A 5-day course of rTMS before pain onset ameliorates future pain and increases sensorimotor peak alpha frequency.

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF and CME were assessed on Day 0 (before rTMS) and Day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered prior to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain.

The effect of staircase stopping accuracy and testing environment on stop-signal reaction time.

The stop-signal task is widely used in experimental psychology and cognitive neuroscience research, as well as neuropsychological and clinical practice for assessing response inhibition. The task requires participants to make speeded responses on a majority of trials, but to inhibit responses when a stop signal appears after the imperative cue. The stop-signal delay after the onset of the imperative cue determines how difficult it is to cancel an initiated action. The delay is typically staircased to maintain a 50% stopping accuracy for an estimation of stopping speed to be calculated. However, the validity of this estimation is compromised when participants engage in strategic slowing, motivated by a desire to avoid stopping failures. We hypothesized that maintaining stopping accuracy at 66.67% reduces this bias, and that slowing may also be impacted by the level of experimenter supervision. We found that compared with 50%, using a 66.67% stopping accuracy staircase produced slower stop-signal reaction time estimations (≈7 ms), but resulted in fewer strategic slowing exclusions. Additionally, both staircase procedures had similar within-experiment test-retest reliability. We also found that while individual and group testing in a laboratory setting produced similar estimations of stopping speed, participants tested online produced slower estimates. Our findings indicate that maintaining stopping accuracy at 66.67% is a reliable method for estimating stopping speed and can have benefits over the standard 50% staircase procedure. Further, our results show that care should be taken when comparing between experiments using different staircases or conducted in different testing environments.

Alterations in cortical excitability during pain: A combined TMS-EEG Study.

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n = 29), multiple sustained thermal stimuli were administered to the forearm, with the first, second and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n = 10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

Is cortical inhibition in primary motor cortex related to executive control?

Recent research using paired-pulse transcranial magnetic stimulation (TMS) has shown that the speed with which people can stop an action is linked to GABAergic inhibitory activity in the motor system. Specifically, a significant proportion of the variance in stop signal reaction time (SSRT; a widely used measure of inhibitory control) is accounted for by short-interval cortical inhibition (SICI). It is still unclear whether this relationship reflects a broader link between GABAergic processes and executive functions, or a specific link between GABAergic processes and motor stopping ability. The current study sought to replicate the correlation between SSRT and SICI while investigating whether this association generalises to other measures of inhibitory control and working memory, and to long-interval cortical inhibition (LICI). Participants completed a battery of inhibition (Stop-Signal, Stroop, Flanker) and working memory (n-back, Digit Span, and Operation Span) tasks. We replicated the correlation between SICI and SSRT but found no other correlations between behavioural measures of executive control and the two cortical measures of inhibition. These findings indicate that the relationship between SSRT and SICI is specific to a particular property of response inhibition and likely reflects the function of local inhibitory networks mediated by GABAA.

The reliability of two prospective cortical biomarkers for pain: EEG peak alpha frequency and TMS corticomotor excitability.

BACKGROUND: Many pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and an inability to accurately classify at-risk individuals. Preliminary evidence has shown that high pain sensitivity is associated with slow peak alpha frequency (PAF), and depression of corticomotor excitability (CME), potentially due to impairments in ascending sensory and descending motor pathway signalling respectively NEW METHOD: The present study evaluated the reliability of PAF and CME responses during sustained pain. Specifically, we determined whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. RESULTS: Using a weighted peak estimate, PAF reliability (n = 75) was in the excellent range even without standard pre-processing and ∼2 min recording length. Using a single peak estimate, PAF reliability was in the moderate-good range. For CME (n = 74), 80% of participants showed facilitation or depression of CME beyond an optimal cut-off point, with the stability of these changes in the good range. COMPARISON WITH EXISTING METHODS: No study has assessed the reliability of PAF or feasibility of classifying individuals as facilitators/depressors, in response to sustained pain. PAF was reliable even in the presence of pain. The use of a weighted peak estimate for PAF is recommended, as excellent test-retest reliability can be obtained even when using minimal pre-processing and ∼2 min recording. We also showed that 80% of individuals exhibit either facilitation or depression of CME, with these changes being stable across sessions. CONCLUSIONS: Our study provides support for the reliability of PAF and CME as prospective cortical biomarkers. As such, our paper adds important methodological advances to the rapidly growing field of pain biomarkers.

The influence of sensory potentials on transcranial magnetic stimulation - Electroencephalography recordings.

OBJECTIVE: It remains unclear to what extent Transcranial Magnetic Stimulation-evoked potentials (TEPs) reflect sensory (auditory and somatosensory) potentials as opposed to cortical excitability. The present study aimed to determine; a) the extent to which sensory potentials contaminate TEPs using a spatially-matched sham condition, and b) whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two. METHODS: Twenty healthy participants received active or sham stimulation, with the latter consisting a sham coil click combined with scalp electrical stimulation. Two additional conditions i) electrical stimulation and ii) auditory stimulation alone, were included in a subset of 13 participants. RESULTS: Signals from active and sham stimulation were correlated in spatial and temporal domains > 55 ms post-stimulation. Relative to auditory or electrical stimulation alone, sham stimulation resulted in a) larger potentials, b) stronger correlations with active stimulation and c) a signal that was not a linear sum of electrical and auditory stimulation alone. CONCLUSIONS: Sensory potentials can confound interpretations of TEPs at timepoints > 55 ms post-stimulation. Furthermore, TEP contamination cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both. SIGNIFICANCE: Future studies may benefit from controlling for sensory contamination using spatially-matched sham conditions, and which consist of combined auditory and somatosensory stimulation.

The Effect of Acute and Sustained Pain on Corticomotor Excitability: A Systematic Review and Meta-Analysis of Group and Individual Level Data.

Pain alters motor function. This is supported by studies showing reduced corticomotor excitability in response to experimental pain lasting <90 minutes. Whether similar reductions in corticomotor excitability are present with pain of longer durations or whether alterations in corticomotor excitability are associated with pain severity is unknown. Here we evaluated the evidence for altered corticomotor excitability in response to experimental pain of differing durations in healthy individuals. Databases were systematically searched for eligible studies. Measures of corticomotor excitability and pain were extracted. Meta-analyses were performed to examine: (1) group-level effect of pain on corticomotor excitability, and (2) individual-level associations between corticomotor excitability and pain severity. 49 studies were included. Corticomotor excitability was reduced when pain lasted milliseconds-seconds (hedges g's = -1.26 to -1.55) and minutes-hours (g's = -0.55 to -0.9). When pain lasted minutes-hours, a greater reduction in corticomotor excitability was associated with lower pain severity (g = -0.24). For pain lasting days-weeks, there were no group level effects (g = -0.18 to 0.27). However, a greater reduction in corticomotor excitability was associated with higher pain severity (g = 0.229). In otherwise healthy individuals, suppression of corticomotor excitability may be a beneficial short-term strategy with long-term consequences. PERSPECTIVE: This systematic review synthesised the evidence for altered corticomotor excitability in response to experimentally induced pain. Reduced corticomotor excitability was associated with lower acute pain severity but higher sustained pain severity, suggesting suppression of corticomotor excitability may be a beneficial short-term adaptation with long-term consequences.

OSARI, an Open-Source Anticipated Response Inhibition Task.

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task.

Spatial presence depends on 'coupling' between body sway and visual motion presented on head-mounted displays (HMDs).

This study investigated the effects of simulating self-motion via a head-mounted display (HMD) on standing postural sway and spatial presence. Standing HMD users viewed simulated oscillatory self-motion in depth. On a particular trial, this naso-occipital visual oscillation had one of four different amplitudes (either 4, 8, 12 or 16 m peak-to-peak) and one of four different frequencies (either 0.125, 0.25, 0.5 or 1 Hz). We found that simulated high amplitude self-oscillation (approximately 16 m peak-to-peak) at either 0.25 Hz or 0.5 Hz: 1) generated the strongest effects on postural sway; and 2) made participants feel more spatially present in the virtual environment. Our findings provide insight into the parameters of simulated self-motion that generate the strongest postural responses within virtual environments. These postural constraints have valuable implications for improving our understanding of sensory processes underlying the ergonomic experience of virtual environments simulated using HMDs.

Motor cortex dysfunction in problem gamblers.

Impairments in response inhibition have been implicated in gambling psychopathology. This behavioral impairment may suggest that the neural mechanisms involved in response inhibition, such as GABAA -mediated neurotransmission in the primary motor cortex (M1), are also impaired. The present study obtained paired-pulse transcranial magnetic stimulation markers of GABAA and glutamate receptor activity from the left M1 of three groups-problem gamblers (n = 17, 12 males), at-risk gamblers (n = 29, 19 males), and controls (n = 23, six males)-with each group matched for alcohol use, substance use, and attention-deficit hyperactivity disorder (ADHD) symptomology. Response inhibition was measured using the stop signal task. Results showed that problem gamblers had weaker M1 GABAA receptor activity relative to controls and elevated M1 glutamate receptor activity relative to at-risk gamblers and controls. Although there were no differences in response inhibition between the groups, poorer response inhibition was correlated with weaker M1 GABAA receptor activity. These findings are the first to show that problem gambling is associated with alterations in M1 GABAA and glutamate-mediated neurotransmission.

A novel cortical biomarker signature for predicting pain sensitivity: protocol for the PREDICT longitudinal analytical validation study.

INTRODUCTION: Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan. METHODS: This study uses a multisite longitudinal, experimental study to follow individuals for a period of 30 days as they progressively develop and experience complete resolution of NGF-induced muscle pain. One hundred fifty healthy participants will be recruited. Participants will complete twice daily electronic pain diaries from day 0 to day 30 and undergo assessment of pressure pain thresholds, and recording of PAF and CME on days 0, 2, and 5. Intramuscular injection of NGF will be given into the right masseter muscle on days 0 and 2. The primary outcome is pain sensitivity. PERSPECTIVE: PREDICT is the first study to undertake analytical validation of a PAF and CME biomarker signature. The study will determine the sensitivity, specificity, and accuracy of the biomarker signature to predict an individual's sensitivity to pain. REGISTRATION DETAILS: ClinicalTrials.gov: NCT04241562 (prospective).

Linking cortical and behavioural inhibition: Testing the parameter specificity of a transcranial magnetic stimulation protocol.

Across a series of studies, our laboratory has shown that the efficiency of action stopping is associated with the strength of GABAA-mediated short-intracortical inhibition (SICI) as measured using transcranial magnetic stimulation (TMS). However, these studies used fixed TMS parameters, which may not optimally probe GABAA receptor activity for each individual. In the present study, we measured the relationship between stopping efficiency and SICI using a range of TMS parameters. Participants completed a right-hand unimanual stop signal task to obtain a measure of stopping efficiency. Resting-state SICI was measured from the left primary motor cortex using six combinations of interstimulus intervals and conditioning pulse intensities. We also established the parameters which generated the strongest SICI (SICImax) and weakest SICI (SICImin) for each individual. We found that stopping efficiency was significantly predicted by SICI using various TMS parameters, including SICImax. Interestingly, SICImin accounted for a similar proportion of variance in stopping efficiency as SICI measured using other TMS parameters. The findings suggest that the relationship between stopping efficiency and SICI is robust, reliable, and not influenced by the extent to which SICI is optimally probed.

Stop Signal Task Training Strengthens GABA-mediated Neurotransmission within the Primary Motor Cortex.

We have recently shown that the efficiency in stopping a response, measured using the stop signal task, is related to GABAA-mediated short-interval intracortical inhibition (SICI) in the primary motor cortex. In this study, we conducted two experiments on humans to determine whether training participants in the stop signal task within one session (Experiment 1) and across multiple sessions (Experiment 2) would increase SICI strength. For each experiment, we obtained premeasures and postmeasures of stopping efficiency and resting-state SICI, that is, during relaxed muscle activity (Experiment 1, n = 45, 15 male participants) and SICI during the stop signal task (Experiment 2, n = 44, 21 male participants). In the middle blocks of Experiment 1 and the middle sessions of Experiment 2, participants in the experimental group completed stop signal task training, whereas control participants completed a similar task without the requirement to stop a response. After training, the experimental group showed increased resting-state SICI strength (Experiment 1) and increased SICI strength during the stop signal task (Experiment 2). Although there were no overall behavioral improvements in stopping efficiency, improvements at an individual level were correlated with increases in SICI strength at rest (Experiment 1) and during successful stopping (Experiment 2). These results provide evidence of neuroplasticity in resting-state and task-related GABAA-mediated SICI in the primary motor cortex after response inhibition training. These results also suggest that SICI and stopping efficiency are temporally linked, such that a change in SICI between time points is correlated with a change in stopping efficiency between time points.

Contralateral and Ipsilateral Relationships between Intracortical Inhibition and Stopping Efficiency.

We have recently shown that the efficiency of stopping a response is correlated with GABAergic activity in primary motor cortex (M1) measured using the short interval intracortical inhibition (SICI) protocol. However, this finding was observed when SICI was measured in left M1 and when stopping efficiency was measured with a bimanual response task. The aim of the present study was to examine the extent to which the relationship between SICI and stopping is lateralized to the hemisphere controlling the response (e.g. left M1 and stopping a right hand response) and/or reflects bilateral inhibitory mechanisms (as might be seen between left M1 and left hand stopping). We measured resting SICI (i.e. during relaxed muscle activity) in left and right M1 and stopping efficiency in the left and right hand, in 38 healthy individuals. We found that SICI was significantly correlated between hemispheres (r = 0.51) and stopping efficiency was correlated between hands (r = 0.77). When controlling for other relevant variables, we found that stopping efficiency in each hand was uniquely predicted by SICI in the contralateral hemisphere, but not the ipsilateral hemisphere. These results suggest that there is a hemispheric-specific contribution of SICI to stopping efficiency.

Individual differences in intracortical inhibition during behavioural inhibition.

The time required to abort an initiated response can be measured as the Stop Signal Reaction Time (SSRT). We determined whether GABAergic activity in the primary motor cortex (M1), measured using paired-pulse Transcranial Magnetic Stimulation (TMS) was related to SSRT. GABAergic activity in M1 was assessed by measuring Short-Interval Intracortical Inhibition (SICI). In two experiments, participants (males and females) completed the Stop Signal Task while we measured SICI from the first dorsal interosseous muscle. In Experiment 1, SICI was measured at fixed time points after Stop signal onset on Stop trials (50ms, 100ms, 150ms, 200ms), and at corresponding time points for Go trials. In Experiment 2 SICI was measured at fixed time points before the end of the SSRT interval (125ms, 75ms, 25ms) on Stop trials, and at corresponding time points for Go trials. In each experiment, 30 participants were classified as fast stoppers or slow stoppers based on a median split of their SSRTs. Fast stoppers had more SICI than slow stoppers, both when executing a response (Go trials) and when inhibiting a response (Stop trials). Indeed, the correlation between mean SICI and SSRT on successful Stop trials was 0.81. Experiment 2 showed that for fast stoppers (relative to baseline) there was reduced SICI on Go trials and recovery of SICI on Stop trials. Slow stoppers however, showed reduced SICI on Stop and Go trials relative to baseline. Our results show that individuals who are faster at stopping not only show more GABAergic activity in M1, but can more effectively control M1 GABAergic activity to inhibit motor cortical excitability when stopping a response and disinhibit excitability when executing a response.

Variations in response control within at-risk gamblers and non-gambling controls explained by GABAergic inhibition in the motor cortex.

Paired-pulse Transcranial Magnetic Stimulation (TMS) is used to study inhibitory and excitatory mechanisms in the motor cortex through the measurement of short-interval intracortical inhibition (SICI), indicative of GABAergic activity, and intracortical facilitation (ICF), indicative of glutamatergic activity. In the present study, TMS was delivered to the left motor cortex of 40 participants while we measured SICI and ICF at rest. We were interested in whether variation between individuals in these modulatory mechanisms is related to inhibitory control over responding measured as stop signal reaction time (SSRT). Within the same group of participants, we investigated whether SICI, ICF, SSRT, and self-reported impulsivity, are impaired in participants identified as At-Risk gamblers (n = 20) compared to non-gambling controls (n = 20). We found a significant negative correlation between SICI strength and SSRT, but no correlation between ICF strength and SSRT after controlling for the correlation between SICI and SSRT. Thus, poor inhibitory control of responding was associated with weak GABAergic activity. When taking into account the effects of substance/alcohol use and attention-deficit hyperactivity disorder (ADHD) symptom severity, At-Risk gamblers showed elevated self-reported impulsivity, but did not differ from controls on SSRT or SICI/ICF. Our study is the first to show that individual differences in motor cortex inhibition can predict stopping performance, and the first to investigate paired-pulse TMS parameters (together with other impulse control measures) in a gambling population.

Pathological Gambling and Motor Impulsivity: A Systematic Review with Meta-Analysis.

Motor impulsivity, which is an impairment in withholding and cancelling inappropriate responses, may account for the inability for pathological gamblers (PGs) to inhibit their urges to gamble. The aim of this systematic review was to perform a quantitative and qualitative synthesis of existing studies in order to assess whether PGs without comorbid substance use disorder have elevated motor impulsivity, relative to healthy controls. An exhaustive literature search led to the identification of 20 studies which met inclusion criteria. A meta-analysis was then conducted on the following measures: stop signal reaction time from the stop signal task; commission errors, omission errors, and Go reaction time from the Go/No-Go task; and the motor impulsiveness subscale of the Barratt Impulsiveness Scale (BIS-Motor). The results revealed a moderate to large mean effect size of stop signal reaction time, small to moderate mean effect sizes for commission errors, omission errors and Go reaction time, and a large mean effect size for the BIS-Motor. Significant heterogeneity in effect sizes was observed on most behavioural measures, but not for the BIS-Motor or omission errors on the Go/No-Go task. Overall, these results suggest that motor impulsivity may be one of the features of PG psychopathology, accounting for their poor inhibitory control over gambling behaviours. Moreover, other deficits in sustained attention, or more generally in executive/cognitive control, may be present in PGs. We discuss the implications, limitations of existing research, and suggested avenues for future studies, particularly the need to acknowledge heterogeneity amongst PGs and amongst different behavioural measures.

Translucency and the perception of shape.

Previous studies have shown that the perceived three-dimensional (3D) shape of objects depends on their material composition. The majority of this work has focused on glossy, flat-matte, or velvety materials. Here, we studied perceived 3D shape of translucent materials. We manipulated the spatial frequency of surface relief perturbations of translucent and opaque objects. Observers indicated which of two surfaces appeared to have more bumps. They also judged local surface orientation using gauge probe figures. We found that translucent surfaces appeared to have fewer bumps than opaque surfaces with the same 3D shape (Experiment 1), particularly when self-occluding contours were hidden from view (Experiment 2). We also found that perceived local curvature was underestimated for translucent objects relative to opaque objects, and that estimates of perceived local surface orientation were similarly correlated with luminance for images of both opaque and translucent objects (Experiment 3). These findings suggest that the perceived mesoscopic shape of completely matte translucent objects can be underestimated due to a decline in the steepness of luminance gradients relative to those of opaque objects.

Image Statistics and the Fine Lines of Material Perception.

We experience vivid percepts of objects and materials despite complexities in the way images are structured by the interaction of light with surface properties (3D shape, albedo, and gloss or specularity). Although the perception of gloss (and lightness) has been argued to depend on image statistics (e.g., sub-band skew), studies have shown that perceived gloss depends critically on the structure of luminance variations in images. Here, we found that separately adapting observers to either positive or negative skew generated declines in perceived gloss, contrary to the predictions of theories involving image statistics. We also found similar declines in perceived gloss following adaptation to contours geometrically correlated with sharp specular edges. We further found this aftereffect was stronger when contour adaptors were aligned with specular edges compared with adaptation to the same contours rotated by 90°. These findings support the view that the perception of gloss depends critically on the visual system's ability to encode specular edge structure and not image skew.