Motor inhibition refers to the ability to suppress inappropriate or prepotent actions that interfere with goal-driven behavior. Go/No-Go tasks are designed to provide experimental epochs of movement preparation, response execution, and motor inhibition. Consequently, they are widely used to investigate neural responses specifically attributable to motor inhibition (1). Typically, during the task, participants are requested to press a button or otherwise respond to one type of stimuli, such as a set of alphabet letters, a colored dot, or an image (Go stimuli), and withhold or inhibit a response to another type of stimuli, such as a specific single letter, a different color dot, or a contrasting image (No-Go stimuli). Inhibition is a conversion process of motor behavior, reflecting the capacity to selectively withhold voluntary movements (2).

A large accumulation of neuroscientific evidence from functional (fMRI) studies has reported an increase in the concentration of oxygenated hemoglobin during successful No-Go inhibition in the predominantly right-lateralized brain network comprising the orbitofrontal cortex, dorsolateral pre-frontal cortex, supplementary motor areas (SMA)/pre-SMA areas, basal ganglia circuits, and inferior frontal gyrus (IFG) (3–6). The results indicate that motor inhibition is a largely lateralized process within (generally) the right hemisphere, with the right IFG believed to be particularly sensitive to response suppression (7). Within this inhibition network, the right IFG is predicted to serve as an execution center when inhibition is required (8–10).

Following a literature review, a power spectrum analysis based on adults' electroencephalogram (EEG) studies demonstrated that the theta frequency band (4–8 Hz) plays an important role during motor inhibitory control (11–13). Considering the demand for motor inhibition, theta band activity revealed a correlation with right IFG during inhibition tasks (14). The power change between the Go and No-Go conditions were also observed in electrocorticography (ECoG) studies. A previous ECoG study of 16 patients with intracranial electrodes recording for medically refractory epilepsy found significantly increased gamma band activity in the right IFG after No-Go signal cueing (15). Motor inhibition-evoked gamma-band responses during No-Go trials localize to the right IFG (15), which is compatible with the activation of blood oxygenation level-dependent (BOLD) response in functional MRI (fMRI) studies (3, 8). The aforementioned findings, based on EEG and ECoG studies, show that the right IFG has a role in the motor inhibition of adults.

Age-related functional and anatomical neural development has been observed (16). In a meta-study including 2–12-year-old children from 65 EEG studies, the No-Go-related negative amplitude became progressively negative by age, compared with the Go conditions. The results implied that No-Go-related EEG signals as indexing motor inhibition would change with age (17). In the pediatric population, the findings of frontal activation in No-Go conditions were similar to those in adult populations (2, 18, 19), with some notable differences, including an overall greater engagement of more widespread brain networks (19) and left frontal engagement, which was predicted to contribute to motor inhibition in the immature nervous system (20). Yet, to date, the vast majority of electrophysiological investigations of response in inhibition have been based on adult populations; the dominance of right IFG, the contributions of left IFG during motor inhibition, and the connectivity of frontal and other parts of brain regions between Go and No-Go conditions in children have not been explored using ECoG. Because subdural recordings provide the greatest fidelity of gamma-band dynamics, confirmatory recordings using ECoG in pediatric populations during response-inhibition are warranted.

The processing of motor inhibition included not only IFG, but also other parts of the brain, including the pre-SMA, orbitofrontal cortex, dorsolateral pre-frontal cortex, and basal ganglia (3–6). Considering the neural network of motor inhibition, power changes across different parts of the cortex between Go and No-Go conditions were proven to be related to cortical connectivity and response accuracy in tasks (11, 21). Thus, taken all together, phase-amplitude coupling (PAC) is a suitable cross-frequency coupling approach used to evaluate cortical coupling and functional connectivity. For example, in a magnetoencephalography (MEG) study, high-gamma power (HG, 30–70 Hz) was phase-locked to alpha neural oscillation (8–13 Hz) with the human eyes closed within occipital channels (22). Furthermore, in ECoG studies, the phase of canonical low-frequency bands, such as theta (4–8 Hz), has been shown to modulate power in HG band (80–150 Hz) signals (23). The task-related coupling effects were also observed between the phase of low-frequency (0–3.5 Hz) and amplitude of gamma band (28–70 Hz) neural signals (24). Comparing the coupling effect between the ECoG and fMRI signals in the resting state of brain connectivity, PAC mimicked comparable patterns in these two measurements (25). Collectively, it is believed that PAC represents a neural gating mechanism where the presence of significant coupling indicates the phase of a low-frequency oscillator, which serves to briefly facilitate the high-frequency activity of a second, distant cortical region (23, 26).

It has been predicted that PAC may serve as a neurophysiological mechanism underlying the maturation of neural communication (26) and as a driving mechanism for orchestrating function, including motor inhibition (27). However, the degree to which this neural network and physiological mechanism of motor inhibition exist within pediatric populations is unclear. The aim of this study is to investigate the neural activity, extracted from in-dwelling ECoG electrodes, during motor inhibition in the pediatric population, and estimate the degree to which PAC is associated with the maturation of motor inhibition.

In this study, we investigated movement inhibition in the eight pediatric patients who received transient subdural grid implantation for localizing epileptic foci. Our observations highlight two things. First, HG activation in No-Go conditions was higher than that in the Go condition over both the left and right side IFGs. The PAC values in the No-Go condition, calculated between low-frequency (2–40 Hz) phase and high-frequency amplitude (70–200 Hz) from IFG, were higher than those in Go conditions, and we also observed in both left and right cortices. This indicates that activation of IFG in the No-Go condition may modulate the cortical activities to inhibit movements. Second, in the left IFG, the HG and PAC ratio decreased, while the theta ratio increased, with increasing age. In the previous literature, maturational patterns of EEG activity in the resting state revealed that theta-band power decreased while the alpha-band power increased with age (38). The theta-band activity was replaced by the alpha-band first in the occipital regions and progressed later to frontal regions by ages (39). Many studies suggested changes in the white matter (WM) volume was thought to reflect the process of increased myelination, whereas myelination increases the speed of nerve impulse propagation across the brain's region-specific neurocircuitry, especially in the prefrontal cortex, up until 24 years old (40). Thus, growth-related changes in WM might lead decreasing in resting-state theta-band activity with development. In this study, we used the baseline-normalized event-related spectral perturbation (ERSP) (41) to determine the activation of ECoG data under the No-Go trial. There was an increasing power ratio of theta oscillation with stronger theta activity in No-Go trials as lower resting-state theta activity (baseline) by age. The observed age-dependent relationship between theta activity and inhibitory control at the neurophysiological and behavioral level may relate to biophysical properties of theta oscillations and their role in coordinating information processing in a network in the maturation process (42, 43). Critically, relative to adult populations, our results support the hypothesis that the center of motor inhibition in the pediatric populations is not limited to the right IFG, but rather is a product of bilateral contributions from the IFG (20).

The process of motor inhibition is generally assumed to be a multiple step, functional process, mapping onto multiple regions of the cortex (7). In an fMRI study, 26 healthy volunteers (mean age: 23.4 years old) were asked to continuously tap a button with their right index finger, stopping the movement following occasional visual cues, in order to compare the brain activation between the voluntary and forced inhibition of ongoing actions. The results revealed that during the period of inhibition there were greater activations over the SMA, middle cingulate cortex, bilateral insula, and inferior parietal cortex in addition to the right IFG (44). In another fMRI study of 26 healthy subjects, BOLD signals were measured in a Go/No-Go task. Greater activation over the right IFG and pre-SMA regions were noted in No-Go conditions than in Go conditions (45). A 15-participant study (mean age = 27.5 years old) compared different degrees of difficulty of the stop signal task and found that the right IFG and adjacent anterior insula had more activation during more difficult tasks (46). Additional insight regarding the role of the left IFG in Go/No-Go task execution was demonstrated in a 22-participant fMRI study. The study included two variants of the Go/No-Go ratio: a high frequency of Go cues (Go: No-Go = 3: 1), and a high frequency of No-Go cues (Go: No-Go = 1: 3). The results revealed that the left IFG and a dorsal portion of the pre-SMA were more reactive to No-Go cues compared with Go cues, whether the frequency of No-Go cues was high or low (47). Together, these studies indicate that the right IFG participates in a network that orchestrates the process of motor inhibition. The findings of this study support the conclusion that in addition to the right IFG, which is well-established as being involved in motor inhibition in adults, the left IFG also plays a role in motor inhibition within the maturing brain (20).

Considering the whole neural network for movement inhibition, the change of neural activations over extended regions of the cortex, such as motor, premotor, and pre-SMA regions, would also be observed between Go and No-Go conditions. In a stop-event-related study of 12 adult epileptic patients, event-related spectral power was measured by intracranial ECoG to identity the movement-related spectral change over the sensorimotor cortex. The early increased mu band (10–20 Hz) reflected a transient state of motor inhibition over the precentral gyri (48). In another Go/No-Go task, the middle frontal gyrus (MFG) demonstrated transiently increased HG power during stop signals, and the increased HG over MFG was stronger for unsuccessful stop conditions compared to successful stop conditions, which implied the role of MFG in behavioral monitoring (49). The processing of motor inhibition not only included the frontal region, but also the pre-SMA, orbitofrontal cortex, dorsolateral pre-frontal cortex, and basal ganglia (3–6).

Modulating effects between different brain regions, including the IFG, anterior insula, pre-SMA, and sensorimotor cortex, with interaction with basal ganglia, were demonstrated in a neural network study of movement inhibition (47). The movement context was modulated by the neural activity of the basal ganglia, anterior cingulate cortex, and frontal cortex (50, 51). In an fMRI study, response-related amplitudes were calculated via logistic regression analysis. Covariance was applied to evaluate the coupling effects between two regions. The results revealed the coupling between the fronto-parietal regions and right IFG increased in successful stop signal tasks compared with that of unsuccessful stop signal tasks, suggesting that the right IFG had more neural interaction during movement inhibition (52). The role of the left IFG in movement inhibition was also evaluated by correlation in another fMRI study by a Go/No-Go task. In No-Go trials, the left IFG revealed positive connectivity with the dorsal portion of the pre-SMA, but negative connectivity with regions responding to Go cues (left sensorimotor cortex) (47). In a clinical case report, the fMRI data analysis in the Go/No-Go task revealed left IFG compensated the original right IFG function after brain injury, which may be the reactivation of the original left IFG function (53). These findings are congruent with the results of our study, which revealed that both the right and left IFG serve to modulate focal activity with the motor cortex during No-Go conditions.

Age-related neural development has been widely discussed, including changes in cortical thickness (16), cortical structure (54), the number of synapse formations (55), and functional activity (54). For example, visual acuity has been correlated to the structure and thickness of the visual cortex (16). Most neural development, such as the sensorimotor cortex, matures symmetrically over both sides (56). However, the language function lateralizes to the dominant cortex with age (57). Utilizing structural MRI, lateralization was strongly correlated with volume and thickness over the left IFG (58). For the function of motor inhibition, the presented studies show that right IFG plays an important role (2, 7, 8, 15), but some reports have revealed equal contribution by bilateral IFG (20). In an MRI study, decreasing WM tracts over right IFG was observed in the patients with Attention Deficit Hyperactivity Disorder, compared with the normal population. For the motor inhibition, the results identified the pathogenesis of WM tracts over IFG potentially related to deficient inhibitory control (59). Our study indicated that both IFG played a role in motor inhibition in the pediatric population, but with age, lateralization to the right IFG becomes dominant.

There were some limitations in this study. The brain activity recorded by the ECoG signal was limited by the location of grids and strips, and coverage of the regions of interest was determined entirely by the clinical need. In the future, more cases are needed to investigate the correlation between age and motor inhibition, which may reveal the developmental pattern from bilateral IFG involvement in children to solely right IFG involvement in adults.

In our pediatric patients, both the right and left IFG had roles in motor inhibition. The power ratio between the No-Go and Go conditions revealed age-related lateralization from the bilateral-to-right side IFG. The PAC modulation over IFG was more synchronized in No-Go trials than in Go trials. The correlation of age computed by the PAC ratio between two conditions further supported age-related right side IFG lateralization.

The datasets generated for this study are available on request to the corresponding author.

The studies involving human participants were reviewed and approved by Seattle Children's Hospital Institutional Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

C-HK, KCa, JW, PR, KW, and JO designed the study. C-HK, KCa, JW, KCo, and JO participated in data collection. EN and JO provided the data resource. C-HK, KCa, B-WC, S-HY, Y-CL, and Y-YC analyzed the data. C-HK, KCa, KCo, Y-YC, Y-CL, KW, and JO wrote and reviewed the manuscript. All the authors reviewed and approved the final version of the manuscript.

We are grateful for support from the Ministry of Science and Technology of Taiwan under Contract numbers of MOST 110-2321-B-010-006, 109-2811-E-010−502, 109-2221-E-010-004-MY2, and 108-2321-B-010-008-MY2. We also are grateful for support from the Higher Education Sprout Project of the National Chiao Tung University and Headquarters of University Advancement at the National Cheng Kung University, Ministry of Education (MOE), Taiwan.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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