- Email: [email protected]
No-Go task
Neuroscience Research 85 (2014) 65–68
Contents lists available at ScienceDirect
Neuroscience Research journal homepage: www.elsevier.com/locate/neures
Rapid communication
Timing of response differentiation in human motor cortex during a speeded Go/No-Go task David A.E. Bolton a,b,∗ , Michael Vesia a,b,c , Bimal Lakhani d,e , W. Richard Staines a,b , William E. McIlroy a,b,c,d,e a
Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada Heart and Stroke Foundation Centre for Stroke Recovery, ON, Canada c Sunnybrook Health Sciences Centre Research Institute, Toronto, ON, Canada d Graduate Department of Rehabilitation Science, University of Toronto, Toronto, ON, Canada e Mobility Research Team, Toronto Rehabilitation Institute, Toronto, ON, Canada b
a r t i c l e
i n f o
Article history: Received 14 March 2014 Received in revised form 1 May 2014 Accepted 23 May 2014 Available online 26 June 2014 Keywords: Response inhibition Go/No-Go Transcranial magnetic stimulation Motor cortex Speed of processing
a b s t r a c t We explored the brain’s ability to quickly prevent a pre-potent but unwanted motor response. To address this, transcranial magnetic stimulation was delivered over the motor cortex (hand representation) to probe excitability changes immediately after somatosensory cues prompted subjects to either move as fast as possible or withhold movement. Our results showed a difference in motor cortical excitability 90 ms post-stimulus contingent on cues to either promote or prevent movement. We suggest that our study design emphasizing response speed coupled with well-defined early probes allowed us to extend upon similar past investigations into the timing of response inhibition. © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
The capacity to prevent a pre-potent but unwanted response is an important feature of motor control. While there is now considerable insight into neural networks regulating response inhibition (Aron et al., 2007; Swick et al., 2011), temporal aspects of this process are much less understood. Hoshiyama and colleagues (1996) were the first to investigate temporal dynamics of response inhibition at the primary motor cortex (M1) using transcranial magnetic stimulation (TMS) and since then a select group of studies have explored this issue using either Go/No-Go (GNG) tasks emphasizing response restraint (Hoshiyama et al., 1997; Leocani et al., 2000; Waldvogel et al., 2000; Yamanaka et al., 2002; Sohn et al., 2002) or some version of stop-signal paradigm emphasizing response cancellation (Coxon et al., 2006; van den Wildenberg et al., 2010). A general outcome from such work is that corticospinal excitation, indexed via motor-evoked potentials (MEP), progressively increases following an imperative ‘Go’ cue, starting ∼100 ms prior to onset of the responding muscle. Conversely, after a cue to withhold or cancel movement, M1 excitability is comparably reduced.
∗ Corresponding author at: School of Psychology, Queen’s University Belfast, University Road, Belfast, Northern Ireland BT7 1NN, UK. Tel.: +44 028 9097 5476; fax: +44 028 9097 5486. E-mail addresses: [email protected], [email protected] (D.A.E. Bolton).
Imaging work reveals response inhibition to be an active process and not merely an absence of response drive (Aron et al., 2007; Swick et al., 2011), and it has been suggested that frontal networks upstream of M1 act to restrain a pre-potent response following presentation of a ‘No-Go’ cue (Hoshiyama et al., 1997). Overall, the timing for divergence in MEP amplitude following cues to stop or move tends to reflect speed demands of the task. To date, the earliest stage where this excitability has been reported to diverge has been ≥120 ms following the cue to stop movement (Coxon et al., 2006; Stinear et al., 2009). It is however unclear if this represents a temporal limit for response inhibition over M1. To extend upon past work, we used a GNG version of a simple reaction time task recently developed by Lakhani and colleagues (2012). In that study, electrophysiological measures tracked the progression of median nerve stimulation (Go cue) as it transformed into motor cortical potentials, and ultimately execution of a button press. For present purposes, this sensorimotor mapping offers an estimate for inserting TMS probes to test early response inhibition at M1. Specifically, we delivered single-pulse, supra-threshold TMS at 50 ms, 90 ms and 125 ms after an imperative sensory cue to either move or withhold movement. Based upon results from Lakhani et al. (2012), this first probe at 50 ms should come prior to motor cortical activity related to response generation, therefore no difference in MEP amplitude would be predicted relative
http://dx.doi.org/10.1016/j.neures.2014.05.008 0168-0102/© 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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D.A.E. Bolton et al. / Neuroscience Research 85 (2014) 65–68
Fig. 1. For each trial a visual pre-cue was presented via computer monitor to the participant 2–7 s prior to an imperative Go or NO-Go cue on the left hand. This was followed by a response with the right hand (i.e. mouse click). Test stimuli using TMS were delivered over the hand representation of the left motor cortex following the cue at one of 3 time points (50 ms, 90 ms, or 125 ms) in separate blocks.
to either go or stop commands. In contrast, we predicted a clear distinction in MEP amplitudes by 125 ms, manifested as reduced amplitudes for No-Go versus Go cues. This probe at 125 ms would verify the earliest reported stopping influence measured at M1 (Stinear et al., 2009). Our final TMS probe was timed to correspond with early stages of increasing motor cortical activity from the electrophysiological profile described by Lakhani et al. (2012). In that study, muscle onsets occurred ∼170 ms after the Go stimulus, and since MEP amplitudes reportedly increase 60–100 ms before muscle onset (Starr et al., 1988) our final probe was positioned 80 ms before this point (i.e. 90 ms). Overall, the later two probes should reflect activity in motor areas either during the production or prevention of movement while the earliest probe should remain unaffected. Therefore, we hypothesized a progressive increase in MEP amplitudes following Go cues and a progressive decrease in MEP amplitudes following No-Go cues. Correspondingly, we hypothesized a clear distinction between Go and No-Go cues evident in our earliest time probe where motor cortical activity would be predicted (i.e. 90 ms). Ten healthy adults (5 male, age: 21–30) provided informed written consent before participating in this study (approved by the University of Waterloo’s Office of Research Ethics). Participants sat in a chair resting their arms on a table. For each trial, a visual ‘attend’ signal was followed by a temporally unpredictable single-pulse transcutaneous electrical stimulus, delivered 2–7 s later to the left (cue) hand at: (1) the median nerve (Go) or (2) the hypothenar eminence (No-Go). Electrical stimuli consisted of 1 ms square waves delivered through a surface bar electrode, placed over the target location (GRASS S88X dual-output, square-pulse stimulator with SIU-V stimulus isolation unit; West Warwick, Rhode Island, USA). Go signal stimulation intensity was set at 1.5× motor threshold (motor threshold defined as a barely visible thumb twitch), and 2× sensory threshold for No-Go stimuli delivered at the hypothenar
eminence (sensory threshold defined as the minimal stimulus intensity required to produce barely detectable sensation). Participants were instructed to either (a) respond as quickly as possible by pressing a mouse button with their right index finger (Go) or (b) not to move (No-Go). In between trials, participants were instructed to keep their hands as relaxed as possible. The proportion of Go versus No-Go stimuli was 4:1 to bias the Go response, with stimuli presented in random order. TMS was delivered over left M1 at 3 separate time points following the sensory cue: (1) 50 ms, (2) 90 ms and (3) 125 ms (Fig. 1). Testing consisted of 3 blocks of 60 trials, using one time probe per block (total of 180 stimuli). These test blocks were presented in random order with participants blinded to the timing condition. Importantly, we sought to explore the brain’s ability to quickly inhibit pre-potent motor action. Therefore, to promote rapid responses: (a) participants were provided with visual feedback of their response time immediately after each trial and (b) experimenters continually prompted participants to react as quickly as possible, while concurrently reminding them to avoid responses to No-Go stimuli. Notably, the total trial number for each session was limited (i.e. <200 trials) to avoid any potential loss in response times associated with diminished alertness (Paus et al., 1997). Single pulse TMS was delivered using a custom-built 50mm inner diameter figure-of-eight branding coil connected to a Magstim 2002 stimulator (Magstim, Whitland, UK). To determine the motor hotspot for the first dorsal interosseous (FDI) representation in motor cortex of the left hemisphere, the coil was oriented 45◦ to the mid-sagittal line to induce a current in the posterior-to-anterior direction. The motor hotspot was defined as the motor cortex location optimal for eliciting an MEP in the contralateral relaxed right FDI muscle. Resting motor threshold (RMT) was determined as the minimum intensity required to elicit MEPs
D.A.E. Bolton et al. / Neuroscience Research 85 (2014) 65–68
MEP Amplitude (mV)
*
*
8 6
*
4
*
*
2
Go No-Go
0 50
90
125
Time of TMS after Cue (ms) Fig. 2. MEP amplitudes for each combination of sensory cue and TMS timeprobe ± standard error. Go cues represented as grey circles; NO-Go represented as black squares. * denotes significant difference at p < 0.05 (shown for both interactions and prior-planned comparisons).
of >50 V (peak-to-peak) in 5/10 consecutive trials in subjects at rest (Rossini et al., 1994). TMS intensity was set at 120% of RMT for the entire experimental session. Electromyography was used to monitor muscle activity from FDI of the right (response) hand. Recording electrodes were fixed 1 cm apart over the muscle belly, amplified 1000× and filtered from 20 to 2500 Hz using an Intronix Model 2024F isolated amplifier (Intronix Technologies Corporation, Bolton, Canada) and acquired using Signal Software and a Cambridge Electronic device (Power 1401, Cambridge Electronic Design, Cambridge, UK). Data was averaged separately for each combination of TMS timeprobe and sensory cue. Response time was defined by the time of mouse click relative to stimulus delivery time and acquired using a custom LabView programme (National Instruments; Austin, Texas, USA). Peak-to-peak MEP amplitudes were analysed using a twoway repeated measures analysis of variance (rmANOVA) with task (Go, No-Go) and time (50 ms, 90 ms, 125 ms) as within-subjects factors. Only successfully inhibited No-Go trials were included for this analysis. Pre-planned comparisons tested the hypothesis that amplitude would be greater for Go versus No-Go trials at the two later time points (i.e. 90 ms and 125 ms). Significance was set at p < 0.05. To address the specific question of progressive facilitation/inhibition associated with the Go or No-Go cues respectively, separate one-way rmANOVA with 3 levels of TIME (50 ms, 90 ms, 125 ms) were used for each sensory cue. Behaviourally, mean response times were 247.4 ± 29.7 ms (50 ms), 264.6 ± 38.2 ms (90 ms), and 242.5 ± 27.6 ms (125 ms) with an overall error rate of 26.1 ± 9.7%. Fig. 2 plots group data for mean MEP amplitudes at each time relative to cue onset. MEP amplitudes showed a significant interaction between time and task (F2,18 = 20.65, p < 0.001). Prior planned comparisons revealed no difference between the Go and No-Go cues at 50 ms (t9 = 0.202, p = 0.422), however there were significant differences at 90 ms (t9 = 1.853, p = 0.048) and 125 ms (t9 = 4.409, p = 0.001). One-way rmANOVA for the Go cue demonstrated a significant effect of time on MEP amplitude (F2,18 = 38.84, p < 0.001). Pairwise comparisons revealed that MEP amplitudes were facilitated at 90 ms versus 50 ms (p = 0.035) and at 125 ms versus both 50 ms (p < 0.001) and 90 ms (p < 0.001). For the No-Go cue there was no significant effect of time (F2,18 = 0.937, p = 0.41). Present findings revealed a difference in motor cortical excitability 90 ms after imperative somatosensory cues instructed subjects to either promote or prevent movement. This extends
67
upon previous work exploring response inhibition where this distinction was limited to later stages of the sensorimotor transformation (Stinear et al., 2009). Our results demonstrated that this difference in excitability was due to an increase in excitation following Go signals whereas MEP amplitudes remained unchanged following No-Go cues. Although the predicted decline in MEP amplitude following No-Go cues was not observed, it appears that set-related facilitation of baseline excitability may have biased against our ability to perceive an overt drop in amplitude. The elevated MEP amplitudes, even with our earliest probe (∼3 mV at 50 ms post-cue), supports this claim as these values exceed what would be expected using 120% RMT test-pulses with FDI at rest (Bashir et al., 2011). Regardless, an early distinction in excitability based on command cue reflects an important link to the eventual behaviour. One potential explanation for present findings is that the time point of 90 ms after the imperative cues in this study may reflect the release of the temporarily-restrained, pre-potent response in Go trials. Alternatively, these results may represent the earliest effect of an active braking process in No-Go trials. Present methods prevent confirmation of specific mechanisms, however inclusion of pairedpulse TMS techniques in future studies may reveal processes that serve this early distinction in cortical excitability. Given that the GNG task is thought to involve active response cancellation, particularly when the Go response is made predominant with training (Swick et al., 2011), we believe our results may indicate an early capacity for rapid prevention of excitatory drive acting upon M1. To explore the timing of response inhibition, a necessary feature of our study was to promote extremely fast pre-potent reactions. To achieve this, participants were continually encouraged to respond as quickly as possible to frequent Go cues while performance feedback was provided after each trial. Importantly, our study also limited the number of trials, using just enough TMS probes to address our specific research question, as it has been shown that reaction times become slower with prolonged collection sessions due to a drop in participant alertness (Paus et al., 1997). Whereas the total trial number in the current study was <200, the few studies investigating temporal dynamics of response inhibition have used significantly greater trial numbers. For example, in a comprehensive investigation into the temporal dynamics of response cancellation, van den Wildenberg et al. (2010) used over 1200 trials in test sessions exceeding 3 h. Although in their study the large quantity of trials were necessary to satisfy multiple outcome measures, response times were significantly slower than those presently reported. Therefore even when subjects have been encouraged to go ‘as fast as possible’ a decline in arousal with protracted testing may slow response times, ultimately interfering with the ability to reveal early response inhibition. In addition to concerns regarding absolute response speed, previous studies examining temporal dynamics of response inhibition have either employed Go and No-Go cues at equal probability (Hoshiyama et al., 1997; Leocani et al., 2000; Yamanaka et al., 2002) or used TMS probes later in the sensorimotor transformation (Hoshiyama et al., 1996; Sohn et al., 2002; Waldvogel et al., 2000). By contrast, our study was purposely designed to both emphasize and measure early response inhibition of rapid pre-potent action. Overall, present results provide evidence for a distinction in motor cortical excitation during a speeded response inhibition task earlier than previously asserted. Given that many scenarios in daily life require movements to be accomplished with both speed and contextual adaptation (e.g. obstacle avoidance during a corrective balance response), this early capacity to modify pre-potent but inappropriate motor behaviour is of critical importance.
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D.A.E. Bolton et al. / Neuroscience Research 85 (2014) 65–68
Acknowledgements This work was supported by research grants to WEM and WRS from the Natural Sciences and Engineering Research Council of Canada and by funds from the Canada Research Chairs programme to WRS. DAEB and MV were supported by postdoctoral fellowships from the Ontario Ministry of Research and Innovation and the Heart and Stroke Foundation Centre for Stroke Recovery. The authors also thank Jeff Rice for technical assistance. References Aron, A.R., Durston, S., Eagle, D.M., Logan, G.D., Stinear, C.M., Stuphorn, V., 2007. Converging evidence for a fronto-basal-ganglia network for inhibitory control of action and cognition. J. Neurosci. 27, 11860–11864. Bashir, S., Edwards, D., Pascual-Leone, A., 2011. Neuronavigation increases the physiologic and behavioral effects of low-frequency rTMS of primary motor cortex in healthy subjects. Brain Topogr. 24, 54–64. Coxon, J.P., Stinear, C.M., Byblow, W.D., 2006. Intracortical inhibition during volitional inhibition of prepared action. J. Neurophysiol. 95, 3371–3383. Hoshiyama, M., Kakigi, R., Koyama, S., Takeshima, Y., Watanabe, S., Shimojo, M., 1997. Temporal changes of pyramidal tract activities after decision of movement: a study using transcranial magnetic stimulation of the motor cortex in humans. Electroencephalogr. Clin. Neurophysiol. 105, 255–261. Hoshiyama, M., Koyama, S., Kitamura, Y., Shimojo, M., Watanabe, S., Kakigi, R., 1996. Effects of judgement process on motor evoked potentials in Go/No-go hand movement task. Neurosci. Res. 24, 427–430. Lakhani, B., Vette, A.H., Mansfield, A., Miyasike-daSilva, V., McIlroy, W.E., 2012. Electrophysiological correlates of changes in reaction time based on stimulus intensity. PLoS ONE 7, e36407.
Leocani, L., Cohen, L.G., Wassermann, E.M., Ikoma, K., Hallett, M., 2000. Human corticospinal excitability evaluated with transcranial magnetic stimulation during different reaction time paradigms. Brain 123 (Pt 6), 1161–1173. Paus, T., Zatorre, R.J., Hofle, N., Caramanos, Z., Gotman, J., Petrides, M., Evans, A.C., 1997. Time-related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task. J. Cogn. Neurosci. 9, 392–408. Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco, R.Q., Dimitrijevic, M.R., Hallett, M., Katayama, Y., Lucking, C.H., 1994. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr. Clin. Neurophysiol. 91, 79–92. Sohn, Y.H., Wiltz, K., Hallett, M., 2002. Effect of volitional inhibition on cortical inhibitory mechanisms. J. Neurophysiol. 88, 333–338. Starr, A., Caramia, M., Zarola, F., Rossini, P.M., 1988. Enhancement of motor cortical excitability in humans by non-invasive electrical stimulation appears prior to voluntary movement. Electroencephalogr. Clin. Neurophysiol. 70, 26–32. Stinear, C.M., Coxon, J.P., Byblow, W.D., 2009. Primary motor cortex and movement prevention: where Stop meets Go. Neurosci. Biobehav. Rev. 33, 662–673. Swick, D., Ashley, V., Turken, U., 2011. Are the neural correlates of stopping and not going identical? Quantitative meta-analysis of two response inhibition tasks. Neuroimage 56, 1655–1665. van den Wildenberg, W.P., Burle, B., Vidal, F., van der Molen, M.W., Ridderinkhof, K.R., Hasbroucq, T., 2010. Mechanisms and dynamics of cortical motor inhibition in the stop-signal paradigm: a TMS study. J. Cogn. Neurosci. 22, 225–239. Waldvogel, D., van Gelderen, P., Muellbacher, W., Ziemann, U., Immisch, I., Hallett, M., 2000. The relative metabolic demand of inhibition and excitation. Nature 406, 995–998. Yamanaka, K., Kimura, T., Miyazaki, M., Kawashima, N., Nozaki, D., Nakazawa, K., Yano, H., Yamamoto, Y., 2002. Human cortical activities during Go/NoGo tasks with opposite motor control paradigms. Exp. Brain Res. 142, 301–307.
Contents lists available at ScienceDirect
Neuroscience Research journal homepage: www.elsevier.com/locate/neures
Rapid communication
Timing of response differentiation in human motor cortex during a speeded Go/No-Go task David A.E. Bolton a,b,∗ , Michael Vesia a,b,c , Bimal Lakhani d,e , W. Richard Staines a,b , William E. McIlroy a,b,c,d,e a
Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada Heart and Stroke Foundation Centre for Stroke Recovery, ON, Canada c Sunnybrook Health Sciences Centre Research Institute, Toronto, ON, Canada d Graduate Department of Rehabilitation Science, University of Toronto, Toronto, ON, Canada e Mobility Research Team, Toronto Rehabilitation Institute, Toronto, ON, Canada b
a r t i c l e
i n f o
Article history: Received 14 March 2014 Received in revised form 1 May 2014 Accepted 23 May 2014 Available online 26 June 2014 Keywords: Response inhibition Go/No-Go Transcranial magnetic stimulation Motor cortex Speed of processing
a b s t r a c t We explored the brain’s ability to quickly prevent a pre-potent but unwanted motor response. To address this, transcranial magnetic stimulation was delivered over the motor cortex (hand representation) to probe excitability changes immediately after somatosensory cues prompted subjects to either move as fast as possible or withhold movement. Our results showed a difference in motor cortical excitability 90 ms post-stimulus contingent on cues to either promote or prevent movement. We suggest that our study design emphasizing response speed coupled with well-defined early probes allowed us to extend upon similar past investigations into the timing of response inhibition. © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
The capacity to prevent a pre-potent but unwanted response is an important feature of motor control. While there is now considerable insight into neural networks regulating response inhibition (Aron et al., 2007; Swick et al., 2011), temporal aspects of this process are much less understood. Hoshiyama and colleagues (1996) were the first to investigate temporal dynamics of response inhibition at the primary motor cortex (M1) using transcranial magnetic stimulation (TMS) and since then a select group of studies have explored this issue using either Go/No-Go (GNG) tasks emphasizing response restraint (Hoshiyama et al., 1997; Leocani et al., 2000; Waldvogel et al., 2000; Yamanaka et al., 2002; Sohn et al., 2002) or some version of stop-signal paradigm emphasizing response cancellation (Coxon et al., 2006; van den Wildenberg et al., 2010). A general outcome from such work is that corticospinal excitation, indexed via motor-evoked potentials (MEP), progressively increases following an imperative ‘Go’ cue, starting ∼100 ms prior to onset of the responding muscle. Conversely, after a cue to withhold or cancel movement, M1 excitability is comparably reduced.
∗ Corresponding author at: School of Psychology, Queen’s University Belfast, University Road, Belfast, Northern Ireland BT7 1NN, UK. Tel.: +44 028 9097 5476; fax: +44 028 9097 5486. E-mail addresses: [email protected], [email protected] (D.A.E. Bolton).
Imaging work reveals response inhibition to be an active process and not merely an absence of response drive (Aron et al., 2007; Swick et al., 2011), and it has been suggested that frontal networks upstream of M1 act to restrain a pre-potent response following presentation of a ‘No-Go’ cue (Hoshiyama et al., 1997). Overall, the timing for divergence in MEP amplitude following cues to stop or move tends to reflect speed demands of the task. To date, the earliest stage where this excitability has been reported to diverge has been ≥120 ms following the cue to stop movement (Coxon et al., 2006; Stinear et al., 2009). It is however unclear if this represents a temporal limit for response inhibition over M1. To extend upon past work, we used a GNG version of a simple reaction time task recently developed by Lakhani and colleagues (2012). In that study, electrophysiological measures tracked the progression of median nerve stimulation (Go cue) as it transformed into motor cortical potentials, and ultimately execution of a button press. For present purposes, this sensorimotor mapping offers an estimate for inserting TMS probes to test early response inhibition at M1. Specifically, we delivered single-pulse, supra-threshold TMS at 50 ms, 90 ms and 125 ms after an imperative sensory cue to either move or withhold movement. Based upon results from Lakhani et al. (2012), this first probe at 50 ms should come prior to motor cortical activity related to response generation, therefore no difference in MEP amplitude would be predicted relative
http://dx.doi.org/10.1016/j.neures.2014.05.008 0168-0102/© 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
66
D.A.E. Bolton et al. / Neuroscience Research 85 (2014) 65–68
Fig. 1. For each trial a visual pre-cue was presented via computer monitor to the participant 2–7 s prior to an imperative Go or NO-Go cue on the left hand. This was followed by a response with the right hand (i.e. mouse click). Test stimuli using TMS were delivered over the hand representation of the left motor cortex following the cue at one of 3 time points (50 ms, 90 ms, or 125 ms) in separate blocks.
to either go or stop commands. In contrast, we predicted a clear distinction in MEP amplitudes by 125 ms, manifested as reduced amplitudes for No-Go versus Go cues. This probe at 125 ms would verify the earliest reported stopping influence measured at M1 (Stinear et al., 2009). Our final TMS probe was timed to correspond with early stages of increasing motor cortical activity from the electrophysiological profile described by Lakhani et al. (2012). In that study, muscle onsets occurred ∼170 ms after the Go stimulus, and since MEP amplitudes reportedly increase 60–100 ms before muscle onset (Starr et al., 1988) our final probe was positioned 80 ms before this point (i.e. 90 ms). Overall, the later two probes should reflect activity in motor areas either during the production or prevention of movement while the earliest probe should remain unaffected. Therefore, we hypothesized a progressive increase in MEP amplitudes following Go cues and a progressive decrease in MEP amplitudes following No-Go cues. Correspondingly, we hypothesized a clear distinction between Go and No-Go cues evident in our earliest time probe where motor cortical activity would be predicted (i.e. 90 ms). Ten healthy adults (5 male, age: 21–30) provided informed written consent before participating in this study (approved by the University of Waterloo’s Office of Research Ethics). Participants sat in a chair resting their arms on a table. For each trial, a visual ‘attend’ signal was followed by a temporally unpredictable single-pulse transcutaneous electrical stimulus, delivered 2–7 s later to the left (cue) hand at: (1) the median nerve (Go) or (2) the hypothenar eminence (No-Go). Electrical stimuli consisted of 1 ms square waves delivered through a surface bar electrode, placed over the target location (GRASS S88X dual-output, square-pulse stimulator with SIU-V stimulus isolation unit; West Warwick, Rhode Island, USA). Go signal stimulation intensity was set at 1.5× motor threshold (motor threshold defined as a barely visible thumb twitch), and 2× sensory threshold for No-Go stimuli delivered at the hypothenar
eminence (sensory threshold defined as the minimal stimulus intensity required to produce barely detectable sensation). Participants were instructed to either (a) respond as quickly as possible by pressing a mouse button with their right index finger (Go) or (b) not to move (No-Go). In between trials, participants were instructed to keep their hands as relaxed as possible. The proportion of Go versus No-Go stimuli was 4:1 to bias the Go response, with stimuli presented in random order. TMS was delivered over left M1 at 3 separate time points following the sensory cue: (1) 50 ms, (2) 90 ms and (3) 125 ms (Fig. 1). Testing consisted of 3 blocks of 60 trials, using one time probe per block (total of 180 stimuli). These test blocks were presented in random order with participants blinded to the timing condition. Importantly, we sought to explore the brain’s ability to quickly inhibit pre-potent motor action. Therefore, to promote rapid responses: (a) participants were provided with visual feedback of their response time immediately after each trial and (b) experimenters continually prompted participants to react as quickly as possible, while concurrently reminding them to avoid responses to No-Go stimuli. Notably, the total trial number for each session was limited (i.e. <200 trials) to avoid any potential loss in response times associated with diminished alertness (Paus et al., 1997). Single pulse TMS was delivered using a custom-built 50mm inner diameter figure-of-eight branding coil connected to a Magstim 2002 stimulator (Magstim, Whitland, UK). To determine the motor hotspot for the first dorsal interosseous (FDI) representation in motor cortex of the left hemisphere, the coil was oriented 45◦ to the mid-sagittal line to induce a current in the posterior-to-anterior direction. The motor hotspot was defined as the motor cortex location optimal for eliciting an MEP in the contralateral relaxed right FDI muscle. Resting motor threshold (RMT) was determined as the minimum intensity required to elicit MEPs
D.A.E. Bolton et al. / Neuroscience Research 85 (2014) 65–68
MEP Amplitude (mV)
*
*
8 6
*
4
*
*
2
Go No-Go
0 50
90
125
Time of TMS after Cue (ms) Fig. 2. MEP amplitudes for each combination of sensory cue and TMS timeprobe ± standard error. Go cues represented as grey circles; NO-Go represented as black squares. * denotes significant difference at p < 0.05 (shown for both interactions and prior-planned comparisons).
of >50 V (peak-to-peak) in 5/10 consecutive trials in subjects at rest (Rossini et al., 1994). TMS intensity was set at 120% of RMT for the entire experimental session. Electromyography was used to monitor muscle activity from FDI of the right (response) hand. Recording electrodes were fixed 1 cm apart over the muscle belly, amplified 1000× and filtered from 20 to 2500 Hz using an Intronix Model 2024F isolated amplifier (Intronix Technologies Corporation, Bolton, Canada) and acquired using Signal Software and a Cambridge Electronic device (Power 1401, Cambridge Electronic Design, Cambridge, UK). Data was averaged separately for each combination of TMS timeprobe and sensory cue. Response time was defined by the time of mouse click relative to stimulus delivery time and acquired using a custom LabView programme (National Instruments; Austin, Texas, USA). Peak-to-peak MEP amplitudes were analysed using a twoway repeated measures analysis of variance (rmANOVA) with task (Go, No-Go) and time (50 ms, 90 ms, 125 ms) as within-subjects factors. Only successfully inhibited No-Go trials were included for this analysis. Pre-planned comparisons tested the hypothesis that amplitude would be greater for Go versus No-Go trials at the two later time points (i.e. 90 ms and 125 ms). Significance was set at p < 0.05. To address the specific question of progressive facilitation/inhibition associated with the Go or No-Go cues respectively, separate one-way rmANOVA with 3 levels of TIME (50 ms, 90 ms, 125 ms) were used for each sensory cue. Behaviourally, mean response times were 247.4 ± 29.7 ms (50 ms), 264.6 ± 38.2 ms (90 ms), and 242.5 ± 27.6 ms (125 ms) with an overall error rate of 26.1 ± 9.7%. Fig. 2 plots group data for mean MEP amplitudes at each time relative to cue onset. MEP amplitudes showed a significant interaction between time and task (F2,18 = 20.65, p < 0.001). Prior planned comparisons revealed no difference between the Go and No-Go cues at 50 ms (t9 = 0.202, p = 0.422), however there were significant differences at 90 ms (t9 = 1.853, p = 0.048) and 125 ms (t9 = 4.409, p = 0.001). One-way rmANOVA for the Go cue demonstrated a significant effect of time on MEP amplitude (F2,18 = 38.84, p < 0.001). Pairwise comparisons revealed that MEP amplitudes were facilitated at 90 ms versus 50 ms (p = 0.035) and at 125 ms versus both 50 ms (p < 0.001) and 90 ms (p < 0.001). For the No-Go cue there was no significant effect of time (F2,18 = 0.937, p = 0.41). Present findings revealed a difference in motor cortical excitability 90 ms after imperative somatosensory cues instructed subjects to either promote or prevent movement. This extends
67
upon previous work exploring response inhibition where this distinction was limited to later stages of the sensorimotor transformation (Stinear et al., 2009). Our results demonstrated that this difference in excitability was due to an increase in excitation following Go signals whereas MEP amplitudes remained unchanged following No-Go cues. Although the predicted decline in MEP amplitude following No-Go cues was not observed, it appears that set-related facilitation of baseline excitability may have biased against our ability to perceive an overt drop in amplitude. The elevated MEP amplitudes, even with our earliest probe (∼3 mV at 50 ms post-cue), supports this claim as these values exceed what would be expected using 120% RMT test-pulses with FDI at rest (Bashir et al., 2011). Regardless, an early distinction in excitability based on command cue reflects an important link to the eventual behaviour. One potential explanation for present findings is that the time point of 90 ms after the imperative cues in this study may reflect the release of the temporarily-restrained, pre-potent response in Go trials. Alternatively, these results may represent the earliest effect of an active braking process in No-Go trials. Present methods prevent confirmation of specific mechanisms, however inclusion of pairedpulse TMS techniques in future studies may reveal processes that serve this early distinction in cortical excitability. Given that the GNG task is thought to involve active response cancellation, particularly when the Go response is made predominant with training (Swick et al., 2011), we believe our results may indicate an early capacity for rapid prevention of excitatory drive acting upon M1. To explore the timing of response inhibition, a necessary feature of our study was to promote extremely fast pre-potent reactions. To achieve this, participants were continually encouraged to respond as quickly as possible to frequent Go cues while performance feedback was provided after each trial. Importantly, our study also limited the number of trials, using just enough TMS probes to address our specific research question, as it has been shown that reaction times become slower with prolonged collection sessions due to a drop in participant alertness (Paus et al., 1997). Whereas the total trial number in the current study was <200, the few studies investigating temporal dynamics of response inhibition have used significantly greater trial numbers. For example, in a comprehensive investigation into the temporal dynamics of response cancellation, van den Wildenberg et al. (2010) used over 1200 trials in test sessions exceeding 3 h. Although in their study the large quantity of trials were necessary to satisfy multiple outcome measures, response times were significantly slower than those presently reported. Therefore even when subjects have been encouraged to go ‘as fast as possible’ a decline in arousal with protracted testing may slow response times, ultimately interfering with the ability to reveal early response inhibition. In addition to concerns regarding absolute response speed, previous studies examining temporal dynamics of response inhibition have either employed Go and No-Go cues at equal probability (Hoshiyama et al., 1997; Leocani et al., 2000; Yamanaka et al., 2002) or used TMS probes later in the sensorimotor transformation (Hoshiyama et al., 1996; Sohn et al., 2002; Waldvogel et al., 2000). By contrast, our study was purposely designed to both emphasize and measure early response inhibition of rapid pre-potent action. Overall, present results provide evidence for a distinction in motor cortical excitation during a speeded response inhibition task earlier than previously asserted. Given that many scenarios in daily life require movements to be accomplished with both speed and contextual adaptation (e.g. obstacle avoidance during a corrective balance response), this early capacity to modify pre-potent but inappropriate motor behaviour is of critical importance.
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