The Behavioral Neurology Unit studies the human brain systems underlying learning and adaptation with the goal of finding interventions to make these processes more efficient. This study will observe neural reorganization underlying episodic memory performance. The protocol will investigate how engaging in a memory task alters the activity and connectivity of the network and the relevance of those changes to successful task performance. Also, how this adaptation influences plasticity of the network will be examined. Using simultaneous TMS, EEG, and cognitive testing, this study will examine the network basis of memory processing, as well as elucidating potential mechanisms of TMS-induced memory improvement. The overall objective of this study is to (1) examine the effects of TMS on EEG biomarkers of successful memory performance and (2) investigate how the task state of the episodic memory network influences the effect of faciliatory TMS on memory. The results will answer basic science questions about the network basis of memory processing, with potential application to other cognitive networks and domains. Additionally, these data will provide a greater understanding of TMS as a tool for influencing the hippocampus, the network, and memory performance, allowing for optimization of stimulation for that purpose. Finally, this work will address clinical questions on how to improve memory and re-channel activity in networks via noninvasive stimulation for clinical purposes. Episodic memory provides a means by which we reflect on the past, make decisions about the future, and form a learned identity. Deficits in this system occur in a variety of neurological and psychiatric disorders, making them one of the most debilitating problems in neurology. However, there currently exist no effective treatments for memory impairment. A better understanding of how the brain adapts to perform a memory demand will not only expand our basic knowledge of memory processing but could inform novel treatments for individuals with memory impairments. Episodic memory depends on the hippocampus and a distributed set of regions which form the hippocampal-cortical network (HCN), including medial prefrontal, posterior cingulate, and medial and lateral parieto-occipital cortex. This network shows changes in fMRI activity and connectivity in response to successful memory encoding and retrieval. Likewise, abnormal function of this network has been associated with memory impairment in many disorders, including traumatic brain injury, epilepsy, and Alzheimer s disease. Additionally, the HCN generates real-time EEG signatures of successful encoding and retrieval, most notably the Late Positive Posterior Event-Related Potential (ERP) and oscillatory activity in the theta/alpha band. There has been substantial recent interest in using brain stimulation to manipulate brain networks, both to test the role of particular regions and networks in memory processing causally and as a potential therapeutic tool in treating memory disorders. Noninvasive transcranial magnetic stimulation (TMS) has been used to manipulate activity and connectivity in the HCN and improve memory performance in healthy adults. Repeated treatment over days produces lasting effects, but single sessions of cTBS have been effective and time-locked cTBS can produce facilitation at the trial-by-trial level. However, while enhancement of connectivity in the HCN is positively correlated with memory improvement, how TMS treatment increases the retention of information in the HCN and particularly the hippocampus remains unknown. Additionally, while the effects of time-locked cTBS have been examined in relation to fMRI activity in the hippocampus39, the effect of HCN cTBS on EEG measures of successful memory has not been studied. Establishing these mechanisms will improve the basic understanding of how the brain successfully meets a memory demand and inform translational studies for the treatment of memory impairment. One goal of this project is to examine the effects of on-line TMS on the electrophysiological signatures of successful memory performance to provide more information on the mechanism by which TMS improves episodic memory to develop new and specific biomarkers of target engagement for future clinical studies. The effects of brain stimulation have been shown previously to vary depending on neural state, such as the phase of oscillations relevant to the stimulated network and network activation by simultaneous task performance. However, the influence of brain state on HCN facilitation with TMS has not been investigated, despite its likely importance. A second goal of this project is to examine this question of task state-dependent modulation for the HCN and episodic memory. Using simultaneous EEG, TMS, and memory testing, we will investigate the EEG activity related to successful memory performance and examine how TMS modulates that activity. In healthy volunteers, we will deliver brief, facilitatory TMS before and during the encoding trials of a memory task to either the HCN, via an inferior parietal cortex site with maximal hippocampal connectivity, or to the vertex as a control. We will additionally deliver stimulation during a control task with similar attentional demands and processing load, and there will be a no-stimulation condition for both tasks. We will record task performance and time-locked EEG activity, focusing on episodic memory performance and the late positive posterior ERP, theta/alpha power, and EEG functional connectivity measured during encoding and retrieval as our outcome measures.
- INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Stated willingness to comply with all study procedures and availability for the duration of the study 2. Ability of subject to understand and the willingness to sign a written informed consent document. 3. Age 18-40 (inclusive) EXCLUSION CRITERIA An individual who meets any of the following criteria will be excluded from participation in this study: 1. Any current major neurological or psychiatric disorder such as (but not limited to) stroke, Parkinson disease, Alzheimer disease, schizophrenia or major depression 2. History of seizure 3. Medications acting on the central nervous system, such as those that lowers the seizure threshold such as neuroleptics, beta lactams, isoniazid, metronidazole; benzodiazepines, tricyclic or other antidepressants; or prescription stimulants. 4. Inability to provide informed consent 5. Ferromagnetic metal in the cranial cavity or eye, implanted neural stimulator, cochlear implant, or ocular foreign body 6. Implanted cardiac pacemaker or auto-defibrillator or pump 7. Non-removable body piercing 8. Claustrophobia 9. Inability to lie supine for 1 hour 10. Pregnancy, or plans to become pregnant during the study. 11. Members of the NINDS BNU 12. Subjects who have contraindications to MRI will follow the NMR Center guidelines for MR safety.