Attentional influences on short-interval intracortical inhibition

Clinical Neurophysiology 119 (2008) 52–62 www.elsevier.com/locate/clinph

Attentional influences on short-interval intracortical inhibition Richard H.S. Thomson, Michael I. Garry *, Jeffery J. Summers School of Psychology, University of Tasmania, Hobart, Tasmania, Australia Accepted 7 September 2007 Available online 19 November 2007

Abstract Objective: The allocation of attention to sensory stimulation and movement might influence cortical activity. Two experiments were conducted to investigate the effect of variation of intensity of attention (Experiment 1) and direction of attention (Experiment 2) on cortical excitability and short-interval intracortical inhibition (SICI) during performance of a simple index finger abduction task. Methods: Subjects responded to subtle cutaneous electrical stimulation delivered to the index finger while single and paired TMS pulses were delivered during muscle relaxation between successive responses. In Experiment 1, attentional resources allocated to the task were manipulated using a dual task paradigm involving a backward-counting task. In Experiment 2, spatial attention was varied by delivering cutaneous stimuli to the responding or the non-responding index finger. Results: In Experiment 1, SICI was reduced during performance, but was unaffected by variation in the intensity of attention. The results of Experiment 2, however, showed that SICI was significantly lower when attention was directed to the responding hand compared with when it was directed to the non-responding hand. Conclusions: While SICI was not affected by variation of attentional resources, it was influenced by spatial attention. Significance: These findings may be relevant in future investigations of the underlying neurophysiology of plasticity.  2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Intracortical inhibition; Spatial attention; Transcranial magnetic stimulation

1. Introduction Previous studies (Johansen-Berg and Matthews, 2002; Noppeney et al., 1999; Rosenkranz and Rothwell, 2004; Rowe et al., 2002) have suggested that the allocation of attention to sensory stimulation and movement influences cortical activity. Attention is thought to have several dimensions including, but not restricted to, direction or focus of attention (spatial attention), and intensity or effort, described in terms of attentional resources (Summers and Ford, 1995). A TMS study by Rosenkranz and Rothwell (2004) showed that by manipulating the allocation of spatial attention, short-interval intracortical inhibition (SICI) levels could be modulated. This extended their previous finding (Rosenkranz and Rothwell, 2003) that both cortical excitability and SICI were *

Corresponding author. Tel.: +61 3 6226 2204; fax: +61 3 6226 2883. E-mail address: [email protected] (M.I. Garry).

affected during the application of short-duration (1-2 s) muscle vibration. Vibration of the target (homotopic) muscle increased motor-evoked potential (MEP) amplitudes and decreased SICI; the opposite pattern was seen when a neighboring (heterotopic) muscle was vibrated. Rosenkranz and Rothwell (2004) showed that these effects were modified by a 15-min intervention of phasic, simultaneous vibration of two muscles, but the nature of the modification depended on whether attention was allocated to the vibration stimuli. In one condition (passive), subjects did not attend to the vibration stimuli, and either read or listened to music. In another condition (attention), subjects actively attended to the vibration to detect changes in vibration frequency of either muscle. Following the passive condition, the effects of homotopic and heterotopic vibration were reduced. By contrast, the homotopic effect was unchanged following the attention condition while the heterotrophic effect was reversed, such that it now resembled the homotopic effect.

1388-2457/$32.00  2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2007.09.060

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The finding that SICI can be influenced by attention suggests the possibility that SICI circuits, which utilize the inhibitory neurotransmitter GABA (camino-butyric acid), may be a primary target of attentional processes. This may also shed light on a possible SICI mechanism for the modulatory influence of attention upon cortical plasticity suggested by Stefan et al. (2004). If correct, this hypothesis has implications for interventions designed to induce plasticity and promote motor learning, as both are dependent on the GABAergic system (Butefisch et al., 2000). However, it remains unknown how SICI is affected during task performance by manipulations of attention, and whether variations of intensity and direction of attention are equally important. The hypothesis tested in the following studies was that variation of both the intensity and direction of attention can influence SICI and that this influence can be observed during the performance of a motor task. We suggest that since SICI plays a critical role in the induction of use-dependent plasticity in the motor cortex (Butefisch et al., 2000), it could be that the attentional influence on plasticity described by Stefan et al. (2004) may be explained by a SICI mechanism. In the present study, two experiments were conducted to investigate the influence of attentional processes on SICI to the first dorsal interosseous muscle (FDI) during performance of a simple, sensorimotor task. In both experiments subjects performed ballistic abduction movements of the index finger in response to subtle cutaneous stimuli applied to the same finger (Experiments 1 and 2) or to the index finger of the opposite hand (Experiment 2). SICI was examined during task performance in the period between successive responses while the target muscle was at rest. In Experiment 1 we investigated the effect of varying the intensity of attention on SICI by asking subjects to perform the motor task either alone (singletask) or while concurrently performing a backwardcounting task (dual-task). Consistent with dual-task theory (Pashler, 1992), we assumed the dual-task condition would reduce the intensity of attention to the motor task via allocation of attentional resources to the counting task. We hypothesized that SICI would be lower in the single-task condition when there was a greater intensity of attention to the motor task. In Experiment 2 we investigated the role of direction of attention on SICI by asking subjects to respond to stimuli applied to either the target finger (the finger from which MEPs were recorded) or the opposite finger. In a subset of subjects, we also examined SICI when the response was performed by the opposite finger. It was hypothesized that SICI would be lower when attention was directed to the target hand compared with when attention was directed to the opposite hand. Whereas previous studies (Rosenkranz and Rothwell, 2004; Stefan et al., 2004) examined excitability before and after the attention task, in the present study excitability was examined while attention was actively engaged. This allowed greater insight into the sensitivity of SICI circuits to attentional processes online.

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2. Methods 2.1. Subjects Experiment 1 tested 15 healthy right-handed subjects (9 females, mean age = 28 years, range = 18-60 years) and Experiment 2 tested 10 healthy subjects (6 females, 3 lefthanded, mean age = 22 years, range = 18–32 years). All participants were recruited from the university population and handedness was determined by asking them which hand they used to write with. The experimental procedures conformed to the Declaration of Helsinki and were approved by The Southern Tasmanian Social Sciences Ethics Committee. All participants gave written informed consent. 2.2. EMG and transcranial magnetic stimulation EMG activity was recorded continuously from Ag/AgCl surface electrodes placed over the FDI muscle in a bellytendon montage. The EMG signal was amplified (1000·), bandpass filtered (20–2000 Hz), and then sampled at 5 kHz. Data were stored on a computer hard-disk for offline analysis. TMS was applied using a 90-mm circular coil connected to two Magstim 200 magnetic stimulators via a BiStim module (Magstim, Whitland, Dyfed, UK). This type of coil has been used in numerous studies to examine cortical excitability and SICI (Chen et al., 1998a; Garry et al., 2004; Quatrale et al., 2003; Tinazzi et al., 2003; Trompetto et al., 1999; Zanette et al., 2004; Zoghi et al., 2003). In addition, it is easier to maintain a stable position using a circular coil in comparison with a figure of eight coil (Orth et al., 2003). The magnetic coil was oriented tangentially to the scalp with the appropriate side up to preferentially stimulate the hemisphere contralateral to the subject’s dominant hand (‘‘A’’ side up for right hand and ‘‘B’’ side up for left hand). Optimal coil location was identified by initially placing the coil at the vertex and then moving it in small steps until the site which consistently yielded the largest MEPs in the FDI muscle was found using a moderately suprathreshold intensity. This location was marked on the scalp with a felt-tip pen to allow consistent coil placement during the experiment. Resting motor threshold (rMT) was defined as the minimal TMS intensity needed to evoke an MEP in the FDI of the dominant hand that was larger than 50 lV in three of five consecutive trials (Garry et al., 2004). To assess SICI, the two Magstim stimulators were configured to deliver paired pulse stimulation with an interstimulus interval (ISI) of 3 ms (Kujirai et al., 1993). The intensity of the test TMS was adjusted to elicit an MEP of approximately 1 mV peak-to-peak in the resting FDI muscle. The intensity of the conditioning stimulus was initially set at 70% of resting motor threshold (rMT) and adjusted upward or downward until the MEP was suppressed by at least 50% though still present on every trial. This was done to avoid a ceiling effect and ensure

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maximum sensitivity for detecting a release of SICI (Stinear and Byblow, 2003). This procedure resulted in more than 50% suppression in most subjects. Average conditioning stimulus intensity was 69 ± 2% of rMT while the test stimulus was 126 ± 2%. Some studies of SICI have found that estimates of SICI can vary with the size of the test MEP (Chen et al., 1998a). On this basis many studies adjust the intensity of the test TMS across conditions if there are changes in test MEP amplitudes. However, in line with a recent study (Coxon et al., 2006) we opted to maintain a constant test intensity across conditions, rather than a constant MEP size, as the dynamic nature of the tasks made matching test MEP size extremely difficult. There is a considerable body of literature indicating that SICI is unaffected by variations in test MEP amplitudes in the 1–4 mV range (Daskalakis et al., 2002; Ridding et al., 1995; Roshan et al., 2003; Sailer et al., 2002; Sanger et al., 2001). Indeed, a number of studies have reported that where differences in test MEP amplitude have occurred, matching MEP sizes makes no difference to estimates of SICI (Rosenkranz and Rothwell, 2003; Rosenkranz et al., 2005). Average test MEP amplitudes for each condition are reported in the Results section and since they are within this 1–4 mV range, it is unlikely that differences in SICI reported in this study are a consequence of changes in test MEP amplitude. 2.3. Cutaneous stimulation In both experiments, subjects responded to subtle cutaneous stimuli delivered to the posterior surface of the middle phalange of the index finger via Ag/AgCl surface electrodes. The purpose of using cutaneous stimuli was to ensure that attentional processes were directed to the sensorimotor system. In Experiment 1, stimuli (5 ms duration) were delivered using a custom built battery powered electrical stimulator. In Experiment 2, stimuli (2 ms duration) were delivered using a Digitimer DS7A constant-current stimulator. The intensity of stimulation was adjusted relative to perceptual threshold, which was determined using the following procedure. Beginning from an initially subthreshold intensity, stimuli were delivered at random intervals of 2–6 s and subjects were instructed to respond by briskly abducting the index finger whenever a stimulus was detected. Intensity was gradually increased until the lowest intensity at which subjects successfully responded to five consecutive pulses was identified. This was defined as the perceptual threshold (PT). The stimulator output was set to 120% of this perceptual threshold. This intensity was chosen to ensure that continuous monitoring of the index finger would be required to detect the stimuli; continuous monitoring may not be necessary if strong stimulus intensities (e.g. 3· perceptual threshold) are used since stimuli at these intensities may ‘capture’ attention directly. Second, low stimulus intensities minimized the possibility that SICI would be directly affected by the cutaneous stimulation. Previous studies have reported reduced SICI with

strong (2–3· perceptual threshold) cutaneous stimuli (Kobayashi et al., 2003; Ridding et al., 2005) but not with low stimulus intensities (e.g. perceptual threshold) (Ridding et al., 2005). 2.4. Procedure 2.4.1. Experiment 1 Subjects were seated in a comfortable chair with hands laid flat on arm-rests, palms down with the arms semiflexed and elbows at approximately 90. Each condition consisted of a single trial in which cutaneous stimuli were delivered at random intervals (2–7 s) to the index finger of the dominant hand. In each trial, a total of 10 single and 10 paired TMS pulses were applied at intervals of approximately 5–7 s1 with the restriction that the TMS pulse was delivered at least 1800 ms following and 1200 ms before the next stimulus (Fig. 1a). This was included to minimize possible effects of both the previous response on corticospinal excitability and motor threshold (Chen et al., 1998b; Zaaroor et al., 2001, 2003), as well as the stimulus itself. The following four conditions were examined. (1) BASE: Baseline, no cutaneous stimuli were delivered and subjects remained at rest; (2) STIM: cutaneous stimuli were delivered but subjects were not required to attend to the stimuli or respond. This condition was used to determine whether the stimuli alone effected cortical excitability; (3) SINGLE: In this condition subjects attended to the stimuli and responded by performing a brisk abduction of the index finger; (4) DUAL: This condition was similar to SINGLE condition, but subjects were additionally required to perform a concurrent, backward-counting cognitive task. This task was chosen based on previous research (Johansen-Berg and Matthews, 2002), but instead of counting backwards in 3 s, subjects counted backwards in 7 s to increase the difficulty and maximize the intensity of attention allocated to the cognitive task. This was further ensured by instructing subjects to prioritize the cognitive task. Trial order was randomized across subjects and one practice block was given for conditions SINGLE and DUAL to ensure full understanding of task requirements. 2.4.2. Experiment 2 In Experiment 2 we examined whether cortical excitability and SICI were sensitive to variations of spatial attention. To achieve this, subjects performed a task similar to the SINGLE task in Experiment 1 (i.e., they responded to cutaneous stimuli by abducting the index finger of the dominant hand). However, in one condition the cutaneous stimuli were delivered to the responding hand, while in a second condition they were delivered to the contralateral (non-responding) hand. Thus, while the motor component 1

Not all cutaneous stimuli were followed by a TMS pulse, thus the range of interstimulus intervals for cutaneous stimuli and TMS were not identical.

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Fig. 1. (a) Experiment 1, timing diagram for cutaneous stimulation and TMS. TMS was delivered at least 1.8 s after and a minimum of 1.2 s before a cutaneous stimulus. Either one or two stimuli were delivered in between TMS pulses. (b) Experiment 2, timing diagram for TMS and cutaneous stimulation. TMS was delivered either 0.5 or 1 s after applied force returned to baseline. Cutaneous stimuli were delivered at intervals of 5–7 s.

of the two conditions was identical, the attention component of the task was varied. As in Experiment 1, TMS was delivered in the interval between responses; however, in this case TMS was triggered a fixed time following the response (Renner et al., 2005). This was done by having subjects abduct the index finger against a force transducer and triggering the TMS 1000 ms after the force signal returned to baseline levels. When electromechanical delay is taken into account (Fig. 1b), TMS at this latency was well-outside the postresponse period known to affect excitability (Chen et al., 1998b). All subjects performed two trials in each of three conditions. BASE: Baseline. Subjects were at rest and no cutaneous stimuli were delivered. The other two conditions were distinguished on the basis of which of the two components of the task, attention and movement, was allocated to the hand that was the target of TMS (i.e., dominant hand). Prior to each condition, subjects were informed as to which hand would receive the cutaneous stimuli. In the BOTH condition, the target hand executed the response and attention was directed to the same hand via delivery of the cutaneous stimuli. In the RESPOND condition the target hand again executed the response, but attention was directed to the contralateral hand via delivery of the cutaneous stimuli in between movement responses to that hand. In both conditions, the timing of the TMS allowed for corticospinal activity to be assessed while the subjects were attending to the upcoming stimulus following a movement. The order

of latter two conditions was counterbalanced across subjects. In a subset of seven subjects we also examined cortical excitability when the response was performed by the contralateral hand and at an earlier time following the response (500 ms) when response-related effects on excitability might still be present (Chen et al., 1998b). In addition to the BOTH and RESPOND conditions, two other conditions were included. Consistent with the previous conditions, these additional conditions were defined based on the target hand’s (for TMS) role in the task. In the ATTEND condition, attention was directed to the target hand, while the response was performed by the contralateral hand. In the NONE condition, the target hand had no role in the task; attention was directed to the contralateral hand and the same hand also executed the response. In all seven subjects single and paired-pulse TMS were delivered at both 1000 and 500 ms post-response. Two further conditions were included to assess whether cutaneous stimuli alone had an effect on SICI. In the STIM_TARGET condition, cutaneous stimuli were delivered to the target hand, but subjects were not required to attend or respond to these stimuli. In the STIM_CONTRA condition, stimuli were delivered to the contralateral hand. These latter two conditions and the BASE condition were performed at the start of the experiment to ensure that subjects did not learn to associate the stimuli with the generation of a response, which might then require active suppression.

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2.5. EMG recording MEP size was measured by calculating the maximum absolute value from 20 ms post-TMS to 100 ms postTMS. MEPs were discarded if the root mean square (RMS) EMG exceeded 15 lV (Carson et al., 2004) during the 40 ms immediately preceding the TMS pulse. In Experiment 1, one subject’s data was discarded as 80% of MEPs in two conditions were rejected. Further three subjects had a maximum of three MEPs rejected. In Experiment 2, one subject had 50% of MEPs rejected in a single condition. 2.6. Data analysis As MEPs are known to have high intra-individual variability, median MEP size was chosen as the measure of central tendency (Garry et al., 2005; Hajcak et al., 2007; Hammond et al., 2004; Hammond and Garvey, 2006; Hammond and Vallence, 2006; Hasbroucq et al., 1999; Izumi et al., 1995; Kiers et al., 1997). For consistency, medians were also used as the measure of central tendency for all other variables. SICI was calculated according to the formula 100 (1 (paired MEP/test MEP)). From this formula, larger values indicate greater SICI (Stinear and Byblow, 2003). In Experiment 1, response times to cutaneous stimuli were used as a behavioral index of allocation of attention to the motor task. This time was defined as the interval between the presentation of a stimulus and the onset of EMG activity in the responding FDI (defined as exceeding a threshold of 110% of resting EMG activity). Each response onset was visually inspected and readjusted if necessary. 2.7. Statistical analysis Prior to analysis, test MEP amplitudes were normalized to the largest median MEP in all conditions. Repeated measures ANOVAs were used for all analyses. The Huynh Feldt correction was used to adjust for violations of sphericity. Where indicated by a significant F-value, post-hoc pairwise comparisons were carried out using Tukey’s HSD. In all figures error bars are presented as standard error of the mean (SEM).

Fig. 2. Experiment 1: (a) Single MEPs were larger in the DUAL condition than the baseline (BASE) and cutaneous stimulation only (STIM) conditions. This difference was not evident for the SINGLE condition. (b) SICI was lower in the two movement conditions (SINGLE and DUAL) compared with the non-movement conditions (STIM and BASE). Intensity of attention (SINGLE vs. DUAL) did not elicit any significant effect on SICI. There was no significant effect of cutaneous stimuli alone on SICI. Error bars, SEM.

motor task was reduced when concurrent performance of the backward-counting task was required.

3. Results 3.1. Experiment 1 3.1.1. Response times Repeated measures ANOVA on response times showed a significant main effect of Condition, F(1, 9) = 15.0, p < 0.005. Consistent with dual-task theory, response times in the DUAL condition (381 ± 70 ms) were significantly longer than in the SINGLE condition (275 ± 24 ms). This indicates that the intensity of attention allocated to the

3.1.2. Cortical excitability ANOVA showed a significant main effect of Condition: F(3, 42) = 5.0, p < 0.005. Overall, MEPs were larger in the two movement conditions (SINGLE, DUAL) in comparison with the non-movement conditions (STIM and BASE) (Fig. 2a). Post-hoc comparisons revealed that this was significant for the DUAL condition, but not for the SINGLE condition. The STIM and BASE conditions did not differ significantly indicating no effect of the cutaneous stimuli on MEP size. Average peak-to-peak amplitudes of BASE,

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STIM, SINGLE, and DUAL were 1.65, 1.87, 2.30, and 2.72 mV, respectively. 3.1.3. SICI There was a significant main effect of Condition on SICI: F(2.5, 35.0) = 11.9, p < 0.001 (Fig. 2b). Post-hoc comparisons demonstrated that both movement conditions (SINGLE, DUAL) had significantly less SICI than the non-movement conditions (STIM, BASE). However, SICI did not differ between the DUAL and SINGLE conditions. SICI did not differ between the BASE and STIM conditions indicating no effect of the cutaneous stimuli alone on SICI. 3.2. Experiment 2 As our main interest was whether varying direction of attention would affect excitability when the target hand was responding, the primary analysis was conducted on the data from the conditions BASE, BOTH and RESPOND for all 10 subjects. A secondary analysis was then performed on the subset of seven subjects in whom the ATTEND and NONE conditions were examined to further explore the effects of TMS latency and responding hand. 3.2.1. Primary analysis 3.2.1.1. Motor output. An analysis was conducted on the peak abduction force to determine whether there were differences in force output in the BOTH and RESPOND conditions. No significant difference was found: p > 0.1. Thus, any effects of condition on SICI and MEP amplitude could not be attributed to variations in motor output between conditions. 3.2.1.2. Cortical excitability. Repeated measures ANOVA showed a significant main effect of Condition (BASE, RESPOND, BOTH) at 1000 ms post movement: F(2, 18) = 4.1, p < 0.05 (Fig. 3a). Post-hoc comparisons revealed that the effect of Condition was due to a trend towards higher excitability in RESPOND (p = 0.055) and BOTH (p = 0.059) relative to baseline, consistent with the findings of Experiment 1. The difference between BOTH and RESPOND was not significant (p > 0.1) indicating that direction of attention had no effect on excitability. This is an important finding as it rules out the possibility that any differences in SICI between the two experimental conditions could be a consequence of differences in MEP size. Average peak-to-peak amplitudes of BASE, RESPOND, and BOTH were 1.44, 2.46, and 2.50 mV, respectively. 3.2.1.3. SICI. The main effect of Condition was significant: F(2, 18) = 16.9, p < 0.0001 (Fig. 3b). Post-hoc comparisons revealed that SICI was significantly lower during the BOTH condition compared with RESPOND and BASE. The difference between BASE and RESPOND was non-

Fig. 3. Experiment 2: Primary analysis, (a) the increase in single MEP size from baseline during the response conditions was marginally significant. However, direction of attention had no effect on MEPs. (b) SICI was significantly ( ) lower when attention was allocated to the responding hand (BOTH) compared with when it was allocated to the contralateral hand (RESPOND). Only the BOTH condition differed significantly from baseline (*). Error bars, SEM.

significant. These results indicate that reduced SICI in the movement conditions was not solely a result of response generation. Instead, SICI depended in part on whether the responding hand was also the target of attention. 3.2.2. Secondary analysis 3.2.2.1. Cortical excitability. There was no effect of latency (500, 1000 ms): F(1, 6) = 1.1, p > 0.1. However, there was a main effect of Condition (BASE, NONE, ATTEND, RESPOND, BOTH): F(2.6, 15.6) = 4.0, p < 0.05 and an interaction between Condition and Latency: F(3.1, 18.3) = 4.3, p < 0.02 (Fig. 4a). To explore the interaction, separate

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Fig. 4. Experiment 2: Secondary analysis, (a) comparison of normalized single MEP amplitudes between conditions and latencies. At 500 ms, there was a significant elevation in MEP size (*) from BASE and NONE during the BOTH condition. There was no significant effect of Condition at 1000 ms. (b) At 1000 ms post-movement, SICI was significantly reduced from baseline when attention was directed to the target hand (BOTH, ATTEND), regardless of whether a response was required. When the target hand executed the response, SICI was significantly ( ) lower when attention was also directed to that hand (BOTH) compared with when attention was directed to the contralateral hand (RESPOND). SICI was also significantly ( ) lower in the BOTH condition than the NONE condition. At 500 ms SICI was significantly reduced from baseline only when the target hand executed a response (BOTH, RESPOND). Asterisks indicated significant difference from baseline. Error bars = SEM.

one-way ANOVAs were conducted to examine the effects of Condition at each Latency. The effect of Condition was not significant at 1000 ms: F(2.8, 16.6) = 2.2, p > 0.1; however, it was significant at 500 ms: F(3.5, 21.2) = 6.1, p < 0.005. MEPs tended to be larger when the target hand was responding (BOTH, RESPOND) compared with the other conditions (ATTEND, BASE, NONE). Post-hoc comparisons revealed that MEPs were significantly larger during the BOTH condition relative to BASE and NONE. The difference between the RESPOND condition and BASE was marginally significant (p = 0.07). Again, the difference between RESPOND and BOTH conditions was not significant. Thus, any differences in SICI between those conditions cannot be

accounted for by differences in MEP size. Average peak-topeak amplitudes of BASE, NONE, ATTEND, RESPOND, and BOTH at a latency of 500 ms were 1.57, 1.47, 2.38, 2.86, and 3.65 mV; and at a latency of 1000 ms were 1.48, 1.79, 1.88, 2.73, and 2.87 mV, respectively. 3.2.2.2. SICI. There was no significant main effect of Latency: F(1, 6) = 5.9, p > 0.05. However, the main effect of Condition: F(2.9, 17.4) = 6.2, p < 0.005 and the Condition by Latency interaction were significant: F(4, 24) = 5.0, p < 0.005 (Fig. 4b). To explore the interaction, separate one-way ANOVAs were conducted to examine the effects of Condition at each Latency. At 1000 ms, the effect

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of condition was significant: F(4, 24) = 6.8, p < 0.001. SICI was significantly reduced relative to baseline only when attention was directed to the target hand (BOTH, ATTEND), regardless of whether the target hand executed the motor response. Again, SICI was lower when attention and response were allocated to the target hand (BOTH) compared with when the target hand only executed the response (RESPOND). It is worth noting that the BOTH and NONE conditions had the lowest and highest SICI, respectively, among the four response conditions, and that the difference between them was significant. While the BOTH condition requires generation of a response and allocation of attention with the same hand, neither is required in the NONE condition. That these are the two most extreme conditions in terms of SICI suggests that both response generation and direction of attention affect SICI. The effect of Condition was also significant at 500 ms: F(2.5, 14.7) = 5.4, p < 0.05, though the pattern of SICI was somewhat different. Post-hoc comparisons revealed that SICI was lowest when the target hand executed the response (BOTH, RESPOND) in comparison with the baseline condition. There was a trend (p = 0.051) towards lower SICI in the RESPOND condition compared to when attention was directed to the non-moving hand (ATTEND). There was also a trend (p = 0.09) towards lower SICI in the NONE condition compared to Baseline. Unlike the results at 1000 ms, however, direction of attention had no effect on SICI in these conditions. 3.2.2.3. Cutaneous stimulation. There was no significant main effect of Condition (STIM_TARGET, STIM_CONTRA) on SICI: F(1, 6) = 3.8, p > 0.1 and no significant main effect of Latency: F(1, 6) < 1, p > 0.1 or interaction between Condition and Latency: F(1, 6) = 1.6, p > 0.1. There was also no significant main effect of Condition on cortical excitability: F(1, 6) < 1, p > 0.1 and no significant main effect of Latency: F(1, 6) = 3.2, p > 0.1 or interaction between Condition and Latency: F(1, 6) = 2.5, p > 0.1. Therefore, any differences in SICI or MEPs cannot be explained by the presence of electrical stimulation. 4. Discussion In two experiments we examined the effect of attentional manipulations; specifically the intensity of attention (Experiment 1) and the direction of attention (Experiment 2), on cortical excitability and SICI while attention was actively engaged for the performance of a simple motor task. The results from Experiment 1 did not provide any evidence that SICI is sensitive to variations in the intensity of attention. In contrast, Experiment 2 revealed a sensitivity of SICI to variations in the direction of attention. However, this effect was visible only when SICI was probed a sufficiently long time after the response. These results are discussed below.

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4.1. Experiment 1 MEPs measured in the two movement conditions (SINGLE and DUAL) were higher than in the non-movement conditions (BASE and STIM). This is consistent with two previous studies that investigated cortical excitability 1 s post-movement (Renner et al., 2005; Schubert et al., 2004). However, contrary to the present results, those studies did not find evidence of accompanying disinhibition. This may be explained by differences in the allocation of spatial attention between the two tasks that will be discussed later. Instead, they found an increase in intracortical facilitation (ICF) at this post-movement latency and concluded that facilitatory circuits were responsible for the increase in cortical excitability (Renner et al., 2005). Based on those results and previous research, they suggested that the circuits operated independently of the inhibitory circuits. It is difficult to conclude from our data whether the post-movement increase in cortical excitability is solely due to the reduction in intracortical inhibition or if facilitatory circuits are also responsible since we did not measure ICF. It should also be mentioned that cortical excitability was significantly elevated from baseline levels only during the performance of the dual task, not during the single task. This increase may have resulted from the counting task itself (Andres et al., 2007) or it may be due to an increase in general arousal resulting from the addition of the secondary task. Response times in the DUAL condition were significantly prolonged relative to the SINGLE condition, consistent with a reduced intensity of attention to the motor task (Temprado et al., 2002). Despite this behavioral effect of variation of intensity of attention, no difference in SICI was found between the SINGLE and DUAL conditions, thus there is no evidence that variation in the intensity of attention allocated to the motor task can modulate SICI. However, for both conditions SICI was reduced relative to baseline indicating that excitability of SICI circuits was affected by some aspect of the task. This suggests the effect on SICI was due to a factor common to both conditions. We will consider the following three possibilities. (1) The reduction of SICI was a consequence of the cutaneous stimulation that was present in both conditions. (2) The reduction of SICI was a consequence of the response. (3) The reduction of SICI was a consequence of spatial attention directed to the responding hand. The first possibility can be immediately rejected as neither MEP amplitude nor SICI differed from baseline in the STIM condition. However, the second and third alternatives are both plausible, and not necessarily mutually exclusive. Previous research has reported a modulation of cortical excitability in the period following a muscle contraction, though this finding is somewhat inconsistent. Chen et al. (1998b) found that MEP amplitudes were increased 200 ms after a contraction, but decreased from 500 to 1000 ms following a contraction. By contrast, Renner et al. (2005) found increased MEP amplitudes 1 s after

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completion of a wrist extension movement and, importantly, no effect on SICI. In our study, TMS was applied a minimum of 1.8 s after the stimulus. When the response time (400 ms in the DUAL condition) and duration of the EMG burst are taken into account, the time of TMS delivery was at least 1 s after the muscle contraction. It therefore seems unlikely that the reduction of SICI we observed could be accounted for solely by the preceding response. The third alternative, that SICI was influenced by spatial attention directed to the responding hand, is plausible since during both the SINGLE and DUAL conditions, index finger movements were cued by stimuli applied to the finger thus requiring attention to be directed to the sensorimotor system of the index finger in order to successfully perform the task. Although it does not seem that the intensity of attention devoted to the task modulated SICI, it may be that SICI was affected by processes associated with directing attention to the hand. Previous studies are in line with this possibility. Liepert et al. (1998) asked subjects to perform simple, repetitive thumb movements. SICI was measured in muscles acting on the little finger before and after the thumb movement task. In one condition the movements were performed without explicitly directing attention to the little finger. In a second condition, subjects were explicitly instructed to relax the finger during exercise; a condition that required directing attentional processes to the little finger. The two conditions had a differential effect on SICI in the little finger, suggestive of a role for attention on SICI. Further evidence is found in a study by Renner et al. (2005). In that study, subjects initiated simple wrist extension movements in response to an auditory stimulus presented intermittently at 5 s intervals; MEPs and SICI were measured 1 second after the end of the movement. Similar to the present results, MEP amplitudes were increased relative to rest, however, SICI was unchanged. The lack of modulation of SICI may reflect the fact that in that study, subjects performed movements in response to an external stimulus and therefore did not need to direct attention to the sensorimotor system to perform the task, attention was allocated to the visual system in order to attend to the next stimulus. The change in SICI we observed might reflect processes associated with directing attention to the hand. The second study addressed this possibility. 4.2. Experiment 2 By varying the locus of attention, we were able to tease out a modulatory effect of attention on SICI. For the primary analysis of all 10 subjects, the condition in which attention was allocated to the responding hand (BOTH) was equivalent to the SINGLE condition in Experiment 1, and a similar reduction in SICI from baseline was observed. The allocation of attention to the hand when coupled with movement (BOTH) resulted in reduced SICI.

When attention was allocated away from the responding hand to the opposite hand (RESPOND), SICI levels did not differ from baseline, suggesting that attention, and not simply the motor response, was the dominant modulatory influence on SICI at long post-response latencies. Thus, differences in direction of attention in the BOTH and RESPOND conditions resulted in significantly different levels of SICI. This is further supported by the fact that MEP amplitudes were nearly identical, though increased relative to baseline, in these conditions. It therefore seems unlikely that the difference in SICI could be accounted for by differences in excitability at either the cortical or spinal levels. The effect of direction of attention on SICI may in part be due to whether the ipsilateral or contralateral sensory cortex monitors the cutaneous stimuli. The BOTH and RESPOND conditions are identical in terms of which M1 executes the motor response. However, in the BOTH condition it is the ipsilateral sensory cortex that monitors the cutaneous stimuli, while in the RESPOND condition this role is handled by the contralateral sensory cortex. From this perspective the present results suggest that SICI is lower when the task requires ipsilateral sensory and motor areas (BOTH) relative to when contralateral sensory and motor areas are involved (RESPOND). This could account for the lack of difference in Experiment 1 between the SINGLE and DUAL conditions as both conditions involved the ipsilateral sensory cortex. This result strongly suggests that the reduction in SICI observed in Experiment 1 in the movement conditions (SINGLE, DUAL) was not just an effect of movement itself, but also an effect of spatial attention to that movement. It is unlikely that cutaneous stimulation itself might be the modulatory factor since there was no difference in baseline SICI levels between the STIM_TARGET and STIM_CONTRA conditions. Furthermore, in Experiment 1 there was no difference between the BASE and STIM conditions. Finally, index finger abduction force did not differ between conditions so the observed effects on cortical excitability cannot be explained by changes in motor output (Floyer-Lea and Matthews, 2004). In the secondary analysis on the subset of 7 subjects, we measured MEPs at two latencies following movement, both inside (500 ms) and outside (1000 ms) the region in which the preceding movement has been shown to influence excitability (Chen et al., 1998b). It was hypothesized that attentional effects would be more salient and clearly visible at the longer latency, while movement effects would be the dominant influence at the shorter latency. The results are consistent with this view. When TMS was delivered at 1000 ms post-movement, the allocation of attention to the hand, either when coupled with movement (BOTH) or at rest (ATTEND), resulted in reduced SICI. A similar reduction of SICI from baseline in the BOTH condition was observed when TMS was delivered at 500 ms; however, in contrast to the 1000 ms data, a reduction was also seen in the RESPOND condition, consistent with persistent

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effects on SICI from the preceding motor response. Another possibility is that the movement itself required that attention be allocated to the responding hand, and this may still have been present at 500 ms, thus reducing SICI even in the RESPOND condition. However, given the simplicity of the movement and the known effects of preceding contractions on excitability (Chen et al., 1998b), this seems unlikely. Therefore the most parsimonious interpretation is that the effects of attention on SICI are most easily observed at long post-response latencies. SICI measured using the paired-pulse TMS paradigm is an indirect measure of the state of the GABAergic system (Kujirai et al., 1993). Motor learning and plasticity of M1 are known to involve this system as demonstrated by studies of the effects of the GABA agonist Lorazepam (Ziemann et al., 1996). It is thought that Lorazepam increases GABAergic inhibition in the motor system, preventing release of inhibition that is a necessary substrate for neural plasticity (Ziemann et al., 2001). Thus, if the allocation of attention has a modulatory effect on SICI, then it is possible that it could have a modulatory effect on motor learning and plasticity. Evidence for this is found in a study by Stefan et al. (2004) involving PAS induced plasticity. Allocation of spatial attention to the hand receiving the stimulation was required for a change in excitability of M1, and this change was not present if attention was allocated to the other hand. Our studies provide evidence that this manipulation of the direction of attention could be modulating plastic change in M1 by a SICI mechanism. Stefan et al. (2004) also demonstrated an absence of change in M1 excitability when attention was allocated to a cognitive task, a manipulation that could have affected intensity of attention. However, rather than interpreting the results of this component of the Stefan et al. study as the effect of varying the intensity of attentional resources allocated to the hand on plasticity, it may instead be demonstrating effects due to the presence or absence of spatial attention to the target hand. Subjects could allocate all their attention to the cognitive task since there was no additional requirement to attend to the stimulation delivered to the hand. The results of Experiment 1 did not demonstrate a modulation of SICI by the intensity of attention; however, there was a requirement for spatial attention to be directed to the hand in order to respond to the stimuli delivered throughout the performance of the cognitive task, a requirement that was not present in the PAS task. If the allocation of attention has the effect on SICI that our studies suggest, the absence of spatial attention could have modulated the SICI circuits in such a way as to raise SICI to levels unfavorable for the PAS paradigm to induce plasticity. The implications of an attentional influence on plasticity via a SICI mechanism may be far reaching. It is possible that the design of tasks with consideration of the direction of attention during their performance of these tasks may expedite rehabilitation following stroke and enhance motor learning. The importance of this is already implicitly

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acknowledged in some nerve or muscle stimulation studies, with subjects instructed to ‘‘attend to the stimulated hand’’ (Ridding and Taylor, 2001). The presence of the desired physiological changes may be dependent upon the change in SICI resulting from that attention. In summary, the principal finding of the two studies is that SICI is reduced by the allocation of spatial attention. No evidence was found supporting the hypothesis that varying the allocation of attentional resources has a modulatory effect upon SICI. Although the attentional resource allocation manipulations in Experiment 1 were demonstrated behavioraly by significant differences in response time, this did not manifest as an observable change in cortical excitability or intracortical inhibition. Overall, the results demonstrate that the allocation of spatial attention is a factor in the modulation of SICI agreeing with previous studies (Rosenkranz and Rothwell, 2004) and importantly confirming that these attentional effects impact on SICI continuously throughout the task. The demonstrated modulatory effect of spatial attention on SICI may be relevant in future investigations of the underlying neurophysiology of plasticity as well as pathologies involving intracortical inhibition such as focal dystonia. Acknowledgements This research was supported by a grant from the Australian Research Council (DP0451217). We also thank three anonymous reviewers for their helpful comments. References Andres M, Seron X, Olivier E. Contribution of hand motor circuits to counting. J Cogn Neurosci 2007;19:563–76. Butefisch CM, Davis BC, Wise SP, Sawaki L, Kopylev L, Classen J, et al. Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci USA 2000;97:3661–5. Carson RG, Riek S, Mackey DC, Meichenbaum DP, Willms K, Forner M, Byblow WD. Excitability changes in human forearm corticospinal projections and spinal reflex pathways during rhythmic voluntary movement of the opposite limb. J Physiol 2004;560:929–40. Chen R, Tam A, Butefisch C, Corwell B, Ziemann U, Rothwell JC, et al. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol 1998a;80:2870–81. Chen R, Yaseen Z, Cohen LG, Hallett M. Time course of corticospinal excitability in reaction time and self-paced movements. Ann Neurol 1998b;44:317–25. Coxon JP, Stinear CM, Byblow WD. Intracortical inhibition during volitional inhibition of prepared action. J Neurophysiol 2006;95:2271–83. Daskalakis ZJ, Christensen BK, Fitzgerald PB, Roshan L, Chen R. The mechanisms of interhemispheric inhibition in the human motor cortex. J Physiol 2002;543:317–26. Floyer-Lea A, Matthews PM. Changing brain networks for visuomotor control with increased movement automaticity. J Neurophysiol 2004;92:2405–12. Garry MI, Kamen G, Nordstrom MA. Hemispheric differences in the relationship between corticomotor excitability changes following a fine-motor task and motor learning. J Neurophysiol 2004;91:1570–8. Garry MI, Loftus A, Summers JJ. Mirror, mirror on the wall: viewing a mirror reflection of unilateral hand movements facilitates ipsilateral M1 excitability. Exp Brain Res 2005;163:118–22.

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