European Journal of Neuroscience, Vol. 40, pp. 2850–2858, 2014

doi:10.1111/ejn.12651

COGNITIVE NEUROSCIENCE

An unavoidable modulation? Sensory attention and human primary motor cortex excitability Diane Ruge,1 Neil Muggleton,2,3,4,5 Damon Hoad,1 Antonio Caronni1 and John C. Rothwell1 1

Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, 33 Queen Square (Box 146), London WC1N 3BG, UK 2 Institute of Cognitive Neuroscience, University College London, London, UK 3 Institute of Cognitive Neuroscience, National Central University, Jhongli, Taiwan 4 Laboratories for Cognitive Neuroscience, National Yang-Ming University, Taipei, Taiwan 5 Department of Psychology, Goldsmiths, University of London, London, UK Keywords: attention, cognition, cortex, human, motor control

Abstract The link between basic physiology and its modulation by cognitive states, such as attention, is poorly understood. A significant association becomes apparent when patients with movement disorders describe experiences with changing their attention focus and the fundamental effect that this has on their motor symptoms. Moreover, frequently used mental strategies for treating such patients, e.g. with task-specific dystonia, widely lack laboratory-based knowledge about physiological mechanisms. In this largely unexplored field, we looked at how the locus of attention, when it changed between internal (locus hand) and external (visual target), influenced excitability in the primary motor cortex (M1) in healthy humans. Intriguingly, both internal and external attention had the capacity to change M1 excitability. Both led to a reduced stimulation-induced GABA-related inhibition and a change in motor evoked potential size, i.e. an overall increased M1 excitability. These previously unreported findings indicated: (i) that cognitive state differentially interacted with M1 physiology, (ii) that our view of distraction (attention locus shifted towards external or distant location), which is used as a prevention or management strategy for use-dependent motor disorders, is too simple and currently unsupported for clinical application, and (iii) the physiological state reached through attention modulation represents an alternative explanation for frequently reported electrophysiology findings in neuropsychiatric disorders, such as an aberrant inhibition.

Introduction Clinical observation and self-reports of patients with movement disorders suggest that attention can act as a powerful modulator of motor symptoms. Some patients with task-specific musician’s dystonia, for example, train to be ‘unfocused’ while practising their instrument, because this technique might lead to improvement of symptoms during playing. There have been a large number of studies of the effects of attention on sensory systems. In general, they show that attention to a stimulus of a given modality that is presented at an expected location and time increases the activity evoked in the brain. This occurs mainly in the appropriate primary sensory area of the cortex, together with activity in frontoparietal association areas. The latter is seen during attention to any modality of sensation and may represent a control network for attentional focussing (Behrmann et al., 2004; Ptak, 2012). As a preventative method and for ‘healthy’ training of musicians, techniques of systematic variation of the locus of attention are used,

Correspondence: Dr D. Ruge, as above. E-mail: [email protected] Received 31 January 2014, revised 6 May 2014, accepted 8 May 2014

such as focussing on external (usually tactile) stimuli or diversion away from the fingers involved in the task to distant body parts such as the legs or feet (Loosch, 2004). In contrast to its positive effects on sensory function, attention to movement is often viewed as a negative factor. The sports training literature emphasizes the importance of the focus of attention; attention to movement itself (an ‘internal’ focus) may interfere with optimal performance, whereas attention to the consequences of the action (an ‘external’ focus) may be helpful (Wulf & Prinz, 2001). The same may be true in people with disorders of movement, for example task specific musician’s dystonia. A similar balance between types of attention has been proposed to occur during motor learning. It is a common experience that, if attention is diverted away from a task, learning is generally poorer (Song, 2009). However, excessive focus on the details of a task can be associated with poor performance (Nideffer, 1976) and perhaps even development of a task-specific movement disorder (McDaniel et al., 1989; Sachdev, 1992; Adler et al., 2005). It has been suggested that there are two distinct systems, an attentional (conscious control) and a non-attentional (subconscious) system, that operate during motor learning (Hazeltine et al., 1997; Blischke & Reiter, 2002), and that engaging both systems in the correct proportions

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

Sensory attention effects on motor cortex 2851 during training leads to efficient motor learning. Learning suffers when there is too much conscious attention to details of the task. A comparison of the activation patterns of healthy professional guitar players and those with task-specific dystonia demonstrated that, in healthy players, a switch between systems compatible with the two systems was far more balanced (Pujol et al., 2000). In healthy humans the impact of attention seems less obvious. There have been few investigations into the physiological consequences of attention on the motor system (see, for examples: Noppeney et al., 1999; Johansen-Berg & Matthews, 2002; Rowe et al., 2002; Thomson et al., 2008). Imaging studies have shown that directing attention away from movement to a secondary task reduces activation in secondary motor areas as well as in posterior regions of the primary motor cortex (M1). Consistent with this, transcranial magnetic stimulation (TMS) studies have shown conversely that attention to a hand muscle can increase the excitability of corticospinal output selectively to that muscle (Gandevia & Rothwell, 1987). Attention also affects excitability in intracortical connections. Focussing on the hand increases short-latency interactions in the motor cortex between sensory input from the hand and corticospinal output to the hand (short afferent inhibition protocol) (Kotb et al., 2005). Attention to the hand was also reported to modulate excitability in a separate set of circuits involved in intracortical inhibition [shortinterval intracortical inhibition (SICI)] (Thomson et al., 2008), although this was not confirmed by others (Conte et al., 2008). Synaptic plasticity involving precisely timed sensory inputs and motor outputs is also enhanced by attention to the hand (Stefan et al., 2004). The aim of the present study was to investigate the effects of attention on the motor cortex in greater detail. In particular, the modality and locus of attention in several of these previous studies have not been well defined even though these have been shown to be important factors in sensory tasks. We therefore studied the effect of sensory attention in two different modalities [vision (external focus) and touch (internal focus)] and different locations (skin areas on the hand dorsum) on corticospinal and corticocortical excitability in healthy humans. The results show that both the modality and location of attention change excitability in the M1.

Materials and methods Subjects Twelve healthy subjects (mean age 32.2 years, SD 3.8 years, four female) were studied in experiment series 1, and 12 healthy subjects (mean age 34.0 years, SD 5.27 years, four female) in experiment series 2. All subjects gave informed consent and the research was approved by the Research Ethics Committee of the Institute of Neurology. All experiments conformed to the Declaration of Helsinki. Overview of study design The study consisted of two main experiments (experiment series 1 and 2) (Fig. 1). For all parts of the experiments the hand was covered and for all non-visual parts of the experiments the monitor screen was covered. Series 1 had three parts. (A) A resting condition where the participant was instructed to be as relaxed as possible. No further instruction was given. (B) A condition where participants were instructed to pay attention to the hand in order to be able to recognize weak electrical cutaneous stimuli applied via electrodes attached to the hand. In this particular experiment, the electrical stimuli were given over the dorsum of the hand and at the same

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Fig. 1. Experimental design. Experiment series 1 had three main experiments, as follows. (A) A resting condition where the participant was instructed to be as relaxed as possible. In condition (B) the subject was instructed to detect rare and very weak electrical stimuli applied via electrodes attached to the hand. In this particular experiment, the electrical stimuli were given over the skin overlying the dorsum of the hand while at the same time TMS-evoked responses were recorded from the FDI muscle. In condition (C) the subject had to perform a visual attention task (conjunction task). For all three conditions, MEPs were recorded from the FDI muscle of the dominant hand. The output measures were SICI, ICF and MEPs. In experiment series 2, TMS-evoked responses were recorded from the FDI and ADM muscles simultaneously, whereas in condition (A) the subject had to detect rare and very weak electrical shocks given to the skin area overlying the heterotopic muscle (ADM) or in (B) the homotopic (FDI) muscle.

time TMS-evoked responses were recorded from the first dorsal interosseus (FDI) muscle. If subjects detected a stimulus or a series of stimuli, a verbal answer (‘One’ or ‘Three’) was given after the TMS pulses. (C) A condition where the participant performed a visual attention task (Fig. 2). For all three parts, the TMS output was recorded from the FDI muscle. Again, verbal answers were given after the end of the trial and recorded by one investigator. For all parts, no feedback was given to avoid learning effects. The output measures were motor evoked potentials (MEPs), SICI and intracortical facilitation (ICF). In experiment series 2, TMSevoked responses were recorded from the FDI and abductor digiti minimi (ADM) muscles; in one condition the participant had to detect weak electrical shocks given to the skin area overlying the ADM muscle and in the other condition to the skin area overlying the FDI muscle. Transcranial magnetic stimulation Subjects were seated comfortably in an armchair with their forearms resting on a pillow in front of them. The arm and hand muscles were relaxed throughout all experiments. TMS was performed using two MAGSTIM 200 stimulators connected by a Y-cable to a figure-of-eight-shaped coil with an external wing diameter of 9 cm (Magstim, Dyfed, UK). The coil was held with the handle pointing posteriorly and laterally at ~45° to the sagittal midline to evoke an

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858

2852 D. Ruge et al. anteriorly directed current in the brain. Magnetic stimuli were delivered at the optimal scalp site for evoking MEPs in the target muscles. Recording techniques Surface electromyography in a belly-tendon montage was recorded from the FDI muscle (experiment series 1) or the FDI and ADM muscles (experiment series 2). The raw signal was amplified and band-pass filtered from 20 Hz to 1 kHz (Digitimer Ltd). Signals were sampled using a CED Power 1401 interface (Cambridge Electronic Design, Cambridge, UK) at 5 kHz and stored for off-line analysis. Electrical stimulation Cutaneous skin stimulation was applied using two cup electrodes (0.4 cm diameter) placed ~2 cm apart over the skin area of the dorsum of the hand (series 1) or the FDI or ADM muscle (series 2). The cathode was placed proximally and the anode distally. Stimuli consisted of 1 ms electrical square-wave pulses delivered via a constant-current stimulator (DS7; Digitimer Ltd). The individual perceptual threshold (PT) was determined for each subject and skin stimulation was applied just above the threshold (1.1 PT). The PT was defined as the minimal stimulus intensity at which subjects were able to identify five out of five stimuli. The intensity was determined by using several series of stimuli of increasing and decreasing intensities from well below to well above the PT. None of the subjects considered an intensity of 1.1 PT to be painful. Such a low intensity was used to avoid direct ‘capture’ of attention by the stimulus and to assure that the attention task was sufficiently difficult. In the relevant experiments (see below), two different patterns of sensory stimulation were used, a single pulse and a series of three stimuli. Within the complete block that contained a total of 104 trials of randomly intermixed TMS pulses (double and single pulses), ~20% of trials contained sensory stimuli. These appeared randomly within the block. Trials containing electrical stimuli were excluded from off-line analysis of MEPs and intracortical excitability in order to eliminate an unlikely direct impact of the sensory input. However, previous studies have shown that only strong (2–3 9 PT) stimuli, but not around the PT, can change SICI (Kobayashi et al., 2003).

Stimulation protocol Series 1 Intracortical excitability was recorded using paired pulses as previously described (Kujirai et al., 1993) with a subthreshold conditioning pulse preceding a suprathreshold test stimulus. Four different interstimulus intervals (ISIs) were tested: 2 and 3 ms to evaluate SICI, and 12 and 15 ms to evaluate ICF. The first series of experiments was performed under three different experimental conditions: (i) at rest, (ii) during a block involving the detection of cutaneous electrical stimulation to a skin area on the dorsum of the hand, and (iii) during a block during which participants performed the visual attention protocol. The stimulus intensity of the test pulse was adjusted to 130% of the resting motor threshold, which is known to often produce an MEP of ~1 mV. The intensity of the conditioning stimulus was set at 80% of the active motor threshold. The active motor threshold was defined as the lowest intensity able to evoke an MEP of more than 200 lV during a minimal background contraction of 5–10% of the maximal voluntary contraction. The resting motor threshold was defined as the lowest intensity to evoke an MEP of more than 50 lV at rest. For each experimental condition, five randomly intermixed conditions were used (four double pulses presented 12 times each, single test pulses presented 20 times). The intertrial interval was ~5 s. For MEP recordings under different experimental conditions, 20 trials (at 130% resting motor threshold) per condition were recorded using single TMS pulses in series 1. As mentioned above for the cutaneous stimulation (attention-to-hand) condition, the TMS protocols included additional trials with electrical stimuli that occurred at random time points. This was to ensure that the number of trials that were not contaminated by electrical stimulation were equivalent to the rest condition and visual attention condition. Series 2 Somatotopy. We aimed to discover whether effects in the attentionto-hand condition had a somatotopic organization. In separate blocks (randomized order between participants), MEPs were recorded from the FDI and ADM muscles while electrical stimuli were applied over either the FDI or ADM muscle. For TMS we targeted an area where ideally MEPs in both the FDI and ADM muscles could be evoked. If it was not possible to record MEPs of equal size in both muscles, the FDI muscle was prioritized.

Visual stimulation The visual tasks were presented on the screen of a PC at a resolution of 1024 9 768 pixels (Fig. 2). The eye–monitor distance was ~57 cm. Vision was corrected by individual glasses if necessary. Head movement was unnecessary to see the target and only minimal gaze movements were required. Two different visual search tasks, conjunction (Fig. 2A) and feature (Fig. 2B), were used (series 1). The array was 660 9 660 pixels. Ten search elements were placed at random within a (not visible) 6 9 6 grid in this area, then jittered within the ‘square’ in which they were placed. The elements were 60 9 60 pixel red or blue diagonals. In the conjunction search, the distractors were red and blue diagonals in opposite orientations and the target was a blue diagonal pointing in the same direction as the red distractors. In the feature search, a blue diagonal was the target and only red distractors were present. The display duration was 700 ms and blue and red stimuli were isoluminant (~20 cd/m3 on the monitor). The target was present on 50% of the trials.

Control experiments Visual stimulation vs. visual attention This control experiment (n = 4) tested whether the effect on MEP amplitude and intracortical excitability during the visual attention task was purely caused by visual input rather than visual attentional processes. Participants were simply asked to sit in front of the monitor and look at it while it displayed the feature discrimination task. No instruction beyond this was given. Verbal response contamination? This control experiment (n = 5) explored whether the verbal response and speech production by the subject after the detection of cutaneous and visual stimuli had an impact on the output measures. Here the participants were not allowed to spontaneously report their

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858

Sensory attention effects on motor cortex 2853 answer to the investigator but had to report it after a ‘Go’ cue at ~2000 ms after the end of each trial.

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Effect of locus of attention on spinal excitability Here (n = 3) we tested whether the observed changes in MEP amplitude were accompanied by changes in spinal cord excitability. H-reflexes were elicited in the ADM and FDI muscles by transcutaneous electrical stimulation of the ulnar nerve at the elbow (single square-wave shock, 1 ms duration, frequency of stimulation 0.25 Hz). The intensity of stimulation was set to obtain H-reflexes of about 10% of the maximal motor response amplitude. Throughout the experiment, the amplitude of the M-wave was visually controlled for potential fluctuations in stimulus strength. For each experimental condition, i.e. the resting condition and the somatotopic version of the attend-to-hand task and the visual attention task, 20 trials for each condition were recorded and stored for off-line analysis. The peak-to-peak amplitude of each H-reflex was analysed off-line. The size of the conditioned responses (H-reflexes evoked in the attention tasks) was then expressed as a percentage of the size of control responses (H-reflexes evoked in the resting subject).

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Data analysis and statistics Single MEPs were measured from peak to peak and averaged. For SICI and ICF, the amplitude of the conditioned response was normalized to the amplitude of the unconditioned test MEP for each ISI. As participants had to pay attention continuously to be able to detect the rare electrical stimuli, the trials without electrical stimuli reflected excitability during focussed attention on different areas of the hand. Trials containing voluntary electromyographic activity were excluded from further analysis. The effect of the attention locus (baseline, attention to hand, visual attention) on MEP amplitudes (series 1) was examined using repeated-measures ANOVA with factors of Condition and ISI. For SICI and ICF, separate ANOVA s with Condition and ISI as a repeat factor were analysed. More detailed information is given in the Results. If appropriate, correction for multiple comparisons was used. For all experiments significance was set at P < 0.05.

Results Task performance The behavioural results showed similar values for the visual and the attention-to-hand tasks (correct answers: visual attention 87.77  6.5%; attention to hand, cutaneous stimulation above the FDI muscle area 92.48  1.7%; attention to hand, cutaneous stimulation above ADM area 93.32  2.0%), indicating similar difficulty for the two tasks and suggestive of similar levels of attentional demand. Experiment series 1 Motor evoked potentials: (external) visual attention changes motor evoked potential size in the primary motor cortex Figure 3(A) shows the MEP amplitude in the three blocks of trials (no attention, attention to hand, visual attention) as the difference between the two attention blocks and the no-attention block. An ANOVA on the MEP amplitudes (no attention, 1.2  0.1 mV;

Fig. 2. Visual tasks. (A) The attention task of the main experiment (series 1). The visual pattern in B was used for the ‘pure looking at’ control experiment. For B no instruction beyond ‘just look at’ was given to the participant.

attention to hand, 0.87  0.3 mV; visual attention, 1.87  0.2 mV) revealed a significant effect of Condition (F2,22 = 23.67, P < 0.001). Post-hoc analysis confirmed that visual attention significantly increased the MEP size compared with baseline (P < 0.001) and compared with attention to the hand (P < 0.005). Attention to the hand (at this location of the stimulus, i.e. the dorsum manum) did not significantly change the MEP size compared with baseline, although there was a trend (P = 0.06) towards suppression (Fig. 3). (External) visual attention reduces short-latency inhibition (shortinterval intracortical inhibition) in the primary motor cortex There was no difference in any condition between SICI measured at an ISI of 2 or 3 ms. Figure 3(B) shows the mean SICI in the three conditions as the difference between the two attention tasks and the baseline task, Figure 4 shows corresponding absolute values. Twoway ANOVA on the amount of SICI (in % unconditioned test MEP) (no attention: 2 ms, 54.1  8.6; 3 ms, 62.9  13.8; attention to hand: 2 ms, 62.1  15.2; 3 ms, 59.5  12.4; visual attention: 2 ms, 76.5  14.3; 3 ms, 78.1  12.4) revealed a significant main effect of Condition (F2,22 = 4.24, P < 0.05), no significant effect of ISI (F1,11 = 0.06, P > 0.5) and no significant interaction of both (F2,22 = 0.43, P > 0.5). Post-hoc analysis showed that SICI was less effective during visual attention both when compared with the baseline task (P < 0.05) and the attention-to-hand task (P < 0.05).

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Fig. 3. Experiment series 1. Attention effects on MEPs, SICI and ICF. (A) Visual attention enhances corticospinal excitability measured as MEPs. No significant effect, when compared with the resting condition, is evoked by attention to the hand when the subject is paying attention to the dorsum of the hand (na, non-attended) while TMS-evoked responses are recorded from the FDI muscle. (B) Visual attention has a significant effect and reduces SICI in the M1 compared with baseline (resting state) and compared with attention to the hand (dorsum manum). (C) Visual attention and attention to the hand had no significant effects on the effect of attention on ICF. Error bar represents  SEM. In addition, absolute scores are shown in Fig. 4. Asterisks indicate significance.

Fig. 4. Experiment series 1. Results as absolute values. This graph demonstrates the absolute values corresponding to the difference scores shown in Fig. 3. na, non-attended.

(External) visual and (internal) attention to the hand do not change intracortical facilitation in the primary motor cortex There was no difference in the amounts of ICF (in % unconditioned test MEP) at the two ISIs (no attention: 12 ms, 167.5  23.5; 15 ms, 163.2  20.8; attention to hand: 12 ms, 149.0  14.1; 15 ms, 146.2  18.4; visual attention: 12 ms, 159.1  24.1; 15 ms, 137.5  22.1). Figure 3(C) shows the level of ICF for our three conditions as the difference between the two attention tasks and the baseline task. Two-way ANOVA showed no effect of Condition, suggesting that ICF was not modulated by the attention tasks compared with the no-attention baseline, effect of condition (F2,22 = 0.99, P > 0.1), and effect of ISI (F2,11 = 2.63, P > 0.1). Experiment series 2 Locus of attention and somatotopy of corticospinal excitability This experiment tested whether the FDI/ADM muscle MEPs were modulated differently depending on the location of the cutaneous stimulus, i.e. the skin overlying one or the other muscle (Figs 5 and 6). Figure 5 shows the MEP size in the two muscles for each of the

Fig. 5. Experiment series 2. Somatotopy of attention: MEPs. The effect of locus of attention to different parts of the hand on corticospinal excitability measured as MEPs. The interaction between the MEP size and locus of attention is significant. If a subject pays attention to a specific part of the hand the MEP amplitude increases for the homotopic muscle relatively compared with the unchanged heterotopic muscle. Error bar represents  SEM. Asterisk indicates significance.

conditions, no attention (baseline), and attention to the skin above the FDI and ADM muscles as difference scores, Figure 7 as absolute values. A two-way ANOVA with Focus of attention (no attention, FDI and ADM) and Muscle (FDI vs. ADM) as repeat factors revealed a significant interaction (F2,22 = 4.09, P < 0.05), indicating that the locus of attention had different effects for the two muscles. FDI rest 1.12  0.06 mV; ADM rest 0.68  0.08 mV; FDI focus 1.42  0.2 mV; ADM no focus 0.68  0.1 mV; FDI no focus 1.05  0.12 mV; ADM focus 0.80  0.13 mV. Post-hoc one-way ANOVAs did not survive significance. This is illustrated in Fig. 5, where the

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858

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Fig. 8. Control experiment. Pure visual input does not change intracortical excitability. The left side of the graph shows SICI and ICF for the resting condition, and the right side shows the same measures while the subject has specific visual input that does not require specific attention. Error bar represents + SEM.

Change of locus of attention within a body part modulates short-latency inhibition (short-interval intracortical inhibition) Fig. 6. Somatotopy of attention: SICI and ICF. (A) SICI is significantly reduced in a heterotopic hand area compared with the resting state but also in relation to the homotopic excitability. (B) ICF does not change significantly, although a trend can be seen. Error bar represents  SEM. na, nonattended. Asterisks indicate significance.

To test for a somatotopic effect of Locus of attention (FDI homotopic, ADM heterotopic) on M1 excitability, separate two-way ANOVAs were performed for SICI and ICF. Although there was no significant effect of ISI (F1,11 = 5.42; P > 0.1), there was a significant effect of Locus (F2,22 = 5.42; P < 0.05). SICI (in % unconditioned test MEP) was significantly reduced for the non-attention TMS-stimulated muscle (FDI) compared with baseline and compared with the same muscle when attention was homotopic (rest, 63.66  7.07; FDI attention to the FDI area during FDI–TMS, 59.1  4.64; attention to the ADM area during FDI–TMS, 79.3  6.46). A two-way repeated-measures ANOVA for ICF (in % unconditioned test MEP) did not reveal any significant effects (Locus: F2,22 = 2.15, P > 0.1; ISI: F1,11 = 0.30, P > 0.5; rest: 157.32  14.91; attention to FDI area during FDI–TMS: 129.94  12.53; attention to ADM area during FDI–TMS: 152.87  11.49). This negative result was driven by an almost unchanged ICF between baseline and attention to the heterotopic hand area. Note that the results represented FDI muscle excitability with either a homotopic attention (FDI) or heterotopic attention (ADM) locus. Note that the MEP size was not correlated with the amount of SICI or ICF. Control experiments Visual stimulation vs. visual attention: ‘pure’ visual input does not change excitability This experiment tested whether passive viewing of the visual discrimination task alone changed cortical excitability (Fig. 8). A paired t-test showed no significant change of the MEP or SICI or ICF size compared with baseline (P > 0.1). Verbal response contamination

Fig. 7. Experiment series 2. Absolute values. The graph shows the absolute values in addition to the difference scores shown in Figs 5 and 6 for the second main experiment (series 2).

difference in MEP amplitude between the two attention conditions and baseline is shown for each muscle. When participants focussed attention on the skin overlying a muscle, the MEP amplitudes were relatively increased in that muscle.

A verbal response given by the subject shortly after detection of the visual or cutaneous stimulus did not alter the MEP size or intracortical excitability measures (comparison of trials without control of contamination by speech and without contamination by speech: MEPs, P > 0.5; SICI, P > 0.1; ICF, P > 0.5). Spinal vs. cortical: attention does not change spinal excitability H-reflexes could be evoked in the FDI muscle of two participants and in the ADM muscle of a third participant (Fig. 9). Figure 9(A)

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858

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Fig. 9. Control experiment: spinal vs. cortical changes. Spinal excitability, measured using the H-reflex technique, at rest and during two attention tasks (attention to hand and visual attention). (A) Electromyographic traces showing the M-wave and H-reflex evoked in the ADM muscle of a single representative subject. Each trace is the mean of 20 trials; the vertical line marks the stimulation time. (B) Grand average (three subjects) of the ADM and FDI muscle H-reflex amplitudes. In each subject, the amplitude of the conditioned reflexes (i.e. reflexes collected during the two different attention tasks) was expressed as a percentage of the control responses (i.e. reflexes collected at rest); an intrasubject mean value was then calculated for each of the three experimental conditions. The bar represents the  SEM.

shows the mean H-reflex evoked in the ADM muscle at rest (control response, top) and during the attention to the skin overlying the muscle (middle) or the visual attention task (bottom). The H-reflexes were the same in all three conditions. This observation was statistically validated by a one-way repeated-measures ANOVA over all responses elicited in this individual (F2,38 = 2.24, P > 0.05). Similar results were found for each of the other subjects (subject 2: ADM, F2,38 = 0.81, P > 0.05; subject 3: FDI, F2,38 = 1.29, P > 0.05). In Fig. 9(B), the data of all of the participants are combined and show the amplitude of the H-reflex expressed as a percentage of the response amplitude in the control (no-attention) blocks.

Discussion The results show that attention to the skin overlying a muscle (internal focus) affects corticospinal excitability but has no effect on measures of SICI or ICF of that muscle. Conversely, attention to a distant area of the skin has no effect on corticospinal excitability but reduces SICI. In both cases, spinal H-reflexes are unaffected, suggesting that attention influences excitability in circuits within the M1. Attention to a visual task (external focus) also changes cortical excitability, but in this case it increases corticospinal excitability and reduces SICI. These different effects of visual and cutaneous attention on the M1 suggest that they engage different mechanisms. This leads to the conclusion that motor cortical excitability is influenced not only by attention to cutaneous input (internal focus) from a specific area of the skin but also attention to a visual discrimination task (external focus). This occurs even though the tasks engage pure sensory discrimination without any motoric involvement of the hand muscles. The results emphasize the importance when measuring M1 excitability of controlling for attention ‘at rest’ as well as during task performance, particularly when comparing data from healthy participants and people with neurological disease. They also imply that disorders of attention might affect motor output. Attention to a visual discrimination task It was surprising to find that performance of a visual attention task increased cortical excitability to an intrinsic hand muscle (increased MEP and reduced SICI) without affecting spinal H-reflexes, whereas passive viewing had no effect. One possible explanation for this

cross-modal effect is that attention to the task causes an overall increase in arousal that results in a general increase in cortical excitability and a heightened ‘readiness to move’ in the M1. However, generalized arousal cannot explain the effects seen during attention to specific areas of the skin (see below), as these were different in muscles near to and far from the focus of attention. One explanation could be that ‘interoceptive’ attention to specific areas of the body engages more focal mechanisms than are recruited by ‘exteroceptive’ attention to locations outside the body. Attention to discrete areas of the skin: effects on motor evoked potentials There is much literature describing the effects of somatosensory attention on sensory processing and measures of brain activation. Attention to an expected location at an expected time improves sensory discrimination, reduces the electroencephalographic activity of the sensorimotor cortex in the alpha and beta bands, and increases activity in the sensory cortex (e.g. Macaluso et al., 2003; van Ede et al., 2011). However, there are few descriptions of whether there are concomitant effects on the motor cortex. Johansen-Berg & Matthews (2002) showed in a functional magnetic resonance imaging study that diverting attention away from a movement could reduce activation of posterior regions of the M1. Conversely, Macaluso et al. (2003) noted that sensory attention to the hand may increase activity in the pre-central as well as post-central cortex. Similarly, it is interesting to note that the depression of electroencephalographic beta rhythms in the sensorimotor cortex is more traditionally associated with the facilitation of movement rather than somatosensation, although there is some evidence that beta activity can arise in the sensory as well as the motor cortex. A number of other studies have also documented changes in responses to TMS when individuals are instructed to attend to the hand (see Introduction). However, there have been few investigations comparing the effects of different modalities and locations of sensory attention on motor cortex excitability. The present task involved attention to rare electrical stimuli applied directly to the skin. However, although rare, the timing of the stimuli was unpredictable so that participants had to attend continuously to sensation from that area of the skin in order to perform the task correctly. Motor cortex excitability was probed during this sustained attention. The results showed that attention to the skin

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858

Sensory attention effects on motor cortex 2857 overlying the target muscle relatively increased MEPs compared with a no-attention condition. There were no significant effects on MEPs if the skin area was distant from the muscle [middle dorsum (experiment 1) or over the ADM (experiment 2) for MEPs in the FDI]. The results are similar to those described by Gandevia & Rothwell (1987) who found that they could differentially modulate the thresholds for the production of MEPs in two intrinsic hand muscles by focussing attention on one or the other in turn. In their experiments, participants were instructed to focus on ‘motor commands’ to the individual muscles. However, it may well have been that, similar to the present experiments, participants also focussed attention on sensory input from the appropriate hand region to help them achieve the task. Attention to one area of the skin reduces intracortical inhibition (short-interval intracortical inhibition) in corticospinal projections to distant muscles Short-interval intracortical inhibition assesses the excitability of intrinsic GABAA circuits in the motor cortex (Di Lazzaro et al., 1998). In our experiments, attention to one area of the skin had no effect on SICI evoked in a nearby hand muscle; in contrast, SICI was reduced (i.e. less effective inhibition) in a distant muscle. At first sight, the lack of effect in nearby muscles differs from that reported by Thomson et al. (2008) who found that SICI was reduced in the FDI muscle when participants attended to cutaneous input from the index finger. However, Thomson et al. (2008) required participants to react to the cutaneous input by abducting the index finger, whereas there was no motor requirement in the present task. In addition, they did not compare the amount of SICI with that seen at rest (as in the present task), but with the amount of SICI that was measured when participants received inputs to the opposite hand. The reduction in SICI that we observed in a muscle distant from the locus of attention was unexpected and has not been reported previously by others. Indeed, the combined results from experiments 1 and 2 suggest that there may even be a spatial gradient in this effect as attention to the skin in the mid-dorsum had no effect on SICI in experiment 1, whereas attention to the skin overlying the ADM muscle reduced SICI in experiment 2. This contrasts with the findings of Conte et al. (2008) who found that attention to the hand in general had no effect on SICI in a hand muscle. In addition, Ridding & Rothwell (1999) noted that electrical stimulation of cutaneous afferents had no effect on SICI in distant muscles. A likely explanation is that our task differed from previous work in terms of the specificity of the locus of attention, task difficulty as well as different methodological approaches, such as the definition of the baseline resting state [listening to music or reading (Rosenkranz & Rothwell, 2006), closing eyes (Conte et al., 2007), resting with eyes open (Thomson et al., 2008) or the combination of attention paradigms with motor tasks or with simultaneous vibration input to the hand]. It could be, for example, that individuals in the experiments of Conte et al. (2007) paid attention to varying regions of the hand at different times throughout the experiment, so that no overall effects on SICI were seen. The decreased SICI observed in muscles distant from the focus (internal focus) is similar to the decreased SICI during the visual discrimination task (external focus). In both cases, the muscle studied is distant from the locus of attention, and could, as in the visual task, be affected by a general increase in arousal during task performance. In that case, the lack of change in SICI recorded in a muscle near to the focus of attention could reflect the need to maintain excitability of inhibitory mechanisms in that area to reduce neural ‘noise’ in the

corresponding regions of the cortex and improve the detection of threshold inputs. Arousal was not formally assessed in our study, e.g. by scores or skin conductance responses. Therefore, we cannot make judgements regarding the level of arousal. However, the fact that there was a matching in the behavioural results of the tasks does aid the interpretation of the motor data in that any differences seen for the two behavioural conditions are a consequence of differences relating to underlying processes in performing them (presumably related to the differences in external and internal attention) rather than potentially a result of different associated difficulties. Whatever the final explanation, the results are of relevance to a number of different disorders. As noted in the Introduction, focal dystonia often appears to be associated with the repeated performance of movements made under conditions of highly focussed attention, such as occur in professional musicians. Indeed, attention is an important part of learning. However, too great a focus on one area may reduce inhibitory control in other areas and potentially contribute to an overflow of activity. In healthy individuals, this is often seen in the early phases of learning a new skill, but this is gradually reduced as learning progresses. It may that this natural process is defective in focal dystonia and leads to the persisting and unwanted activity characteristic of the condition. Clinical relevance It is remarkable how widespread is the range of disorders that involve abnormal SICI, e.g. dystonia (Sommer et al., 2002), Tourette’s syndrome (Orth & Rothwell, 2009), and first-episode schizophrenia (Wobrock et al., 2008). The interpretation tends to be that intracortical GABAA circuits per se are impaired. The current study demonstrates a modulation towards a reduced amount of SICI when healthy participants pay attention to an internal or external locus. Therefore, the reduced inhibition seen in so many disorders might, in some cases, be explained by differences in cognitive states (attention state) rather than being a genuine physiological marker. A practical relevance of the present results seems more striking. High levels of attention are required for learning that interacts with synaptic plasticity processes (Ziemann et al., 2004). Behavioural data are supported by experimental methods that demonstrate the interaction between attention and plasticity-inducing protocols (Stefan et al., 2004) that are facilitated by directing the subject’s attention to their own hand. This might be mediated via the fine tuning of inhibitory and excitatory circuits in the M1. A necessity of all goal-directed movements is the right balance between inhibiting and facilitating components. To reach an overall economical activation it is vital to be able to relax, for example, antagonistic muscles. The playing-related health problems of musicians are often the end-stage of suboptimal learning processes. The consolidation of ‘bad’ movement patterns is facilitated by attention processes that, via the modulation of inhibitory and excitatory balance, promote processes underlying learning. In summary, this study demonstrates that attention, if directed to an external or internal source, changes excitability in the M1. It further unveils our knowledge gap at the interface of basic motor physiology and cognitive states.

Acknowledgements The authors thank the Tourette Syndrome Association (TSA) USA, the Dorothy Feiss Scientific Research Grant, and National Science Council Taiwan (grant numbers NSC 102-2410-H-008-021-MY3 and NSC-100-2410-H-008074-MY3).

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858

2858 D. Ruge et al.

Abbreviations ADM, abductor digiti minimi; FDI, first dorsal interosseus; ICF, intracortical facilitation; ISI, interstimulus interval; M1, primary motor cortex; MEP, motor evoked potential; PT, perceptual threshold; SICI, short-interval intracortical inhibition; TMS, transcranial magnetic stimulation.

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© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 40, 2850–2858