The purpose was to determine the contribution of GABAB receptor-mediated intracortical inhibition, as assessed by the CSP, to the generation of surround inhibition. The study produced two main findings. First, the ADM MEP amplitude was greater during independent ADM activation (control condition) compared with the phasic movement phase of the index finger flexion. Thus, the presence of surround inhibition was confirmed in the current study. Second, the ADM CSP duration was greater during independent ADM activation compared with the phasic movement phase of the index finger flexion, which indicated that the magnitude of this specific type of intracortical inhibition was reduced during the phasic movement phase. Taken together, these findings indicate that GABAB receptor-mediated intracortical inhibition, as measured by CSP duration, does not contribute to the generation of surround inhibition in hand muscles.
A variety of TMS parameters and task details influence MEP magnitude, CSP duration, and the expression of surround inhibition. Therefore, several experimental controls and methodological considerations were employed to minimise confounding influences. For example, muscle fatigue enhances MEP amplitude and CSP duration (Taylor et al., 1996, 2000). Although the contraction intensities were low and adequate rest periods were given between trial blocks, muscle fatigue was possible due to the number of trials. Nonetheless, the absence of a change between MVCpre and MVCpost for both muscles suggests that muscle fatigue did not influence the results. Another important factor that influences MEP amplitude is the amount of background EMG activity (Capaday, 1997). In the current study, this depended on the ability of the subjects to maintain constant force and ADM EMG levels across conditions, despite having to concurrently produce an index finger flexion movement upon a randomly timed acoustic tone. Accordingly, the similar ADM EMG levels across conditions suggest that motor unit pool excitation was similar in all cases and not responsible for changes in MEP. Thus, subjects performed the complex task in conformity with the task requirements during the experimental blocks after sufficient practice.
An additional potential confound of the study is the possible dependence of CSP duration on MEP amplitude, as some studies have shown a correlation between these variables (Cantello et al., 1992; Taylor et al., 1997; Ho et al., 1998; Orth & Rothwell, 2004). Thus, it could be argued that changes in CSP duration could be exclusively due to concomitant changes in MEP amplitude. However, the evidence for an association between the two variables comes primarily from the aforementioned studies that used a range of stimulus intensities, which would lead to associations as both variables are dependent on stimulus intensity. Although one study using a constant stimulus intensity in a single behavioral condition also found an association between CSP duration and MEP amplitude (Orth & Rothwell, 2004), it has been shown conclusively that MEP amplitude and CSP duration can become uncoupled in different behavioral conditions with a constant stimulus intensity and similar background EMG levels (Tinazzi et al., 2003). Therefore, the possible association between CSP duration and MEP amplitude should not have confounded the current study because the stimulus intensity was constant, background EMG was similar, and the behavioral state was different between experimental conditions. Accordingly, Spearman’s rank correlation indicated that the two variables were statistically independent for each of the four experimental conditions.
The amount of surround inhibition that can be observed depends on several features of the motor task. Specifically, surround inhibition is greater in the dominant (right) hand (Shin et al., 2009), is more pronounced at lower force levels (Beck et al., 2009b), scales with task difficulty (Beck & Hallett, 2010), and is confined to the initiation phase of movement (Sohn & Hallett, 2004b; Beck et al., 2009b; Beck & Hallett, 2011). Therefore, the study included right-handed subjects, a target force of 5% of MVC, a challenging motor task, and measured surround inhibition in the ADM during all of the index finger flexion movement phases as in previous studies (Beck et al., 2008, 2009c). Conversely, the methodological issue of primary importance in interpreting the implications of the CSP duration for a given task is the TMS intensity, because the CSP does not depend on background EMG activity. In the present study, a stimulation intensity of 130% of RMT was utilised for four reasons. First, preliminary work determined that lower stimulation intensities of 115% of RMT and below, which result in short CSP durations, made it difficult for algorithms or visual inspection to quantify the CSP duration of the ADM at the low activation level of 5% of MVC. Second, short CSP durations (< 75 ms) are due to spinal mechanisms, whereas longer silent periods (75–300 ms) are due exclusively to cortical mechanisms (Fuhr et al., 1991; Inghilleri et al., 1996; Chen et al., 1999). Because surround inhibition arises primarily from cortical mechanisms (Sohn & Hallett, 2004a; Beck et al., 2008; Beck & Hallett, 2011), the relatively high stimulus intensity assured that the CSP durations elicited by TMS reflected intracortical inhibition. Third, stimulation intensities higher than 130% could have led to ceiling effects in the CSP duration, which could have precluded the ability to observe significant lengthening of the CSP in some experimental conditions. Fourth, stimulation intensities from 130 to 150% of RMT are the most common in the literature (Orth & Rothwell, 2004). Collectively, these methodological considerations should have optimised the ability to determine the contribution of mechanisms underlying the CSP to surround inhibition.
Surround inhibition and cortical silent period duration
It has been proposed that surround inhibition is an important mechanism that acts to focus excitatory neural drive to muscles responsible for a given movement (agonists) while actively inhibiting activity in muscles not relevant to the movement (surround muscles) (Sohn & Hallett, 2004a; Beck et al., 2008; Beck & Hallett, 2011). Strong support for these contentions comes from observations in movement disorders that are characterised by excessive activation of muscles not required in a given movement (Shin et al., 2010), especially FHD (Hallett, 2011). In contrast to healthy subjects, patients with FHD consistently exhibit facilitation as opposed to inhibition of the MEP of the surround muscle during agonist muscle activation, which indicates a loss of surround inhibition (Sohn & Hallett, 2004a; Beck et al., 2008).
Based on these findings, extensive research has focused on the identification of the mechanisms underlying the generation of surround inhibition in healthy subjects and its impairment in motor disorders. Because the MEP reflects net corticospinal excitability and depends on the balance between numerous cortical excitatory and inhibitory interneuronal circuits, a well-accepted strategy involves the application of paired-pulse TMS to establish which pathways contribute to the suppressed MEP indicative of surround inhibition (Beck & Hallett, 2011). Despite the determination of the impairment of some of these pathways in FHD, none of these studies were able to establish the specific cortical pathway underlying the generation of surround inhibition in healthy subjects. For example, intracortical and intercortical circuits including short intracortical inhibition (Sohn & Hallett, 2004a; Beck et al., 2008), long intracortical inhibition (LICI) (Sohn & Hallett, 2004b), intracortical facilitation (Sohn & Hallett, 2004b), interhemispheric inhibition (Beck et al., 2009c), dorsal pre-motor inhibition (Beck et al., 2009a), and ventral pre-motor inhibition (Houdayer et al., 2012) were not responsible for surround inhibition. Similarly, short afferent inhibition (Richardson et al., 2008), long-latency afferent inhibition (Pirio Richardson et al., 2009), and cerebellar inhibition (Kassavetis et al., 2011) were also not involved. Collectively, these results are surprising given the functional importance and number of the cortical pathways examined in these studies.
The CSP is another index of intracortical inhibition that has been used extensively to study GABAB-mediated inhibition processes during voluntary contractions. In the present study, it was hypothesised that the mechanisms underlying the CSP could participate in the generation of surround inhibition. This expectation was based on several inter-related lines of evidence. First, GABAergic neurons are the most numerous and important class of inhibitory interneurons in the motor cortex (Jones, 1993; Keller, 1993). Second, the CSP duration of agonist muscles has been shown to be abnormal in FHD (Ikoma et al., 1996; Chen et al., 1997; Filipovic et al., 1997) and Parkinson’s disease (Priori et al., 1994a; Nakashima et al., 1995), which are the same patient populations that have exhibited impaired surround inhibition (Sohn & Hallett, 2004a; Shin et al., 2007; Beck & Hallett, 2011). Third, the differential modulation of CSP duration in different tasks suggests that this type of intracortical inhibition has functional significance in the execution of fine motor tasks involving hand muscles (Tinazzi et al., 2003; Sale & Semmler, 2005). Fourth, no previous studies had examined the possible role of the CSP in the generation of surround inhibition. In fact, the standard paradigm in these studies did not permit CSP duration quantification because the surround muscle was required to remain at rest during agonist muscle activation. Therefore, a modification of a previously developed experimental methodology (Sohn et al., 2005) was utilised to assess CSP duration in an active surround muscle during remote muscle activation.
The MEP amplitude of the surround ADM muscle was greater during independent activation compared with the phasic movement phase of the accompanying index finger flexion. This finding is consistent with previous studies that found a reduced MEP in the surround muscle during movement initiation, albeit with the surround muscle at rest (Sohn & Hallett, 2004a,b; Beck et al., 2008, 2009b; Beck & Hallett, 2010; Kassavetis et al., 2011). Thus, the presence of surround inhibition was confirmed in the active surround ADM muscle in the current experimental paradigm. Most importantly, this finding coincided with the observation that the CSP duration of the ADM was also greater (more inhibition) during independent activation compared with the phasic movement phase of the index finger flexion. Therefore, the amount of this type of intracortical inhibition was reduced during the phasic movement phase compared with independent activation. Accordingly, these results are contrary to our original hypothesis, which predicted the exact opposite modulation of CSP duration. In summary, the findings indicate that GABAB receptor-mediated intracortical inhibition, as measured by the duration of the CSP, does not contribute to surround inhibition.
Cortical silent period duration and long intracortical inhibition
The reduced intracortical inhibition (shortened CSP duration) at first seems counterintuitive. However, the finding is similar to previous results obtained from surround inhibition studies involving other inhibitory pathways. For instance, measures of short afferent inhibition (Richardson et al., 2008), long-latency afferent inhibition (Pirio Richardson et al., 2009), interhemispheric inhibition (Beck et al., 2009c), cerebellar inhibition (Kassavetis et al., 2011), and LICI (Sohn & Hallett, 2004b) all exhibited reductions rather than enhancements in inhibition. The similar modulation of LICI and CSP duration in the two studies is particularly noteworthy because the two measures of intracortical inhibition are thought to reflect similar physiological mechanisms. More specifically, pharmacological studies have determined that both measures involve post-synaptic GABAB-mediated inhibition (Chen et al., 1999; Werhahn et al., 1999; McDonnell et al., 2006; Florian et al., 2008). Accordingly, electroencephalography and EMG measures of LICI were significantly associated with CSP duration in the abductor pollicis brevis (Farzan et al., 2010). However, other studies have shown a differential modulation of LICI and CSP duration by drugs (Inghilleri et al., 1996; McDonnell et al., 2006), disease (Berardelli et al., 1996), and fatigue (Benwell et al., 2007). Thus, the balance of the experimental data seems to suggest that the mechanisms underlying LICI and CSP are not identical and display divergent functional responses in various conditions, despite the fact that both measures reflect GABAB-mediated inhibition. Furthermore, it has been proposed that CSP may provide a measure of the duration of GABAB receptor-mediated inhibition, whereas LICI provides a measure of the depth of this inhibition (Cash et al., 2010). Nonetheless, the reduced LICI observed previously (Sohn & Hallett, 2004b) and the shortened CSP duration found in the present study provide consistent evidence that these types of intracortical inhibition act in the same direction in opposition to surround inhibition processes.