Replicable effect of cortical-paired associative stimulation on response inhibition as a function of age

How quickly we stop at a traffic light determines our survival. Similarly, how efficiently one can dodge a craving thought for a pint of beer could define one's relapse probability. Response inhibition, a form of impulsivity, measures one's ability to interrupt an ongoing action, and is central to neuropsychiatric disorders [1,2]. Using cortico-cortical paired associative stimulation (cc-PAS) with transcranial magnetic (TMS) pulses, we targeted the right presupplementary motor area (preSMA) and right-inferior frontal cortex (rIFC). We previously showed an improvement in response inhibition as a function of age [3] using the stop-signal task [1]. Repeated pairs of pulses over two cortical regions induce changes in excitability and functional interaction due to spike timedependent plasticity mechanisms [4]. Specifically, response inhibition improved in older individuals when the rIFC pulse preceded the preSMA pulse by 4milliseconds [3]. Here, we address the problem of reproducibility, a significant issue in TMS studies, by assessing the 4 ms cc-PAS protocol in a different, larger group of healthy volunteers with a broader age range. We recruited 40 healthy volunteers (aged 22e59) through posters and emails to a healthy volunteer database, out of which 3 participants were excluded (software malfunction, early study termination). Exclusion criteria included TMS contra-indications, serious neurological disorders, or hearing impairments. The Cambridge South Research Ethics Committee approved the study, and informed written consent was obtained. The study consisted of a single stimulation session of cc-PAS over the rIFC and preSMA, with pulses paired 4 ms apart, delivered using two Magstim-2002 machines and two figure-of-eight 70mm coils (The Magstim Company Ltd.,Spring Gardens,Whitland,UK). The same targets [3] were used based on a meta-analysis on response inhibition [5]: r-IFC: x,y,z (48,16,16); preSMA: (10,10,60) (Montreal Neurological Institute coordinates in mm). The right IFC coil was 20 angle to the coronal plane (Fig. 1B) with the handle pointing anteriorly and the right preSMA perpendicular to the midline (Fig. 1B). Stimulation accuracy was monitored with neuro-navigation (Brainsight; Rogue Research Inc., Montreal,Quebec,Canada). Resting motor threshold (RMT) was identified with a single TMS pulse to the contralateral motor hotspot, corresponding to the nondominant hand's first dorsal interosseous muscle. RMTwas defined as the lowest intensity stimulation eliciting 5/10 motor-evoked potentials with amplitude >50mVpeak-peak. A total of 100 pulse pairs at 0.2 Hz (8.3-min duration) were delivered with an intensity of 120% RMT.