AGE-RELATED DIFFERENCES IN THE MODULATION OF RESTING-STATE FUNCTIONAL CONNECTIVITY FOLLOWING REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION

Abstract

Resting-state intrinsic functional connectivity (rs-iFC) reveals that the brain is organized in several networks (Smith et al., PNAS.2009. Aug4;106(31):13040–5) that relate to cognition and behavior. Brain networks, particularly the Default-Mode Network (DMN) dynamics, can be disrupted by advancing age (Vidal-Piñeiro et al., FrontAgingNeurosci.2014. Sep25;6:256), which may relate to age-related cognitive decline. Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS), can modulate DMN expression and influence cognitive abilities (Eldaief et al., PNAS.2011. Dec27;108(52):21229–34). In the present study we examined whether the effects of rTMS on DMN connectivity differ between young and elders. Twenty-four young (mean age: 23.42±1.64) and twenty-seven healthy elders (mean age: 68.15±4.61) were randomly assigned to receive real (Nyoung=11, Nelders=15) or sham (Nyoung=13, Nelders=12) intermittent theta burst stimulation (iTBS) over the left inferior parietal lobe (lIPL). Changes in rs-iFC induced by iTBS were investigated using seed-based approaches within DMN nodes (Fig.1). Neuroimaging data was analysed using FSL (http://fsl.fmrib.ox.ac.uk/fsl/). Statistical significance was set at p≤0.05 FWE-corrected, except when stated specifically. An interaction between age and rTMS in mPFC was revealed through seed-to-brain analyses (Fig.2A). A main effect of stimulation was evidenced within PMC and mPFC (Fig.2B). Changes in mPFC were mainly driven by a connectivity increase following rTMS in young participants (Fig.3A). Conversely, connectivity increases were restricted within PMC amongst elders (p<0.005 uncorrected; Fig.3B). Seed-to-seed analyses revealed increased mPFC connectivity in young (p<0.001), whereas in elders, regions showing increased connectivity were proximal to the stimulation site (lIPL: p=0.023; PMC: p<0.001 and rIPL: p<0.001). Amongst elders, greater functional responses to rTMS in mPFC regions were positively related to better baseline memory performance (r=0.686; p=0.014). Our results reveal that resting-state connectivity responses to iTBS within DMN are modulated by age. Advancing age appears to attenuate functional connectivity involving long-range connections, while it increases local connectivity. This pattern of effects is coherent with observational neuroimaging studies (Sala-Llonch et al., NeurobiolAging.2014. Oct;35(10):2193–202). Furthermore, ‘young-like’ responses to rTMS appear to be characteristic of elders with better preserved cognitive function. Further studies might investigate if particular connectivity responses to TMS are distinctive of elders at risk or in preclinical stages of dementia. Seed-based approaches used to explore the iTBS-induced intrinsic functional connectivity (iFC) modulation within the DMN. Through these analyses it was studied the iFC modulation between the stimulation site (represented as a flash) and left inferior parietal lobe (IIPL), right inferior parietal lobe (rIPL), posteromedial cortex (PMC), left hippocampus (IHC), right hippocampus (rHC) and medial prefrontal cortex (mPFC) nodes. Figure 1A. Seed-to-brain approach: Representation of the stimulation site (flash) and the main regions included in the network analyses. Figure 1B. Seed-to-seed approach: Representation of the stimulation site (flash) and the six main DMN nodes selected to explore the iFC modulation in an isolated way. Interaction between stimulation and age. A significant interaction between stimulation and age in mPFC (FWE-corrected, p<0.05) is shown in green. Figure 2B. Main stimulation effect: A main effect of stimulation within PMC and mPFC areas of the DMN (FWE-corrected, p<0.05) is shown in red-yellow. iTBS effects in young group: In young group a significant iFC increase in mPFC after iTBS intervention compared with sham condition (FWE-corrected, p<0.05) is shown in red-yellow. Figure 3B. iTBS effects in elder group: In elder group a significant iFC increase in PMC compared to sham condition is shown at a lower threshold (p<0.005 uncorrected).