Research Article: Online repetitive transcranial magnetic stimulation during working memory in younger and older adults: A randomized within-subject comparison

Date Published: March 22, 2019

Publisher: Public Library of Science

Author(s): L. Beynel, S. W. Davis, C. A. Crowell, S. A. Hilbig, W. Lim, D. Nguyen, H. Palmer, A. Brito, A. V. Peterchev, B. Luber, S. H. Lisanby, R. Cabeza, L. G. Appelbaum, Berthold Langguth.


Working memory is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. The ability to manipulate information in working memory is central to many aspects of human cognition, but also declines with healthy aging. Given the profound importance of such working memory manipulation abilities, there is a concerted effort towards developing approaches to improve them. The current study tested the capacity to enhance working memory manipulation with online repetitive transcranial magnetic stimulation in healthy young and older adults. Online high frequency (5Hz) repetitive transcranial magnetic stimulation was applied over the left dorsolateral prefrontal cortex to test the hypothesis that active repetitive transcranial magnetic stimulation would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in working memory manipulation conditions with the highest cognitive demand in both young and older adults. Repetitive transcranial magnetic stimulation was applied while participants were performing a delayed response alphabetization task with three individually-titrated levels of difficulty. The left dorsolateral prefrontal cortex was identified by combining electric field modeling to individualized functional magnetic resonance imaging activation maps and was targeted during the experiment using stereotactic neuronavigation with real-time robotic guidance, allowing optimal coil placement during the stimulation. As no accuracy differences were found between young and older adults, the results from both groups were collapsed. Subsequent analyses revealed that active stimulation significantly increased accuracy relative to sham stimulation, but only for the hardest condition. These results point towards further investigation of repetitive transcranial magnetic stimulation for memory enhancement focusing on high difficulty conditions as those most likely to exhibit benefits.

Partial Text

Working memory (WM) is a cognitive ability that allows the maintenance and manipulation of information that is retained in the mind for brief periods. Through the interface between long-term memories and moment-to-moment information available in the environment, WM allows humans to carry out successful goal-directed behaviors [1]. As such, WM is widely involved in the achievement of complex tasks such as learning, decision making, and reasoning. Critically, decline in WM is a major factor in cognitive impairment that accompanies healthy aging [2,3]. Therefore, many different approaches are being explored as possible interventions to enhance these abilities, including non-invasive brain stimulation methods such as repetitive transcranial magnetic stimulation (rTMS). rTMS uses brief, high intensity magnetic fields to depolarize neurons underneath the magnetic coil and has been shown to alter cortical function in a frequency-dependent manner, with high frequencies (≥ 5Hz) generally increasing excitability [4]. Although high frequency rTMS has been shown to reduce WM impairment associated with psychiatric disorders [5,6], only a few studies investigated the effect of rTMS to ameliorate age-related cognitive decline [7,8], and to our knowledge, none of these studies have attempted to enhance WM. The current study, therefore, aimed to bridge this gap by testing the capacity of rTMS to enhance WM in healthy younger and older adults. The goal of this study was to implement state-of-the-art, individual fMRI-guided rTMS with neuronavigation and robotic coil placement to investigate two specific questions whose answers may lead to adoption of this technique for improving WM. To provide clear articulation of a priori hypotheses, this study was pre-registered on (NCT02767323).

The goals of this study were, first, to test if online high frequency rTMS to DLPFC could enhance WM manipulation and if this differed as a function to task difficulty. The second goal was to investigate the effect of age on those rTMS effects. The results yielded two main findings. First, active 5Hz rTMS delivered to individualized left DLPFC targets, identified with fMRI and e-field modeling, significantly enhanced WM manipulation abilities over the course of the intervention, but only in the most difficult condition of the task, namely the hardest difficulty level of the Invalid trials. Second, active versus sham rTMS produced similar effects in young and older adults, suggesting that rTMS enhancement was not modulated by age. Each of these findings are discussed in separate sections below.

The current study showed that 5Hz rTMS applied over the left dorsolateral prefrontal cortex can enhance WM manipulation abilities, but only in the most difficult condition, with no differences between young and older adults. This result points towards further investigation of rTMS for memory enhancement, focusing on high difficulty conditions as those most likely to exhibit benefits.




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