Modulation of Episodic Memory Using Theta Burst Stimulation (TBS)

Aims and Hypotheses The purpose of the study is to evaluate the effect of theta burst stimulation (TBS) which is a relatively new paradigm of transcranial magnetic stimulation (TMS) on episodic memory (EM) in healthy older adults (hOA).

Aim1: Evaluate the effect of theta burst stimulation (TBS) on episodic memory (EM) in healthy older adults. Hypothesis 1 - There will be significant improvement in EM compared to baseline with one session of TBS.

Aim 2: Correlate white matter integrity to improvement in task retrieval with TBS. Hypothesis 2- Stronger white matter (WM) tract connections correlate to greater improvement in retrieval performance.

BACKGROUND Alzheimer's disease (AD) affects 5 million Americans, at a cost of over 200 billion dollars. The first and most debilitating symptom of AD is a severe deficit in the ability to remembering personal past events, or episodic memory (EM), which eventually renders patients isolated from family and friends and unable to live independently. This EM deficit reflects primarily the deterioration of medial temporal lobe regions, particularly the hippocampus (HC). AD treatments must start very early in the disease progression, when brain damage is still small, and the earliest stage when AD can be diagnosed is known as mild cognitive impairment due to AD (MCI-AD).

Recently, different forms of noninvasive brain stimulation techniques have been applied to healthy older adults, AD and MCI-AD to improve memory impairment. Most of these trials used high-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC). Although a small number of these studies have shown beneficial effects, considerable questions remain as to whether TMS has clinically relevant effects in elderly populations, as well as to what neuroscience-based mechanisms account for these effects. An obstacle for using TMS to enhance EM is that the brain region most critical for EM and most affected by early AD, the hippocampus (HC), is situated deep inside the brain, beyond TMS direct effects (~1" below the skull). One study attempted to target hippocampus and peri-hippocampal regions for stimulation via TMS. They stimulated the lateral parietal cortex and utilized functional connectivity between this region and hippocampus/peri-hippocampal regions (mainly entorhinal cortex) to enhance performance on an associative memory task. The inferior longitudinal fasciculus connects angular gyrus to hippocampus and para-hippocampal regions, and could propagate stimulation effects from cortical to subcortical structures, although studies on effect on TMS on white matter neuronal populations are limited as detailed below. The effect of TMS on neuronal populations in the white matter tracts was recently modeled using tractography and e-field calculations, and increasingly, these approaches need to account for what percentage of variance in motor threshold (MT) would be accounted for by white matter tracts.