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.
- Participants will be 272 healthy volunteers drawn from the population in the NIH clinical research volunteer program. INCLUSION CRITERIA: Healthy Right-handed Ages 18-70 (inclusive) Have completed high school or college in an English speaking country. All participants must have had a neurological examination by a NINDS physician within the last two years. All participants in the fMRI experiments must also have had a clinical MRI within the last year. EXCLUSION CRITERIA: Individuals with conditions that could pose a risk relating to the safety of the MRI procedure will be excluded from the protocol such as: Those with ferromagnetic metal in the cranial cavity or eye, e.g. aneurysm clip, implanted neural stimulator, cochlear implant, ocular foreign body. Those with an implanted cardiac pacemaker or auto-defibrillator. Those with an insulin pump. Those with an irremovable body piercing. Pregnant women Individuals with conditions that could pose a risk relating to the safety of the TMS procedure will be excluded from the protocol such as: - Those with significant abnormality on neurological examination. - Those with metal in the cranial cavity or eye, e.g. aneurysm clip, implanted neural stimulator, cochlear implant, ocular foreign body. - Those with an implanted cardiac pacemaker or auto-defibrillator. - Those with an insulin pump. - Pregnant women Individuals with conditions that could compromise our interpretation of the TBS and fMRI results will be excluded such as: - Those with significant abnormality on neurological examination. - Those who have a significant psychiatric illness or have a history of psychiatric illness. - Those using medication affecting the DA system, such as phenothiazine antihistamines (promethazine), antiemetics or decongestants within the last month.