Modulating Frontal Networks’ Timing-Dependent-Like Plasticity With Paired Associative Stimulation Protocols: Recent Advances and Future Perspectives

Abstract

Starting from the early 2000s, paired associative stimulation (PAS) protocols have been used in humans to study brain connectivity in motor and sensory networks by exploiting the intrinsic properties of timing-dependent cortical plasticity. In the last 10 years, PAS have also been developed to investigate the plastic properties of complex cerebral systems, such as the frontal ones, with promising results. In the present work, we review the most recent advances of this technique, focusing on protocols targeting frontal cortices to investigate connectivity and its plastic properties, subtending high-order cognitive functions like memory, decision-making, attentional, or emotional processing. Overall, current evidence reveals that PAS can be effectively used to assess, enhance or depress physiological connectivity within frontal networks in a timing-dependent way, in turn modulating cognitive processing in healthy and pathological conditions.

Paired associative stimulations: Novel tools for interacting with sensory and motor cortical plasticity

“…As extensively described in the present review, novel PAS protocols have been developed in the last ten years, showing their usefulness, but also their actual limits, in exploring sensorimotor plasticity in the human brain. Recent evidence also showing the effectiveness of cc-PAS on cognitive functioning [13] provides further support of the goodness and potential of this non-invasive brain stimulation tool for neuroscientists and even for clinicians.…”

“…It has to be noted that PAS protocols targeting frontal cognitive systems, instead of sensorimotor ones, have been recently developed [6][7][8][9][10][11][12]; however, they will not be discussed here being out of the aim of the present work and already reviewed elsewhere [13].…”

Altering stimulus timing via fast rhythmic sensory stimulation induces STDP-like recall performance in human episodic memory

“…Human in-vitro studies conducted on brain tissue show that the strength of synaptic modification depends on the relative timing between pre-synaptic and post-synaptic activity albeit with different time scales, as compared to the critical time window of STDP in animals (Testa-Silva, 2010;Verhoog et al, 2013), which begs the question to what extent the findings in animals apply to the healthy human brain. STDP-like effect has been found in the human motor cortex (Stefan, 2000;Wolters et al, 2003), somatosensory cortex (Wolters et al, 2005), as well as in frontal networks (Guidali et al, 2021), using a transcranial magnetic stimulation (TMS) protocol called paired associative stimulation (PAS) (Müller-Dahlhaus, 2010). Additionally, human psychophysics experiments suggest that precisely controlling the relative timing of two visual inputs within a time window of 40 ms, results in a perceptual pattern resembling STDP (Fu et al, 2002;Yao et al, 2004;Yao & Dan, 2001).…”

Paired associative stimulation (PAS) and Alzheimer’s disease (AD)

“…The protocol of NIBS is called paired associative stimulation (PAS) when a sensory peripheral stimulus is repeatedly paired with a TMS pulse over a cortical area that is known to be activated by the TMS pulse (Guidali et al, 2021;Wischnewski and Schutter, 2016). PAS has been identified as causing synaptic plasticity and inducing both LTP-like and long-term depression (LTD)-like after-effects on cortical excitability.…”