The Effect of Transcranial Magnetic Stimulation on Learning With Reward in Healthy Humans

Objective Theta burst transcranial magnetic stimulation (TBS) produces functional changes in human motor cortex. Continuous inhibitory TBS, (cTBS) over the primary motor cortex (M1) produces a temporary impairment of learning in healthy individuals similar to that seen in patients with traumatic brain injury (TBI) and Parkinson disease (PD). The depression of learning by cTBS may serve as a model for learning and memory deficits in these disorders and provide a means of screening treatments for efficacy and exploring their mechanisms. Our immediate goal is to see whether manipulation of the behavioral contingencies of the task, particularly adding reward, will overcome the virtual lesion produced by cTBS. The first aim of the project is to examine inhibitory effects of cTBS on implicit (serial reaction time /SRT) and explicit (trial-and-error) motor learning of a sequence of target locations. The second aim of the project is to examine the effects of cTBS on non-motor implicit and explicit probabilistic classification learning using the weather prediction task (WPT). We will investigate the involvement of M1 and dorsolateral prefrontal cortex (DLPFC) in implicit and explicit learning by studying participants who will perform these tasks following cTBS over: 1) M1, 2) DLPFC and 3) sham TBS. Our third aim is to examine the effect of manipulating reward during implicit and explicit learning following inhibitory TBS over M1 and DLPFC as it is possible that learning deficits caused by TBS can be improved by increasing the amount of reinforcement during learning. Our fourth aim is to examine the neural networks underlying implicit and explicit learning with and without reward by studying participants who will perform these tasks during functional MRI (fMRI). Finally, we will also perform fMRI during implicit sequence learning and after cTBS over M1 to identify its effects on the neural networks involved in implicit learning. Study population Healthy volunteers (n = 272, aged 18 70), without any contraindication to TBS or MRI. This number includes 60 participants each for Experiments 1 and 2, 24 participants each for Experiments 3-5. In addition, 35 participants are included for piloting behavioral and imaging procedures. In order to account for potential dropouts and withdrawals (up to 20%), the total accrual ceiling includes a further 45 participants to equal 272. Design The study contains five, mixed or crossover design experiments with appropriate controls to eliminate order effects. Outcome measures We will examine the effects of reward and TBS and their interaction on measures of learning. Secondary outcome measures will be how TBS and reward interact to alter the pattern of BOLD activation on MRI and the effects of relevant genetic variation on learning variables and BOLD activation. We will examine the effects of genetic variations in relevant genes on these outcomes.