Research ReportMulti-day rTMS exerts site-specific effects on functional connectivity but does not influence associative memory performance
Introduction
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique with the capacity to modulate brain network connectivity and cognitive function (Fox, Halko, Eldaief, & Pascual-Leone, 2012). A single session of repetitive TMS (rTMS) can induce short-term changes in cortical excitability (Matsunaga et al., 2005) and memory function (Luber et al., 2007) typically lasting less than an hour. Interestingly, recent studies have shown that multiple doses of rTMS delivered over consecutive days may confer longer-lasting (>24 h) cumulative effects on brain function and cognitive performance in healthy individuals (Wang et al., 2014; Wang & Voss, 2015). For example, Wang et al. (2014) reported sustained enhancement of associative memory in a sample of 16 healthy individuals (~24 h) following five sessions of 20 Hz rTMS applied to subject-specific regions of lateral parietal cortex displaying intrinsic functional connectivity (FC) to left hippocampus. Improvements in memory performance were associated with highly specific increases in FC across the targeted cortico-hippocampal network. These findings suggest that multi-day rTMS may be an effective method of modulating distributed networks critical to learning and memory and commonly implicated in psychiatric (Heckers, 2001; MacQueen et al., 2003) and degenerative disease (Fox et al., 1996). Indeed, such multi-day approaches are closer in design to treatment protocols used in psychiatric disorders such as depression (George & Short, 2014) and therefore may inform future therapeutic applications of stimulation for memory disorders.
The ability to induce long-lasting memory improvement with multi-day stimulation is a prime example of the exciting potential of rTMS. However, the physiological response to non-invasive brain stimulation methods is known to be highly variable between individuals (López-Alonso, Cheeran, Río-Rodríguez, & Fernández-Del-Olmo, 2014), and experimental findings have often proven difficult to replicate (Héroux, Taylor, & Gandevia, 2015). Initial demonstrations of large effects with moderate sample sizes are also prone to effect size overestimation (i.e., ‘The Winner's Curse’, see Button et al., 2013). Encouragingly, the declarative memory and FC effects initially reported by Wang et al. (2014) following multi-day 20 Hz to the parietal-hippocampal network have since been replicated in similar moderate sample sizes (N = 15–16) (Freedberg et al., 2019b; Hermiller, Karp, Nilakantan, & Voss, 2019). In light of these findings, investigating the reproducibility (i.e., the robustness and generalisability; Milkowski et al., 2018) of these effects with similar multi-day rTMS protocols and a larger sample remains a crucial step in assessing therapeutic potential.
The capacity of rTMS to modulate the activity of targeted brain networks is central to cognitive and clinical applications of stimulation (Shafi, Westover, Fox, & Pascual-Leone, 2012). Whilst the direct effects of TMS are confined to a small area of cortex adjacent to the TMS coil position, indirect effects on FC may be induced across distributed regions on the basis of shared intrinsic FC (Eldaief, Halko, Buckner, & Pascual-Leone, 2011; Fox et al., 2012). However, recent evidence suggests that the effects of rTMS may vary substantially across different brain regions (Castrillon et al., 2020; Cocchi et al., 2016). Castrillon et al. (2020) demonstrated opposing effects of 1 Hz stimulation between sensory and cognitive networks. Stimulation of a frontal cognitive network resulted in widespread decreases in FC, while stimulation of an occipital sensory network produced a paradoxical increase in FC. Further, applying continuous theta burst stimulation to frontal and occipital brain regions also induced opposing effects on FC (Cocchi et al., 2016). Considering that rTMS is applied to different brain networks to treat different psychopathologies (i.e., dorsolateral prefrontal cortex in depression versus orbitofrontal cortex in obsessive-compulsive disorder), investigating the site-specificity of rTMS-induced effects may be an important step in improving treatment efficacy.
The aims of this study were twofold. The first aim was to investigate the reproducibility of long-lasting improvements in associative memory and resting-state connectivity following multi-day 20 Hz rTMS to individualised parietal-hippocampal networks. The second aim was to investigate the site-specificity of changes to FC and associative memory following multi-day rTMS by also targeting a spatially distinct network. We utilised a multi-day 20 Hz rTMS protocol similar to Wang et al. (2014), adopting the same resting-state fMRI target localisation approach and outcome measures (i.e., change in functional connectivity and the face-cued word recall task). Further, we extended the approach of Wang et al. (2014) by using a comparison site, instead of sham rTMS. To do this we applied multi-day 20 Hz rTMS to the pre-supplementary motor area (pre-SMA) to modulate a pre-SMA-putamen network. We chose pre-SMA as a comparison site as it corresponds to a distinct brain network supporting other facets of memory function, namely procedural memory (Doyon et al., 2009).
We expected improvements in associative memory performance, as indexed by the percentage of correctly recalled items on face-cued word recall task, following multi-day parietal stimulation. Further, following multi-day parietal stimulation, we expected an increase in FC across the targeted cortico-hippocampal network consistent with the findings of Wang et al. (2014). We also hypothesised a significant positive correlation between associative memory and FC changes following parietal stimulation. In contrast, following multi-day pre-SMA-stimulation, we expected an increase in FC across the targeted pre-SMA-putamen network with no corresponding improvement in associative memory.
Section snippets
Ethics approval
The study was approved by the Monash University Human Research Ethics Committee and all participants provided informed consent prior to their participation. The study conformed to the standards set by the Declaration of Helsinki and subjects were remunerated for their participation.
Participants
The sample size was determined from the results of a previous study demonstrating long-lasting changes to cortico-hippocampal functional connectivity and memory performance following multi-day rTMS to left parietal
Results
Data were collected from a sample of 40 participants (19 males, 21 females) with an average age of 25.48 (SD ± 9.35) years. Overall, both conditions of TMS were well tolerated by subjects. Two participants reported transient mild headaches following rTMS (one following parietal stimulation and one following pre-SMA stimulation), but no other adverse events were reported.
TMS intensities (% of maximum stimulator output) for the complete cross-over sample, and week one stimulation groups (used for
Discussion
Multi-day rTMS has shown promise as a method for altering connectivity in brain networks related to memory. The aims of this study were to: 1) investigate the reproducibility of long-lasting enhancement of associative memory and FC following multi-day rTMS to the parietal cortex; and 2) assess the site specificity of any changes in memory or FC following multi-day rTMS by stimulating different sites. We applied multi-day rTMS to a region of the parietal cortex functionally integrated within a
Data and material availability
No part of the study procedures or analyses was pre-registered prior to the research being conducted. We report how we determined our sample size, all data exclusions, all inclusion/exclusion criteria, and whether inclusion/exclusion criteria were established prior to data analysis. We also report all manipulations and all measures relevant to our investigation of the effects of multi-day rTMS on associative memory and functional connectivity. However, additional secondary outcome measures were
Funding
JH is supported by an Australian government research training scholarship. NR, MY, JC, and AF have all received funding from Monash University, the National Health and Medical Research Council, and the Australian Research Council (ARC). In addition, AF was supported by the Sylvia and Charles Viertel Charitable Foundation. MY has received funding from the Australian Defence Science and Technology (DST), and the Department of Industry, Innovation and Science (DIIS). He has also received
CRediT author statement
Joshua Hendrikse: Conceptualisation, Methodology, Software, Formal analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review & Editing, Visualisation, Project administration.
James Coxon: Conceptualisation, Methodology, Software, Writing – Review & Editing, Supervision, Funding acquisition.
Sarah Thompson: Investigation, Writing – Review & Editing, Project administration.
Chao Suo: Software, Formal analysis, Investigation.
Alex Fornito: Software, Resources, Writing – Review
Acknowledgements
We are grateful to Associate Professor Joel Voss and the laboratory for human neuroscience for their seminal research that has motivated this study, and for sharing the face-cued word recall task. We also wish to thank the staff at Monash Biomedical Imaging for their assistance with MRI data acquisition.
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These authors contributed equally to the study.