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Investigating the efficacy of dual-site transcranial alternating current stimulation for alleviating age-related declines in response inhibition

Tan, Angela Jane Hui Ling (2021) Investigating the efficacy of dual-site transcranial alternating current stimulation for alleviating age-related declines in response inhibition. PhD thesis, Murdoch University.

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Response inhibition, the ability to suppress or cancel a pre-potent motor action, is instrumental in the flexible adaptation of behaviour to an ever-changing external environment. Unfortunately, inhibitory performance deteriorates with ageing, which is detrimental to the functional independence of older adults. The main objective of this thesis was two-fold. Firstly, to ascertain if age-related declines in response inhibition can be ameliorated by transcranial alternating current stimulation (tACS), a form of non-invasive brain stimulation. Secondly, to gain mechanistic insight into the neurophysiological underpinnings of response inhibition in healthy older individuals.

A narrative review (Chapter 1) was conducted to examine the available research evidence on the neural correlates of inhibitory performance. It was found that effective response inhibition performance is subserved by the functional connectivity between the right inferior frontal gyrus (rIFG) and the presupplementary motor area (preSMA), especially for neural activity at beta frequencies. The extant literature also indicates that dual-site tACS can exert facilitatory effects on the functional connectivity between brain regions. Specifically, in-phase tACS, which entails the delivery of currents at the same oscillatory phase to two target sites, was found to promote inter-regional connectivity. Conversely, anti-phase tACS, whereby the currents to the target sites are delivered at opposite phases, was found to weaken interregional connectivity. Therefore, it was deduced that the application of beta frequency inphase tACS over the rIFG and the preSMA could potentially mitigate age-related deficits in inhibitory performance.

To test this hypothesis, a double-blind crossover study involving 18 healthy older adults and 15 younger older adults was carried out to elucidate the effects of in- and anti-phase beta tACS (1 mA; 20 min; applied at rest) on stop-signal task performance (Study 1: Chapters 2 to 5). In-phase tACS led to significant improvements in the action cancellation speeds of younger, but not older, individuals. Moreover, in-phase stimulation resulted in a significant brain-behaviour relationship between cancellation speed and resting-state rIFG-preSMA connectivity for younger participants only. The effects of tACS on inhibitory performance appeared to be contingent upon the endogenous beta-band phase angle difference between rIFG and preSMA during resting-state. Anti-phase tACS was also found to exert differential effects on cortico-cortical gamma-band coupling for older and younger individuals. However, these age-related differences in network connectivity were not reflected in inhibitory performance. tACS-induced changes in response inhibition performance also appeared to be independent of task-related rIFG-preSMA phase connectivity on the scalp- and cortical-level for both older and younger adults. A substantial inter-individual variability in tACS-induced neurophysiological outcomes was also detected, particularly for older participants. This suggests that there may be greater heterogeneity in the dose-response relationship of older adults, in comparison to their younger counterparts.

Subsequently, electric field simulation modelling was conducted to explore how the current dosage of the dual-site tACS protocol could be modified to improve the intensity and focality of tACS-induced currents in the brain (Study 2: Chapter 6). It was found that higher field strengths are accompanied by poorer field focality to target sites, and that this strengthfocality trade-off must be considered when deciding on tACS current intensities.

The current dosages of the tACS protocol utilised in Study 1 were revised in consideration of the findings of Study 2. A sham-controlled, double-blind, crossover study was conducted to test the efficacy of this modified tACS protocol (1.0 mA for rIFG, 1.6 mA for preSMA; 20 min) on improving the inhibitory performance of seven healthy older adults (Study 3: Chapter 7). The study also investigated if an ‘online’ approach, where tACS was administered during task performance, would be more efficacious than if tACS was applied ‘offline’, i.e., when participants were at rest and in a task-free state. Due to the small sample size, group-level and single-subject analyses were employed. The findings of Study 3 indicated that neither online nor offline tACS significantly improved stop-signal task performance. Furthermore, not only was cancellation speed not associated with beta-band phase-coupling between rIFG and preSMA during resting-state and task performance, their inter-regional phase connectivity was not a significant predictor of stop outcome, i.e., the success or failure of stop attempts. Instead, task-related gamma-band rIFG-preSMA phase-coupling was found to be a significant predictor of stop outcome. Changes in source-reconstructed cortio-cortical networks from pre- to post-sham stimulation were also indicative of potential fatigue-related changes in network connections – this is an important factor that future research will need to account for when studying tACS-induced changes in phase-coupling during task performance.

Overall, the findings of this thesis suggest that rIFG-preSMA beta tACS was potentially efficacious in facilitating the inhibitory performance of healthy younger adults. However, its effects in healthy older individuals were subject to considerable heterogeneity. Despite the lack of clear evidence supporting the efficacy of this tACS protocol in alleviating age-related declines in response inhibition, the findings of this thesis have provided important insights into the neural underpinnings of inhibitory performance and contributed to a broader mechanistic understanding of the effects of dual-site tACS on functional connectivity.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): Psychology, Counselling, Exercise Science and Chiropractic
Supervisor(s): Fujiyama, Hakuei, Iyer, Kartik and Sohrabi, Hamid
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