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]Aron A.R. From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses.Biol Psychiatr. 2011; 69: e55-e68Abstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar,[2]Dalley J.W. Everitt B.J. Robbins T.W. Impulsivity, compulsivity, and top-down cognitive control.Neuron. 2011; 69: 680-694Abstract Full Text Full Text PDF PubMed Scopus (924) Google Scholar]. Using cortico-cortical paired associative stimulation (cc-PAS) with transcranial magnetic (TMS) pulses, we targeted the right pre-supplementary motor area (preSMA) and right-inferior frontal cortex (rIFC). We previously showed an improvement in response inhibition as a function of age [[3]Kohl S. Hannah R. Rocchi L. Nord C.L. Rothwell J. Voon V. Cortical paired associative stimulation influences response inhibition: cortico-cortical and cortico-subcortical networks.Biol Psychiatr. 2019; 85: 355-363Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] using the stop-signal task [[1]Aron A.R. From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses.Biol Psychiatr. 2011; 69: e55-e68Abstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar]. Repeated pairs of pulses over two cortical regions induce changes in excitability and functional interaction due to spike time-dependent plasticity mechanisms [[4]Stefan K. Kunesch E. Cohen L.G. Benecke R. Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation.Brain. 2000; 123: 572-584Crossref PubMed Scopus (1064) Google Scholar]. Specifically, response inhibition improved in older individuals when the rIFC pulse preceded the preSMA pulse by 4milliseconds [[3]Kohl S. Hannah R. Rocchi L. Nord C.L. Rothwell J. Voon V. Cortical paired associative stimulation influences response inhibition: cortico-cortical and cortico-subcortical networks.Biol Psychiatr. 2019; 85: 355-363Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. 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 22–59) 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]Kohl S. Hannah R. Rocchi L. Nord C.L. Rothwell J. Voon V. Cortical paired associative stimulation influences response inhibition: cortico-cortical and cortico-subcortical networks.Biol Psychiatr. 2019; 85: 355-363Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] were used based on a meta-analysis on response inhibition [[5]Cieslik E.C. Mueller V.I. Eickhoff C.R. Langner R. Eickhoff S.B. Three key regions for supervisory attentional control: evidence from neuroimaging meta-analyses.Neurosci Biobehav Rev. 2015; 48: 22-34Crossref PubMed Scopus (159) Google Scholar]: 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 non-dominant hand's first dorsal interosseous muscle. RMT was defined as the lowest intensity stimulation eliciting 5/10 motor-evoked potentials with amplitude >50μVpeak-peak. A total of 100 pulse pairs at 0.2 Hz (8.3-min duration) were delivered with an intensity of 120% RMT. We assessed response inhibition using the stop-signal task(Cambridge Cognition, Cambridge, UK) at baseline and immediately after cc-PAS, well within the 30-min active window for cc-PAS [[4]Stefan K. Kunesch E. Cohen L.G. Benecke R. Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation.Brain. 2000; 123: 572-584Crossref PubMed Scopus (1064) Google Scholar]. Participants saw a go-signal (left or right-pointing arrow) and pressed one of two buttons with their right or left index finger (Fig. 1C) and withheld responding to stop-signal(audio tone). A lower stop-signal reaction time (SSRT = median go reaction time – stop-signal delay) indicates an efficient inhibitory cancellation of the ongoing motor response. We conducted a non-parametric independent samples t-test for non-normally distributed data (Kolmogorov-Smirnov test) in SPSSv27. In line with our previous analysis [[3]Kohl S. Hannah R. Rocchi L. Nord C.L. Rothwell J. Voon V. Cortical paired associative stimulation influences response inhibition: cortico-cortical and cortico-subcortical networks.Biol Psychiatr. 2019; 85: 355-363Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar], we categorised the participants into either older (n = 17, age in mean and SD: 44.5 ± 9.2) or younger (n = 20, age: 25.3 ± 2.9) group based on the median age of 30 years. The difference between the SSRT (in milliseconds) at baseline (SSRTbaseline: young = 153.33 ± 36.43, old = 179.15 ± 58.13) and after stimulation (SSRTccPAS: young = 157.33 ± 49.58, old = 152.65 ± 43.55) was calculated (SSRTccPAS-baseline: young = 3.99 ± 41.88, old = −26.5 ± 28.11). A Mann-Whitney t-test showed a significant (U = 102, p = 0.03) improvement in stopping in older adults post-stimulation compared to baseline. We successfully replicate our earlier findings in which cortico-cortical stimulation of rIFC 4 ms before preSMA improved response inhibition in older individuals. Our 'older' group is relatively young and may limit generalisability. Cortical excitability measures [[6]Bhandari A. Radhu N. Farzan F. Mulsant B.H. Rajji T.K. Daskalakis Z.J. et al.A meta-analysis of the effects of aging on motor cortex neurophysiology assessed by transcranial magnetic stimulation.Clin Neurophysiol. 2016; 127: 2834-2845Crossref PubMed Scopus (64) Google Scholar], and plasticity changes induced by PAS decline with age, particularly above 60 [[7]Müller-Dahlhaus J.F.M. Orekhov Y. Liu Y. Ziemann U. Interindividual variability and age-dependency of motor cortical plasticity induced by paired associative stimulation.Exp Brain Res. 2008; 187: 467-475Crossref PubMed Scopus (255) Google Scholar]. Age-related anatomical differences in brain volume may further influence the measures, efficacy, and diffusion of the TMS pulse delivered at the scalp, an effect more prominent in older age. However, our findings demonstrate the opposite effect– an increase in cortical excitability using this ccPAS protocol in an older population. Our ccPAS protocol is hypothesized to increase the connectivity strength of the preSMA-STN pathway, thus improving performance. This preSMA-STN tract predicts SSRT, particularly in older individuals [[8]Coxon J.P. Van Impe A. Wenderoth N. Swinnen S.P. Aging and inhibitory control of action: cortico-subthalamic connection strength predicts stopping performance.J Neurosci. 2012; 32: 8401-8412Crossref PubMed Scopus (108) Google Scholar]. Furthermore, the ccPAS protocol might further improve dynamic modulation and efficiency within the frontoparietal network [[9]Nord C.L. Popa T. Smith E. Hannah R. Donamayor N. Weidacker K. et al.The effect of frontoparietal paired associative stimulation on decision-making and working memory.Cortex. 2019; 117: 266-276Crossref PubMed Scopus (11) Google Scholar], decreasing with age. These results strengthen our cc-PAS protocol's validity in modulating cortico-cortical and cortico-subcortical networks as a function of age. These findings have implications for obsessive-compulsive disorder and addiction disorders, commonly characterized by impairments in response inhibition. In future, we plan to combine this cc-PAS protocol with task-based imaging to investigate and quantify the connectivity changes between STN-preSMA and STN-rIFC, respectively, in young and over the age of 60. AM: Experiment design, recruitment and testing, data analysis, and manuscript preparation. KT: Experiment design, recruitment and testing, and manuscript preparation. TP: Experiment design, manuscript preparation. VV: Experiment design, recruitment, data analysis, and manuscript preparation. Valerie Voon is supported by the Medical Research Council Senior Clinical Fellowship ( MR/P008747/1 ).

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