting in a change in goal-directed behavior. Continuous TBS had no effect. While these results are inconsistent with reported TBS effects on motor cortex, the present findings offer normative insights into the magnitude and time course of TBS-induced changes in aMCC excitability during goal-directed behavior. Theta-burst stimulation (TBS) protocols have recently emerged as having a fast and robust faciliatory (intermittent TBS: iTBS) and inhibitory (continuous TBS: cTBS) action on motor cortex excitability1. As a result, several groups have begun exploiting its potential in the study of prefrontal function in both typical2 and atypical3 populations. While TBS effects on motor cortical excitability can be assessed relatively directly by measuring motor‐evoked potentials, the evaluation of TBS when applied to prefrontal regions requires different approaches, such as PET, EEG, and fMRI. However, combined TBS neuroimaging studies designed to investigate the after-effects of TBS beyond the motor cortex have largely produced conflicting results4,5. Collectively, the action of TBS protocols on neurocognitive functioning remain unclear. Here, we used robot-assisted TBS, in combination with scalp electrophysiological recordings, to examine whether TBS protocols applied to the left dorsal lateral prefrontal cortex (DLPFC) can differentially modulate the activity of the anterior midcingulate cortex (aMCC) during goal-directed behavior. The function of aMCC is hotly debated, but an influential theory holds that aMCC utilizes reward prediction error signals (RPEs) for the purpose of reinforcing adaptive behaviors. In humans, this process is revealed by a component of the event-related brain potential called the reward positivity6 (Figure 1C). Converging evidence indicates that the reward positivity is generated in aMCC and indexes an RPE signal6. In parallel, 10-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left DLPFC has been shown to enhance dopamine release7, neuronal activity, and cerebral blood flow8 in the aMCC, as well as increase the amplitude of the reward positivity9. Leveraging these two streams of evidence, we first asked whether iTBS and cTBS applied to the left DLPFC could facilitate or disrupt aMCC activity, as evaluated by the reward positivity. If true, we then asked whether a TBS-induced change in aMCC activity would cause a change in goal-directed behaviour (e.g. win-stay and lose-shift actions). Given the importance of the aMCC to normal and pathological function, it would be a great theoretical and therapeutic advantage if one could specifically drive or inhibit aMCC activity with TBS. bioRxiv preprint doi: https://doi.org/10.1101/707802; this version posted July 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TBS 3 Figure 1. TBS paradigm. A) Block sequence. B) Single-Trial Sequence. C) ERPs elicited by reward feedback (blue), no-reward feedback (red) and difference wave (black). The reward positivity is observed as a differential response in the ERP to reward and no-reward feedback, occurring over frontal–central areas of the scalp about 250–300 msec after feedback. We recorded the electroencephalogram from 19 right-handed participants (9 females, aged 18–28 [M = 22.2, +2.8]) freely navigating a ‘‘virtual” T-maze to find monetary rewards (reward: 5 cents, no-reward: 0 cents). Beginning the experiment, a robotic arm positioned the TMS coil over the left DLPFC (electrode location F3) (Fig. 1A), and continuously tracked this position to ensure precise pulse delivery (< 1 mm). Each participant received iTBS or cTBS on separate sessions (counterbalanced), with each session consisting of four blocks of 100 trials. Following the first block, 600 pulses of either iTBS or cTBS were delivered at 80% resting motor threshold. Subjects then complete three post-TBS blocks (duration 15-20 minutes). An analysis of the reward positivity revealed a significant quadratic interaction between Block and TBS, F1, 18 = 6.7, p <.01, η2 = 0.21. Specifically, the delivery of iTBS following Blk1- Baseline (M = -6.63 μV, +.8) strongly reduced the reward positivity at Blk2-postTBS (M = -4.80 μV, +.7; t(18) -2.78, p