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

Abstract

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.

Site-specific effects of online rTMS during a working memory task in healthy older adults

“…Participants were scheduled for 6 sessions: a consenting visit including screening, resting motor threshold assessment and practice at the delayed-response alphabetization task, followed by an MRI visit and four rTMS visits (Figure 1). The following sections give a brief overview of the methods, and additional information can be found in Beynel et al (2019).…”

“…To constrain the stimulation target within the left lateral parietal cortex, a mask obtained from the group activation of 22 older adults who participated in our previous study was used (Beynel et al, 2019). The mask was defined as the overlap between the parametric interaction between Set Size and Sorting Steps (at z > 1) and the nonparametric delay period activity (at z>1), therefore reflecting cortical regions that were generally activated by the task, but also were specific to difficulty increase.…”

“…To define Eref, computer simulations were used to estimate the E-field distribution within the parietal ROI induced when TMS was applied at amplitude equal to the resting motor threshold in each of 9 subjects from a previous study (Beynel et al, 2019, Figure S2). For each of the 9 subjects, a parietal ROI was constructed by individual fMRI activity (|z|>0; within a group activity mask, Beynel et al, 2019) registered to the individual's space (FSL flirt, Smith et al, 2004) within voxels classified as gray matter (SimNIBS: gm_only.nii.gz). The selected voxel were ranked according to their E-field strength, and a metric, E100, was defined as the minimum strength across the metric is that 100 voxels in the ROI, corresponding to a volume of 100 mm 3 , have E-field strength larger than E100.…”

“…Here, we wished to maximize the difference between active and sham rTMS by stimulating the parietal cortex, which has been shown to be more activated during the DRAT (Davis et al, 2018), and by modifying some stimulation parameters. To compare the effect sizes for these two studies, Cohen's d was calculated from the individual conditions that yielded the largest effects in each study (hardest difficulty level in the Invalid trials in Beynel et al (2019) and 100% Eref strength for the current study). Cohen's d was calculated as follows:…”

“…Given the important role that theta oscillations play in memory processes (Roux, & Ulhas, 2014), our group has recently undertaken a series of studies aimed at testing the effects of 5Hz rTMS to facilitate the manipulation of information in WM. In one such study (Beynel et al, 2019), 5Hz rTMS was applied over the left dorso-lateral prefrontal cortex (DLPFC) while subjects performed a delayed-response alphabetization task (DRAT). During the DRAT, participants were briefly presented with an array of letters and asked to mentally arrange these letters into alphabetical order during a delay period, after they had been removed from view.…”