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.

Fig 1. Consort diagram showing the recruitment, exclusion and inclusion numbers.

Fig 2. Illustration of the protocol describing the six visits and the relative time interval between each.

Fig 3. Schematic illustration of DRAT.

One trial is shown with an array of 4 letters to encode, followed by a 5s delay period, during which participants had to maintain and reorganize the letters into alphabetical order. Examples of the 3 possible responses are shown at the bottom: “New”: the letter was not in the original array; “Valid”: the letter was in the array and the number represented the correct position in the alphabetical order; “Invalid”: the letter was in the array but the number did not match the correct serial position when alphabetized.

Fig 4. TMS targeting procedure illustrated.

From left to right: Peak BOLD activation (1

Fig 5. Mean accuracy in the Invalid trials.

Accuracy for active (black) and sham (grey) rTMS are displayed for each difficulty level. Small lines represent individual data. The longer lines represent the average for each condition.

Fig 6. Mean accuracy in the Invalid trials for active (dark grey) and sham (light grey) rTMS and for each difficulty level, for young (YA) and older adults (OA).

Error bars represent the standard error.

Fig 7. TMS coil position (spheres) and orientation (arrows) for each subject.

The average coil location is displayed in yellow for the young, and in red for the older group. The spheres represent the coil location and the arrows correspond to the direction of the first phase of the induced E-field pulse (some of the arrowheads are not visible because of the 3D view). The green and the blue sphere represent the average coil location across all subjects, for the young and the old group, respectively.