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Cortico-subcortical β burst dynamics underlying movement cancellation in humans

  1. Darcy A Diesburg  Is a corresponding author
  2. Jeremy DW Greenlee
  3. Jan R Wessel  Is a corresponding author
  1. Department of Psychological and Brain Sciences, University of Iowa, United States
  2. Department of Neurosurgery, University of Iowa Carver College of Medicine, United States
  3. Iowa Neuroscience Institute, University of Iowa, United States
  4. Department of Neurology, University of Iowa Carver College of Medicine, United States
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Cite this article as: eLife 2021;10:e70270 doi: 10.7554/eLife.70270

Abstract

Dominant neuroanatomical models hold that humans regulate their movements via loop-like cortico-subcortical networks, which include the subthalamic nucleus (STN), motor thalamus, and sensorimotor cortex (SMC). Inhibitory commands across these networks are purportedly sent via transient, burst-like signals in the β frequency (15–29 Hz). However, since human depth-recording studies are typically limited to one recording site, direct evidence for this proposition is hitherto lacking. Here, we present simultaneous multi-site recordings from SMC and either STN or motor thalamus in humans performing the stop-signal task. In line with their purported function as inhibitory signals, subcortical β-bursts were increased on successful stop-trials. STN bursts in particular were followed within 50 ms by increased β-bursting over SMC. Moreover, between-site comparisons (including in a patient with simultaneous recordings from SMC, thalamus, and STN) confirmed that β-bursts in STN temporally precede thalamic β-bursts. This highly unique set of recordings provides empirical evidence for the role of β-bursts in conveying inhibitory commands along long-proposed cortico-subcortical networks underlying movement regulation in humans.

Editor's evaluation

This work makes an important contribution to the literature and addresses timely and interesting questions relating to the role of transient beta oscillations in cancelling motor responses in a rare and valuable dataset.

https://doi.org/10.7554/eLife.70270.sa0

Introduction

Movement cancellation – that is, the ability to stop ongoing or prepotent movements when necessary – allows humans to adapt their behavior quickly to changing environmental demands. A predominant paradigm used to investigate inhibitory control is the stop-signal task (SST), wherein participants are tasked with executing and sometimes cancelling movements (Logan et al., 1984; Verbruggen et al., 2019). This task allows for computation of the duration of the latent cancellation process (stop-signal reaction time, SSRT), although no overt response is made when participants successfully stop (Verbruggen,, 2008; Boucher et al., 2007.) The neural pathways underlying movement cancellation comprise a fronto-basal ganglia (FBg) network for inhibitory control (Wessel and Aron, 2017), which recruits known anti-kinetic basal ganglia pathways (Jahanshahi et al., 2015). When a stop-signal occurs, the right inferior frontal cortex (rIFC) purportedly excites the subthalamic nucleus (STN) via a monosynaptic ‘hyperdirect’ pathway between the two regions (Nambu et al., 2002; Aron, 2007; Chen et al., 2020). Subsequently, the STN broadly excites the internal segment of the globus pallidus (GPi; Parent and Hazrati, 1993; Gillies and Willshaw, 1998), the output nucleus of the basal ganglia. In turn, the GPi inhibits the ventral oral posterior (Vop) region of the motor thalamus (Inase and Tanji, 1995; Kuo and Carpenter, 1973). It has been proposed that the resultant net-inhibition of thalamocortical signaling loops (i.e., motoric loops between thalamus and sensorimotor cortex) enables the type of rapid movement cancellation found in tasks like the SST (Parent and Hazrati, 1993; Jahanshahi et al., 2015).

Recordings from nodes of this FBg network have revealed that communication through these pathways likely occurs in the β frequency band. During movement execution, decreases in averaged β power are observed over sensorimotor cortex (SMC; both intracranially and on the scalp, Crone et al., 1998; Pfurtscheller and Lopes da Silva, 1999; Kühn et al., 2004; Takemi et al., 2013) and in subcortical motor regions such as the STN (Alegre et al., 2005) and the ventral intermediate (VIM) nucleus of the motor thalamus, a part of motor thalamus adjacent to Vop (Basha et al., 2014). In contrast, averaged β power is increased in SMC and STN when inhibitory control is required, both following stop-signals in the SST (Wessel et al., 2016 ; Swann et al., 2009; Swann et al., 2011; Ray et al., 2012; Alegre et al., 2013; Benis et al., 2014; Bastin et al., 2014) and during motor conflict more broadly (Brittain et al., 2012; Wessel et al., 2019). Similar increases in β power during movement cancellation are observed in cortical regions ostensibly upstream of the STN and thalamus, such as the pre-supplementary motor area (Swann et al., 2012; Picazio et al., 2014) and the rIFC (Swann et al., 2009). Together, these findings have established cortical and subthalamic β activity as an index of inhibitory control.

However, cross-species research has revealed that these changes in β power do not reflect sustained β oscillations at the single-trial level (Feingold et al., 2015; Sherman et al., 2016; Shin et al., 2017; Tinkhauser et al., 2017; Maling et al., 2018; Cagnan et al., 2019). Unaveraged β activity has properties better characterized as intermittent bursting instead of slow-and-steady modulations of amplitude (van Ede et al., 2018). In line with this, β bursts are more predictive of behavior than fluctuations in averaged β power. For example, perceptual stimuli preceded closely by β bursts in somatosensory cortex are less likely to be detected (Shin et al., 2017) and β bursts in motor cortex closely preceding imperative stimuli are associated with slower responses (Little et al., 2019). Biophysical computational models suggest that these bursts in SMC relate to coincident proximal and distal excitatory drives to the synapses of neocortical pyramidal neurons (Sherman et al., 2016). Thus, not only do β bursts carry fine-grained information about behavior on the single-trial level, they also relate more closely to underlying mechanisms than averaged β. Notably, two recent studies have demonstrated that β bursts on the scalp relate to the inhibitory aspects of movement regulation. One study demonstrated reductions in β burst rates over SMC during go trials, as well as increases in burst rates over frontocentral and motor cortices during stop trials, and found that successful stop trials featured a greater number of frontocentral β bursts before SSRT on average than failed stop trials (Wessel, 2020). A subsequent study by Jana et al., 2020 demonstrated that β bursts over prefrontal cortex were followed within 20ms by broad skeleto-motor suppression and within 40ms by outright cancellation detectable at the motor effector.

While these studies identify potential (pre)frontal cortical control signals associated with movement cancellation, they are uninformative regarding the downstream basal ganglia-thalamic dynamics through which inhibitory control of SMC is ostensibly implemented. Although transient β bursts are known to exist in the STN (Torrecillos et al., 2018; Lofredi et al., 2019), it is unclear what functional role subcortical β bursts play during movement regulation, and whether their dynamics conform to the dominant neurophysiological and neuroanatomical models of inhibitory control. Beyond generating basic knowledge about the neurophysiology of basal ganglia motor circuitry, elucidating these dynamics would also greatly inform therapeutic approaches that are already targeting the known pathological β bursting that occurs in these subcortical regions (Tinkhauser et al., 2017; Little and Brown, 2020).

Our aims for the current study were twofold. Firstly, we investigated whether β bursts in subcortical regions of basal ganglia-thalamic inhibitory pathways are associated with movement cancellation. To this end, we investigated the relationship between SST performance and β burst rates in both STN and motor thalamus. Furthermore, we tested whether these subcortical bursts have reliable temporal relationships with movement-related β bursts in SMC, suggestive of an inhibitory influence of the subcortical regions on SMC. Secondly, we evaluated existing models of inhibitory control networks by assessing relative timing of bursts across subcortical recording sites. The dominant model of a fronto-basal ganglia circuit for inhibitory control suggests that movement cancellation is accomplished by net-inhibition of the motor thalamus by STN (Jahanshahi et al., 2015). Hence, in line with the proposition that STN is recruited before the thalamus during cancellation, we expected β bursts related to movement cancellation to emerge first in the STN, followed by bursts in the thalamus.

We collected recordings of local field potentials (LFPs) simultaneously from SMC and a subcortical site (either the STN or motor thalamus) during awake deep-brain stimulation (DBS) lead implantation surgery in two groups of patients: patients with Parkinson’s disease (PD) undergoing STN implantation and essential tremor (ET) patients undergoing implantations in the motor thalamus. Moreover, data from one highly unique PD patient included simultaneous recordings from all three locations: SMC, STN, and motor thalamus. During the recordings, patients performed an auditory version of the SST to test their ability to rapidly cancel movements. This study leverages unique multi-site intracranial recordings and a cognitive paradigm to investigate the circuit dynamics of cortical and subcortical β bursts during movement cancellation.

Results

Behavior

While LFPs were recorded from SMC and either STN or thalamus, 21 participants completed an auditory SST (see Figure 3—figure supplement 1). Behavioral results are shown in Table 1. To confirm that patients’ diagnoses did not affect cognitive performance or task strategies in a way that would preclude comparing the two participant groups, we compared behavioral performance between the STN and thalamic groups. Go accuracy was the only behavioral metric which significantly differed between the STN and thalamic groups, with thalamic patients responding more accurately on go-trials (94% vs 83% accuracy, T(19) = 5.22, p < 0.0001, d = 2.27). Numerically, the thalamic implant group also responded faster during correct go and failed stop trials and cancelled movements more quickly than STN DBS patients, as indicated by SSRT (which was in the typical elongated range for movement disorder patients: Gauggel et al., 2004; Obeso et al., 2011; Hughes et al., 2019). However, none of these results were significant, indicating comparable task performance between both groups. (Go RT: T(19) = –0.19, p = 0.85, d = 0.08; Failed stop RT: T(19) = –0.58, p = 0.57, d = 0.25; SSRT: T(19) = –1.11, P = 0.28, d = 0.48; Stop accuracy: T(19) = 1.59, P = 0.13, d = 0.68.)

Table 1
Means of stop-signal task behavioral performance metrics.

* Indicates significant difference between thalamic and STN groups at p < 0.0001. SD = standard deviation.

Reaction times (ms)Accuracy
GoFailed stopSSRTGo trials*Stop trials
All participants
943 (SD: 213)763 (SD: 174)474 (SD: 232)0.89 (SD: 0.07)0.61 (SD: 0.16)
STN DBS
952 (SD: 234)786 (SD: 213)533 (SD: 296)0.83 (SD: 0.05)0.55 (SD: 0.18)
Thalamic DBS
934 (SD: 203)741 (SD: 136)421 (SD: 150)0.94 (SD: 0.04)0.65 (SD: 0.11)

Averaged event-related spectral perturbation (ERSP) analysis

To confirm accurate electrode placement over hand-related areas of SMC, event-related spectral perturbation (ERSP) was quantified from –100 preceding to 1500 ms following the go-signals in a go-only localizer task. This short, 40-trial block was identical to the main stop-signal task but did not contain stop signals (in other words, it was a speeded two-choice response task) and was administered before the subcortical lead placement. While in the OR, we then visually checked the ERSPs for a decrease in average β band amplitude, a known signature of movement-related activity in SMC (cf., Crone et al., 1998; Pfurtscheller and Lopes da Silva, 1999; Kühn et al., 2004; Takemi et al., 2013), to confirm SMC electrode placement for the main experiment. More information about the localization process can be found in the Methods section. We then quantitatively investigated these relationships after surgery and found decreases in averaged β band (15–29 Hz) power observed at contralateral (to the response) SMC sites following go signals (see Figure 1A). This pattern was evident in both the localizer task and during the main SST.

Figure 1 with 1 supplement see all
Averaged β power and β burst rates decreased across recording sites during movement execution.

(A) Broadband ERSPs shown were computed from 100ms preceding to 1500ms following the go signal. The two left-most plots include ERSPs from the localizer block and the right-most plots include ERSPs during the main block. In averaged ERSPs during movement on go-trials, both localizer and main task sessions show clearly visible β power decreases following the go signal. (B) Average burst rates at each recording location following the go-signal and surrounding response execution (for go and failed stop trials) are depicted in time bins of 100ms. During the main task session, β burst rates decrease quickly following the go signal in STN, thalamus (both ventral and dorsal contacts), and SMC until a response is made.

β is burst-like in subcortex and cortex

To determine whether β was indeed burst-like in our data, as opposed to an ongoing, oscillatory signature, we used a lagged coherence analysis (as in Wessel, 2020). Lagged coherence describes to what degree the current phase of a signal predicts its own phase in the future (Fransen et al., 2015). Signals that are oscillatory in nature can be expected to predict their own activity many cycles on, while phase of a transient signal will be less predictive of future activity in the same frequency band. In line with the assertion that β is a transient and not an oscillatory signal, we observed decreasing levels of lagged coherence in the β band as the number of cycles increased (Figure 2A). Moreover, at three cycles, a trough in lagged coherence is observed in the search band for β bursts (15–29 Hz) compared to surrounding frequencies at all recording locations (Figure 2B). This lagged coherence trough was most pronounced in the SMC and least pronounced in compared to neighboring frequencies in the thalamus, suggesting that SMC β is most burst-like and thalamic β more sustained in nature. STN β was slightly less burst-like compared to SMC β, but we note this could be an artifact of pathologically long STN β bursts characterized in movement disorders (Little et al., 2013; Anidi et al., 2018).

Results from a lagged coherence analysis on epoched data including go and stop trials.

(A) While coherence is relatively high at one cycle (current phase predicts phase in one cycle well), lagged coherence decreases over time so that lagged coherence in the β band is relatively low at three cycles across recording locations. This supports the claim that β is transient and not oscillatory in nature. (B) Coherence shown is at three cycles. The β burst search band (15–29 Hz) represents a relative trough compared to below- and above-β frequencies, indicating that β signals are more transient and less oscillatory than signals in neighboring frequency bands. β is most burst-like in the SMC, slightly less burst-like in STN, and least burst-like compared to neighboring frequencies in the thalamus.

Having confirmed that β is indeed burst-like in our recording, we quantified several qualities of the observed β bursts and found that, on average, peak β burst frequency during the burst search window across the entire recording was 22 Hz in STN, 20 Hz in ventral thalamus, 21 Hz in dorsal thalamus, and 22 Hz in SMC. Average β burst duration was 127 ms in STN, 108 ms in ventral thalamus, 111 ms in dorsal thalamus, and 126 ms in SMC. The subsequent analyses described herein address β burst rates and counts, which have been found to be highly predictive of behavior (Sherman et al., 2016; Shin et al., 2017; Little et al., 2019; Wessel, 2020; Jana et al., 2020; Enz et al., 2021).

β bursts decrease during movement initiation

We first investigated whether the SMC and subcortical sites showed corresponding movement-related reductions in β burst rates leading up to the response (Wessel, 2020; Soh et al., 2021). Implantation in the motor thalamus specifically targeted the ventral intermediate nucleus (VIM, Benabid et al., 1993; Lozano, 2000). Neurosurgical implantation of VIM DBS multi-electrode leads positions electrodes on the border of the VIM and the ventral oral posterior (Vop) nuclei of the thalamus, which receive cerebellar (Na et al., 1997) and pallidal inputs (Inase and Tanji, 1995; Kuo and Carpenter, 1973), respectively. Both VIM and Vop are prominently involved in motor function. Due to volume conduction and the small size of these nuclei, we expected the thalamic depth-electrode recordings to be summative recordings from multiple nuclei within motor thalamus (VIM, Vop, and potentially the ventral oral anterior nucleus). To investigate whether contributions of different thalamic nuclei could be parsed in our thalamic recordings, we analyzed the most ventral and most dorsal contact pairs within motor thalamus separately. Notably, the results from both contact pairs were remarkably similar for most statistical comparisons, suggesting that all thalamic contacts captured contributions from a similar set of thalamic motor nuclei. While the same dorsal-ventral distinction is not typically used in analyses of STN (where one specific electrode contact pair can typically be identified as localized in STN by a clear-cut peak in the β activity spectrum), we also performed STN analyses split by dorsal-ventral pairs. However, these analyses are presented in the Figure supplements only. In the main analyses, we follow the convention of selecting one STN contact pair based on the overall amount of detected β bursts throughout the entire recording.

Burst rates were quantified in non-overlapping bins of 100ms starting from the go signal. Indeed, we observed reductions in β burst rates during movement execution in all recording locations. 3 × 2 ANOVAs revealed significant effects of TIMEPOINT on burst rate in STN (F(2,8) = 8.78, p < 0.0001, η2 = 0.31), ventral thalamus (F(2,10) = 6.79, p < 0.0001, η2 = 0.25), dorsal thalamus (F(2,10) = 15.85, p < 0.0001, η2 = 0.37), and SMC (F(2,19) = 8.04, p < 0.0001, η2 = 0.22; see Figure 1B). In the STN group, there was also a significant effect of TRIAL TYPE (F(2,8) = 4.95, p = 0.02, η2 = 0.02) on burst rate, but no TRIAL TYPE X TIMEPOINT interaction (F(2,8) = 1.58, p = 0.08, η2 = 0.05). On the other hand, for the ventral thalamic electrodes, there was no significant effect of TRIAL TYPE (F(2,10) = 2.85, p = 0.08, η2 = 0.02) on burst rate, but there was a significant TRIAL TYPE X TIMEPOINT interaction (F(2,4) = 1.77, p = 0.04, η2 = 0.05). Dorsal thalamic electrodes did not exhibit significant effects of TRIAL TYPE (F(2,10) = 0.98, p = 0.39, η2 = 0.005) or a TRIAL X TIMEPOINT interaction (F(2,10) = 0.68, p = 0.81, η2 = 0.02).

For response-locked burst rates, ANOVAs revealed significant effects of TIMEPOINT on burst rate in STN (F(2,8) = 4.47, p = 0.0002, η2 = 0.27), ventral thalamus (F(2,10) = 3.07, p = 0.005, η2 = 0.16), dorsal thalamus (F(2,10) = 2.22, p = 0.03, η2 = 0.09), and SMC (F(2,19) = 2.58, p = 0.01, η2 = 0.09; see Figure 1B). For ventral thalamic sites, there were also significant effects of TRIAL TYPE (F(2,10) = 6.92, p = 0.03, η2 = 0.01) and a TRIAL TYPE X TIMEPOINT interaction (F(2,10) = 2.39, p = 0.02, η2 = 0.06). For dorsal thalamus, there was a significant main effect of TRIAL TYPE (F(2,10) = 5.67, p = 0.04, η2 = 0.01), but no TRIAL TYPE X TIMEPOINT interaction (F(2,10) = 3.07, p = 0.005, η2 = 0.03).

These findings are in line with the proposition that β bursts are related to an inhibited state of the motor system, which must be downregulated to achieve a net-disinhibition of the cortico-subcortical motor circuitry and enable movement (e.g. Soh et al., 2021).

β bursts increase during movement cancellation

At rest, the basal ganglia prevent erroneous movement through exertion of tonic inhibition. Furthermore, it has been demonstrated that β bursts are inhibitory with regards to movement (Little et al., 2019; Soh et al., 2021). Accordingly, the main hypothesis of our study was that after stop-signals in the SST, motor inhibition is achieved by a rapid re-instantiation of an inhibited state in SMC, preceded by β burst signaling from the subcortical nuclei. To test this hypothesis, we first investigated whether successful stop-trials were accompanied by an increase in subcortical β bursting compared to matched go-trials and failed stop-trials.

Indeed, during the critical time period between the onset of the stop signal and the end of SSRT, a significant main effect of TRIAL TYPE (successful stop, failed stop, fast and slow matched go) on burst count was found in STN and thalamus (STN: F(9) = 3.89, p = 0.02, η2 = 0.30; ventral thalamus: F(11) = 5.89, p = 0.002, η2 = 0.35; dorsal thalamus: F(11) = 3.01, p = 0.04, η2 = 0.22). Follow-up pairwise t-tests revealed that this was due to a significant increase in bursts in the stop signal delay (SSD)-SSRT period for successful stop trials compared to slow matched go trials (STN: P = 0.04; ventral thalamus: p = 0.03; dorsal thalamus: p = 0.03) and successful stop trials compared to failed stop trials (STN: p = 0.04; ventral thalamus: p = 0.04; see Figure 3). On the other hand, failed stop trials did not contain significantly more bursts in the SSD-SSRT window compared to fast matched go trials (STN: p = 0.38; ventral thalamus: p = 0.15; dorsal thalamus: p = 0.53). These findings are in line with the assumption that early-latency subcortical β bursting reflects a rapid deployment of inhibitory control after a stop-signal.

Figure 3 with 4 supplements see all
β burst rates increase following stop signals.

(A) Increases in average β band activity are observed at all subcortical recording sites during stop trials (contrast shown is between successful stops and correct go trials). (B) The total number of β bursts was quantified between trial-wise stop-signal onset (SSD) and participant-wise SSRT. For matched go-trials, this window began at current SSD stored in the staircase. Each point represents the average burst count for one participant. β bursts increased at early latencies in STN and thalamus during successful cancellation (when quantified between SSD and SSRT) and at later latencies in both thalamus and STN during stop trials (panel D). (C) The differences in burst counts and rates in panels B and D could not be accounted for by differences in pre-go or pre-stop baseline burst rates, quantified in the 100ms preceding go- or stop-signal onset. (D) Average burst rates at each subcortical recording location time-locked to the stop-signal (left) or subject-wise SSRT (right) are depicted in time bins of 100ms. The gray lines on the time-bin plots show the SSRT sample average for STN and thalamic DBS patient groups. (Significant comparisons key: green stars = comparison between successful stop and go trials, navy stars = comparison between successful and failed stop trial; * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001. Significant effects displayed in the plot are effects of TRIAL TYPE, on burst counts (B) or on burst rates at given time points (D).

As a control analysis, we also compared burst rates across trial types in the baseline periods before the stop signal and go signal. A 3 × 1 ANOVA revealed no significant effects of TRIAL TYPE on β bursts in the pre-stop baseline for either STN or thalamus (STN: F(2,8) = 1.09, p = 0.36, η2 = 0.11; ventral thalamus: F(2,10) = 2.45, p = 0.11, η2 = 0.20; dorsal thalamus: F(2,10) = 1.35, p = 0.28, η2 = 0.12). There was also no significant effect of TRIAL TYPE on β bursts in the pre-go baseline at any subcortical recording location (STN: F(2,8) = 0.11, p = 0.89, η2 = 0.01; ventral thalamus: F(2,10) = 1.09, p = 0.35, η2 = 0.10; dorsal thalamus: F(2,10) = 0.25, p = 0.78, η2 = 0.02). Hence, the stop-signal related differences in burst rates were not attributable to differences in the baseline rates between trial types.

Stimulus-locked burst rates

To map out β burst dynamics in the post-go and post-stop periods, we calculated the average burst rate in non-overlapping time bins of 100ms covering the 1000 ms period starting 100ms before the stop-signal (or for matched go trials, the time at which the stop signal would have occurred, as indicated by the current stop-signal delay in the staircase). While this does not take into account each participants’ SSRT, it does provide a more comprehensive picture of the development of subcortical β bursting over time. In the STN, we observed significant effects of TRIAL TYPE (F(2,8) = 35.14, p < 0.0001, η2 = 0.19) and TIMEPOINT (F(2,8) = 4.19, p = 0.0003, η2 = 0.13), as well as a significant TRIAL TYPE X TIMEPOINT interaction (F(4,8) = 5.87, p < 0.0001, η2 = 0.14). The same pattern was observed in the ventral thalamus, again with significant main effects of TRIAL TYPE (F(2,10) = 26.97, p < 0.0001, η2 = 0.20) and TIMEPOINT (F(2,10) = 3.16, p = 0.004, η2 = 0.08), and a TRIAL TYPE X TIMEPOINT interaction (F(4,10) = 6.00, p < 0.0001, η2 = 0.15). Moreover, dorsal thalamic electrodes demonstrated significant main effects of TRIAL TYPE (F(2,10) = 20.05, p < 0.0001, η2 = 0.17) and TIMEPOINT (F(2,10) = 3.77, p = 0.001, η2 = 0.07), and a TRIAL TYPE X TIMEPOINT interaction (F(4,10) = 6.63, p < 0.0001, η2 = 0.17).

Pairwise follow-up t-tests were used to probe differences between successful stops and go trials and between successful and failed stop trials at individual time bins. Burst rates for successful stop trials were significantly greater than for go trials at 601–700ms (p < 0.001), 701–800ms (p < 0.001), and 801–900ms (p < 0.001) following SSD in the STN and at 501–600ms (p = 0.002), 601–700ms (p = 0.02), 701–800ms (p = 0.02), and 801–900ms (p < 0.001) following SSD in the ventral thalamus (see Figure 3). In the ventral thalamus, there were also significant differences between successful and failed stop trial burst rates at 401–500 (p = 0.04) and 501–600ms (p = 0.05) following SSD. In dorsal thalamus, significant differences in burst rates were observed between successful stops and go trials at 501–600 (p = 0.02), 601–700 (p = 0.004), 701–800 (p = 0.002), and 801–900ms (p < 0.001), and between successful and failed stop trials at 701–800ms (p = 0.01). Note that there was no increase in pre-SSRT β bursting on successful stop-trials in this bin-wise quantification, which is at odds with the above-mentioned quantification that measured β burst counts in each individual subjects’ stop-signal-to-SSRT period. This suggests a tight relationship between β burst dynamics and inhibitory control behavior measured by each individual’s SSRT – resulting in the fact that differences in β burst rates after stop-signals are obscured when between-subject differences in SSRT are not taken into account. In line with the hypothesis that β bursts reflect the re-instantiation of tonic rest inhibition, burst rates in the first bin with a significant difference between successful stop-go trial were not significantly different from burst rates in the pre-go baseline (STN: p = 0.97; ventral thalamus: p = 0.43; dorsal thalamus: p = 0.13), during which tonic inhibition is present. However, there were significant differences between burst rates in these time bins and the pre-stop baseline in the thalamus (ventral thalamus: p = 0.003; dorsal thalamus: p = 0.008), but not the STN (p = 0.08).

SSRT-locked burst rates

In the STN, we observed significant effects of TRIAL TYPE (F(2,8) = 25.62, p < 0.0001, η2 = .11) and TIMEPOINT (F(2,8) = 5.25, p < 0.0001, η2 = 0.17), as well as a significant TRIAL TYPE X TIMEPOINT interaction (F(4,8) = 6.99, p < 0.0001, η2 = 0.17) on burst rates in time bins locked to participant-wise SSRT. The same pattern was observed in the ventral thalamus, again with significant main effects of TRIAL TYPE (F(2,10) = 8.57, p = 0.002, η2 = 0.12) and TIMEPOINT (F(2,10) = 5.51, p < 0.0001, η2 = 0.13), and a TRIAL TYPE X TIMEPOINT interaction (F(4,10) = 3.94, p < 0.0001, η2 = 0.11). Moreover, dorsal thalamic electrodes demonstrated significant main effects of TRIAL TYPE (F(2,10) = 5.96, p = 0.009, η2 = 0.07) and TIMEPOINT (F(2,10) = 4.89, p < 0.0001, η2 = 0.09), and a TRIAL TYPE X TIMEPOINT interaction (F(4,10) = 4.56, p < 0.0001, η2 = 0.15).

Pairwise follow-up t-tests were used to probe differences between successful stops and go trials and between successful and failed stop trials at individual time bins surrounding SSRT. In the STN, significant differences between β burst rates during successful stop and go trials were observed at 100–0ms (p = 0.047) preceding the stop-signal and at 101–200ms (p = 0.009), 201–300ms (p = 0.04), and 301–400ms (p = 0.004) following the stop-signal. In the ventral thalamus, significant differences between β burst rates during successful stop and go trials were observed at 201–300ms (p = 0.047) and 301–400ms (p = 0.04) following the stop-signal. In the dorsal thalamus, significant differences between β burst rates during successful stop and go trials were observed at 500–400ms (p = 0.02) before the stop-signal and at 101–200ms (p = 0.02), 201–300ms (p = 0.01), and 301–400ms (p = 0.006) following the stop-signal.

STN β bursts upregulate SMC bursts during cancellation

The proposition that inhibitory control is implemented via a rapid re-instantiation of SMC inhibition following β bursts in STN/Thalamus implies that SMC β burst rates should be increased in the immediate aftermath of subcortical bursts (cf., Wessel, 2020 for a demonstration of the same relationship between β bursts at fronto-central scalp sites likely reflecting cortical regions of the stopping network upstream from the subcortical nuclei investigated here and subsequent β-burst rates over SMC). To test this, we quantified SMC β bursting time-locked to the first subcortical β bursts following the stop-signal within 500ms. Indeed, there was a main effect of TIMEPOINT (F(2,8) = 5.22, p = 0.006, η2 = 0.14) on SMC bursts time-locked to STN bursts. Moreover, follow-up t-tests revealed that bursts in STN were followed within 50ms by a difference between burst rates for successful stops compared to go trials, with burst rates increasing for successful stops, though this difference did not survive multiple-comparisons corrections (uncorrected p = 0.03; see Figure 4).

Figure 4 with 1 supplement see all
β burst rates in SMC increase following STN bursts.

The left column of plots displays the timing of SMC bursts with respect to subcortical bursts, in 50ms time bins. The right column displays timing of subcortical bursts with respect to SMC bursts. All burst rates were calculated in the 500ms following stop-signal onset (or SSD, for matched-go trials). Each gray dot is the average burst rate per participant in the given time bin. In the STN group, the first STN burst following the stop signal (or SSD, for matched-go trials) was followed within 50ms by bursts in the SMC for stop, but not go, trials. This reliable temporal relationship between STN and SMC bursts during movement cancellation did not follow the opposite pattern – STN bursts did not reliably follow SMC bursts at a specific time point. (Significant comparison key: green stars = comparison between successful stop and go trials; * indicates uncorrected p < 0.05. Effects indicated in the figure are effects of TRIAL TYPE on burst rate at given time points.)

Our 2 × 2 ANOVA did not reveal a significant effect of TRIAL TYPE (F(2,8) = 0.54, p = 0.59, η2 = 0.01) or a TRIAL TYPE x TIMEPOINT interaction (F(4,8) = 1.94, p = 0.09, η2 = 0.07) for SMC bursts time-locked to STN bursts. Likewise, no effects of TRIAL TYPE (F(2,10) = 1.55, p = 0.24, η2 = 0.05), TIMEPOINT (F(2,10) = 1.71, p = 0.19, η2 = 0.03), or an interaction (F(4,10) = 0.81, p = 0.58, η2 = 0.04) were found for SMC bursts time-locked to ventral thalamic bursts. There was a significant effect of TIMEPOINT (F(2,10) = 4.15, p = 0.01, η2 = 0.09) on burst rates in SMC following dorsal thalamic bursts, but no effect of TRIAL TYPE (F(2,10) = 0.31, p = 0.74, η2 = 0.01) or a TRIAL TYPE x TIMEPOINT interaction (F(4,8) = 0.15, p = 0.99, η2 = 0.005). There were no significant pairwise differences between burst rates in ventral or dorsal thalamus for successful stops versus failed go trials. As described in the previous paragraph, despite the absence of a significant main effect of TRIAL TYPE, we conducted pairwise tests between successful go and matched go burst rates at individual time points because of our strong a priori hypothesis that β bursts in SMC would increase following STN bursts. This hypothesis was derived directly from a similar observation in Wessel, 2020, wherein SMC β bursts were increased within 25ms of frontocentral β bursts.

Conversely to the increase in SMC burst rate after STN bursts, we did not see an increase of STN β bursts following SMC bursts. A 2 × 2 ANOVA of burst rates in STN, ventral thalamus, and dorsal thalamus time-locked to SMC bursts revealed an effect of TIMEPOINT in all regions (STN: F(2,8) = 3.73, p = 0.02, η2 = 0.08; ventral thalamus: F(2,10) = 3.10, p = 0.04, η2 = 0.05; dorsal thalamus: F(2,10) = 2.89, p = 0.05, η2 = 0.04) and an effect of TRIAL TYPE in ventral thalamus (F(2,10) = 5.32, p = 0.01, η2 = 0.13), but no significant main effects of TRIAL TYPE in STN (F(2,8) = 0.76, p = 0.48, η2 = 0.03) or interactions between the two factors (STN: F(4,8) = 0.69, p = 0.66, η2 = 0.03; ventral thalamus: F(4,10) = 1.12, p = 0.36, η2 = 0.04). In dorsal thalamus, there were no main effects of TRIAL TYPE (F(2,10) = 0.21, p = 0.81, η2 = 0.01) or a TRIAL TYPE x TIMEPOINT interaction (F(4,8) = 0.94, p = 0.47, η2 = 0.02). No significant pairwise comparisons were found for burst rates during successful stops compared to go trials at individual time points in any region except for a difference at the –100 to –50ms timepoint in the STN was significant before multiple comparisons correction (uncorrected p = 0.02).

The observation of elevated SMC β bursts following, but not preceding, STN bursts supports the proposition that subcortical bursts lead to a rapid upregulation of SMC bursts during stopping.

STN β bursts precede thalamic bursts during cancellation

A key prediction of existing network models of inhibitory control is that STN is upstream from motor thalamus (specifically, from the pallidal projection regions in Vop). In other words, during the purported cascade that results in movement cancellation, STN signaling should temporally precede thalamic signals. To test whether this is the case for the β burst signals observed in this study, we calculated the average latency of the first β burst after the stop signal for each subcortical recording site and compared them between groups (as well as within a single subject with simultaneous recordings from both sites). To account for differences in SSRT across participants, we quantified the onset latency of first bursts with respect to participant-wise SSRT. Across the group-level sample, STN bursts on average occurred before ventral and dorsal thalamic bursts during stop trials (see Figure 5A). While there was a significant effect of first burst time on TRIAL TYPE (with the first burst occurring earlier on successful stop trials compared to failed stop-trials in both ventral thalamus and STN; F(1,19) = 8.32; p = 0.01; η2 = 0.02), there was no significant effect of LOCATION on average burst timing (F(1,19) = 1.90; p = 0.18; η2 = 0.08), and no interaction (F(1,19) = 0.42; p = 0.52; η2 = 0.001) when comparing STN to ventral thalamic contacts specifically. However, a 2 × 2 between and within-factors ANOVA revealed a significant TRIAL TYPE X LOCATION interaction for burst timing in STN and dorsal thalamus (F(1,19) = 5.06; p = 0.04; η2 = 0.02), although main effects of TRIAL TYPE (F(1,19) = 1.50; p = 0.24; η2 = 0.005) and LOCATION (F(1,19) = 2.98; p = 0.10; η2 = 0.12) were not present. Moreover, a follow-up t-test revealed significant differences between timing of STN and dorsal thalamic β bursts with respect to SSRT during successful stops (p = 0.03).

β bursts in STN precede bursts in thalamus.

A) The timing of first bursts from the STN in STN DBS patients and thalamic regions in thalamus DBS patients are shown with respect to the stop-signal (left) and participant-wise SSRT (right). First bursts were quantified between stop-signal onset and 1 s following stop-signal onset. Each gray dot represents a participant’s mean burst timing for each trial type and recording location. The central line on the barplots represents the average of single-subject mean burst timings. (B) The timing of first bursts from the STN and thalamic regions in the single subject with both STN and thalamic DBS are shown with respect to the stop-signal (left) and participant-wise SSRT (right). Each dot represents the timing of a burst for a single trial, while the central bar represents the median burst timing. Bursts that occur in each region before SSRT are counted. Across the entire study sample (A) and in our single subject with simultaneous STN and thalamic recording sites (B), STN bursts occurred earlier than dorsal thalamic bursts during cancellation. These findings from subcortical regions in our datasets lend support for an account of subcortical dynamics proposed in a theorized network model of movement cancellation, which posits that the STN is recruited prior to and acts to net-inhibit the thalamus during cancellation (red X indicates reduction of thalamocortical drive). (Significant comparison key: stars = comparison between burst timing in STN and dorsal thalamus; * indicates p < 0.05. Effects indicated in the figure are effects of BURST LOCATION on average burst timing.)

However, the ultimate test of burst timing differences across regions is provided by the single subject who had recordings from both regions, as this provides the only comparison performed in a situation with identical behavior (specifically, equal SSRT, which in this subject was 304ms). In line with the qualitative pattern observed in the group-level comparison, in this single subject, bursts in the STN occurred significantly earlier than bursts in the thalamus (specifically, in the dorsal thalamus) during stop trials with respect to the stop-signal (see Figure 5B), with t-tests between recording regions revealing significant differences between burst timing in STN and dorsal thalamus during successful stop trials (p = 0.03, one-sided), but not during failed stop trials (p = 0.19, one-sided). (These tests are one-tailed because of the strong a priori hypothesis that STN bursts would precede thalamus, and not the other way around.) Though some single-trial bursts across recording locations occurred after subject SSRT, the median burst timing occurred prior to SSRT in STN and ventral thalamus. The majority of STN and ventral thalamic bursts occurred before SSRT as well (see Figure 5B). This observation that cancellation-related STN bursts occur before bursts in the thalamus also supports accounts that movement regulation may be accomplished by STN-facilitated inhibition of the thalamus during a period before behavioral cancellation is observed (i.e., before SSRT).

Discussion

We used simultaneous, multi-site intracranial recordings in awake, behaving humans to delineate the cortico-subcortical β-burst dynamics that underlie the inhibitory control of movement. Our findings have significant implications for our understanding of inhibitory control in the human brain, as well as the nature of β signaling in human motor circuitry.

β bursts in the STN and thalamus relate to movement cancellation

β bursts in the human STN and thalamus relate to the rapid deployment of inhibitory control during movement cancellation in the SST. An analysis of subcortical β burst counts between SSD and SSRT revealed a greater number of bursts present during successful stops than during failed stops or matched go trials. Moreover, the analysis of first-burst timing revealed that in both STN and thalamus, the timing of the first burst distinguished successful from failed stopping, as earlier bursts lead to significantly higher rates of stopping. This is also prominently in line with the horse race model of the stop-signal task (Logan, 1983). (This finding of differential activation in STN depending on the success of stopping appears in conflict with recent 7T fMRI work that found greater BOLD activity in STN for failed compared to successful stops [Miletić et al., 2020]. However, the differences between these findings likely reflect the respective data collection methods [with fMRI having less temporal resolution] and the fact that action errors also activate STN [Cavanagh et al., 2014; Wessel and Aron, 2017]. Hence, we tentatively propose that greater BOLD activation in STN for failed stops reflects an additive effect of a double-activation of STN on failed stop-trials, where the initial stop-related activity and the subsequent error-related activity is summed up, whereas the latter activity is absent on successful stop-trials.)

Though there are inherent limitations to the ability to record from specific nuclei within the human motor thalamus, even when using stereotactic depth electrode recordings, the findings of elevated β bursting for successful stop trials within ventral thalamic electrodes supports the proposition that activity in motor thalamus is involved in movement cancellation. Our findings in intraoperative movement disorder participants mirror results recently obtained from scalp recordings in healthy subjects (Wessel, 2020, Jana et al., 2020), which demonstrated increased and earlier β bursts during movement cancellation at cortical sites that are ostensibly up-stream of the basal ganglia circuitry investigated here (cf., Chen et al., 2020). The current study is the first to concretely demonstrate the relationship between subcortical β bursts across multiple subcortical regions during movement cancellation in the human brain.

In addition to this early-latency β bursting in the SSD-SSRT period, we also observed clear increases in β bursts at later latencies, clearly after SSRT, in both subcortical regions. While we had no hypothesis about such a finding a priori (as the Mosher et al., 2020 report of these late-latency β bursts was published after our investigation concluded), we surmise that these later peaks in β bursting may relate to the slower activation of the basal ganglia indirect pathway during movement cancellation (Jahfari et al., 2011; Sano et al., 2013; Schmidt et al., 2013; Mallet et al., 2016). Indeed, one recent framework of movement cancellation, supported by a body of neurophysiological work in rodents, contains the proposition that stopping is a two-step and not a unitary process (Schmidt et al., 2013; Schmidt and Berke, 2017; Diesburg and Wessel, 2021). This two-step model, termed the ‘Pause then Cancel’ model, consists of two phases. An initial Pause involves rapid gating of STN through hyperdirect pathway activation. Meanwhile, a parallel Cancel phase implements indirect pathway activation to eliminate drive to movement from the direct pathway. The STN plays a critical role during both of these phases. Indeed, computational modeling of the human basal ganglia has suggested that inhibitory control could rely on activation of both the hyperdirect and indirect basal ganglia pathways in parallel. While the former implements the rapid gating of the STN, thereby raising the response threshold, the latter ultimately removes drive to movement from the direct basal ganglia pathway (Frank, 2006; Wiecki and Frank, 2013). If β bursts do in fact relate to both hyperdirect and indirect pathway activation, this has major implications for emerging theories of movement cancellation. Within the current dataset, the subcortical β burst dynamics are in line with this proposition, making them a candidate signature of a unitary signal that coordinates both hyperdirect and indirect pathway inhibition.

STN β bursts may influence motor output by raising SMC burst rates

By leveraging unique simultaneous recordings of SMC and subcortical regions, we found that early bursts in STN following stop signals appear to influence motor output. Indeed, the β burst rates in SMC were increased significantly within about 50ms after cancellation-related bursts in STN. Conversely, there was no such increase in STN bursting following SMC bursts (nor, surprisingly, in motor thalamus, in either direction). This suggests a degree of directionality in the relationship between bursts across these regions. Because of the specific directionality of this finding, it suggests that β bursts in STN might influence β burst rates in SMC. Given that β bursts in SMC have an inhibitory influence on motor output (Little et al., 2019), this points to a possible mechanism by which the STN can influence motor output during movement cancellation, though further research would be required to confirm a causal relationship.

STN β bursts precede thalamic bursts during movement cancellation

In line with the proposed cortico-subcortical cascade underlying inhibitory control, according to which cortical signals to STN lead to inhibition of the thalamus via the GPi, we found that β bursts following the stop signal across our study sample occur in STN earlier on average than in the motor thalamus. Specifically, STN bursts preceded bursts in the dorsal thalamus by a significant delay during successful stops. (Concerns about volume conduction and nuclei size in the motor thalamus notwithstanding, it is worth noting that these dorsal-most contacts are the ones most likely to be located in Vop according to the trajectory of implantation [see Materials and methods section] – i.e., the region that receives ostensibly inhibitory pallidal projections as part of the inhibitory basal ganglia pathways [see below].) A subsequent assessment of subcortical burst latency in the patient with both STN and thalamic recordings confirmed that stop signal-related STN β bursts on average occur prior to dorsal thalamic bursts within the same individual. Notably, this finding was a result of a highly unusual case, wherein thalamic implants were revised and STN implants placed, lending an opportunity to record from both regions at once. This evidence lends insight into human inhibitory control circuits that would be impossible to obtain under any other circumstances or by using noninvasive methodological approaches in humans. We chose to quantify the timing of first post-stop-signal bursts in subcortical regions but not SMC because there are baseline levels of non-evoked β bursting in SMC (which are further increased in proactive control contexts, i.e., Soh et al., 2021) which make quantifying timing of first evoked bursts in SMC difficult. To investigate the relationship between subcortical and cortical bursts we used burst-locked analyses (Figure 4) that are more likely to quantify evoked bursts.

Though our simultaneous recordings from STN and motor thalamus provide unique insights rarely obtained in human neuroscience research, our insights into the exact nuclei of the thalamus that produce the β bursts observed here or provide proximal or distal drives to neocortical neurons during sensorimotor bursts (c.f. Sherman et al., 2016), are somewhat limited. Notably, the VIM receives inputs from cerebellum and shows strong connectivity to the primary motor cortex (Klein et al., 2012). Hence, while this nucleus is well-positioned to influence activity in motor cortex, it is unlikely it would receive inhibitory inputs from the pallidum. On the other hand, Vop receives pallidal efferents and projects broadly to motor-related frontal cortices (mostly SMA, but also to premotor and M1; Sakai et al., 1999; Hyam et al., 2012). Our recordings likely include contributions from both nuclei, given that both dorsal and ventral thalamic contacts showed qualitatively and quantitatively similar patterns throughout the study. In regard to whether either nucleus participates in the thalamic drives that ostensibly generate sensorimotor β bursts (Sherman et al., 2016; Shin et al., 2017), a cycle-by-cycle analysis of the waveform underlying subcortical β bursts might provide insight into whether the progression of β bursts throughout regions of the basal-ganglia-thalamic circuit reflects propagation of a morphologically identical inhibitory signal.

While our results support the view that β bursts signify motor inhibition at the level of the basal ganglia, thalamus, and SMC, we did not find the same systematic temporal relationship between β bursts in thalamus and in SMC that was found for STN and SMC – that is, the ostensible subcortical start- and cortical endpoints of the cascade. While somewhat surprising, this is in line with existing work showing that thalamocortical motor representations may depend on neural interactions outside of the β band (Opri et al., 2019). Therefore, it is possible that the subcortico-cortical cascade of processing underlying motor inhibition starts with burst-like β signals from STN to thalamus and ends with the re-emergence of β bursts in SMC, but that the inhibition of motor activity between thalamus and SMC does not itself involve β bursts. In this scenario, the tight temporal relationship between the emergence of β in STN and SMC during stopping would be merely an indirect effect of the fact that β bursts signify the rapid reinstantiation of inhibition at both levels, rather than directly reflecting the propagation of β commands through the entire basal ganglia-thalamus-SMC chain.

Broad and clinical implications

Here, we present evidence of an association between β bursts and movement cancellation across a cortico-subcortical FBg pathway for inhibitory control. This establishes transient β as a candidate signature of inhibitory commands in fronto-basal ganglia motor circuits, in line with recent proposals regarding the inhibitory neuronal processes reflected in such β bursts (Sherman et al., 2016; Shin et al., 2017). β bursts carry information about motor output on the single-trial level, therefore providing a powerful window into the nature and timing of motor control in the brain.

Notably, these findings also hold relevance for emerging clinical treatments of movement disorders. It is still not well understood how continuous DBS modulates local circuits and network-level activity to change control-related behavior, and studies on this topic have produced mixed findings. For example, in some cases, STN DBS reduces SSRT (Mirabella et al., 2011; Roy et al., 2020), while some studies have observed SSRT increases instead (Ray et al., 2009; Obeso et al., 2013). A better understanding of subcortical control circuits, such as understanding that the STN precedes thalamic recruitment during movement cancellation, may improve our insights into why DBS produces such mixed effects on control-associated behavior. Moreover, such an improved understanding of those subcortical connections may also shed light on why movement disorder neuropathologies bring about deficits in inhibitory control more generally. In addition, adaptive deep brain stimulation (aDBS) is an intervention being tested for the treatment of motor symptoms in movement disorders such as PD. This type of DBS suppresses abnormally high levels of β power in STN by stimulating only when sensors are activated by long, high amplitude β bursts (Little et al., 2013; Little et al., 2016; Meidahl et al., 2017). Although recent testing of aDBS suggests that these stimulation protocols work by curtailing pathological and not physiological bursts (Anidi et al., 2018) – and may in fact spare more physiological β than continuous DBS (Tinkhauser et al., 2017)– no studies have investigated the effects of aDBS on inhibitory control processes. More research of aDBS effects on physiological bursts during inhibitory control would rule out potential complications for control processes and provide the opportunity to evaluate the effects of physiological and pathological β bursts on network-wide β bursts and behavior.

Limitations

Some additional limitations to the current work, beyond the likely volume conduction in the thalamic recordings, are worth mentioning. Notably, our current finding is – superficially – at odds with a recent report from Mosher and colleagues (Mosher et al., 2020), who purportedly showed that human STN and SMC β bursts are dissociated from activity in movement-associated neurons. Specifically, while in their data, movement-related neurons in STN showed reduced firing prior to movement cancellation during successful stops, β bursts were not observed until later latencies. However, while we here replicated the later-latency β bursting, the apparent discrepancy in the early-trial β burst rates is likely a reflection of differences in how β bursts were measured following the stop-signal. Specifically, Mosher and colleagues quantified β burst rates in a continuous manner after the stop signal, using sliding windows (similar to what was done in Figure 1B in the current manuscript). However, since SSRT varies considerably across participants (particularly in clinical samples), this procedure does not take the substantial between-subject variance in SSRT into account. Indeed, while the stop-signal locked bin-quantification in our study also didn’t show significant increases in burst rates between stop and go trials, quantifying β bursts in each individual’s SSD-to-SSRT period revealed clear differences.

Other recent work has also put forth the argument that β bursts – at least in scalp recordings – do not occur regularly enough to index the deployment of inhibitory control during movement cancellation (Errington et al., 2020). We stress that though β bursts may not occur on every single successful stop trial in humans, our current intracranial data show at least one STN β burst on average during the SSD-SSRT interval (see Figure 2, first panel). Moreover, we used a very conservative amplitude threshold for burst identification (adapted from one of the landmark investigations of β bursts in humans, Shin et al., 2017), which limited the number of β bursts analyzed. Future methodological developments may enable researchers to use more adaptive thresholding procedures (as in Enz et al., 2021), which may reveal that actual β burst rates are perhaps higher than what is commonly observed.

Finally, the use of a patient population was necessary to obtain deep brain recordings, but consequentially these findings may not generalize entirely to healthy individuals. Our participants were undergoing brain surgery at the time they performed the behavioral task, which may have caused distraction or fatigue. At the beginning of the surgery, patients were administered dexmedetomidine, an intravenous sedative. Though patients were required to be awake and responding to instructions from the clinical team at least 30 min before our recordings and off all sedatives, we cannot rule out lingering effects of sedation. These limitations are endemic to the endeavor of human intracranial neurophysiology. A related limitation is the possibility that some β bursts in our data may be non-representative due to the higher number of pathologically long, high-amplitude β bursts identified in patients with movement disorders, especially PD (Tinkhauser et al., 2017; Lofredi et al., 2019). However, the use of a high cut-off amplitude threshold to identify β bursts (such as the one we used here) has been shown to bias burst selection in favor of shorter-duration β bursts (Schmidt et al., 2020), suggesting that our quantification methods might have been more likely to sample the shorter (though, still high-amplitude) β bursts.

Conclusion

In conclusion, this study provides network-level neurophysiological evidence for a proposed cascade of cortico-subcortical processing, during which β band burst-like signals between STN, thalamus, and SMC are related to inhibition of motor output. This was achieved using a highly unique sample of multi-site intracranial recordings – including a simultaneous recording from both subcortical sites – that is unprecedented in human cognitive neuroscience studies. We found that both STN and thalamus showed increased β burst signaling in the critical time period following the stop-signal, and that STN bursts in particular were followed at low latency by β bursting in SMC. Given that these SMC bursts have been associated with an inhibited state of the motor system (Little et al., 2019; Soh et al., 2021) this strongly speaks in favor of the theory that action stopping is achieved via a rapid re-instantiation of inhibitory control following β burst signaling from the subcortical basal ganglia. In addition, β bursts in STN temporally preceded bursts in thalamus in a single-subject case, lending preliminary support for circuit models of inhibitory control which propose that inhibitory STN activity precedes activity in the thalamus. These findings further confirm transient β bursts as a signature of inhibitory control in fronto-basal ganglia circuits of the human brain.

Materials and methods

Participants

Twenty-three adult participants were recruited at the University of Iowa Hospitals and Clinics from all neurosurgical candidates slated for DBS electrode implantation in the thalamus (specifically targeting the ventral intermediate nucleus, VIM) or STN. STN DBS patients had a diagnosis of idiopathic PD and thalamic DBS patients had a diagnosis of essential tremor. One patient, with a diagnosis of PD, had existing thalamic implants revised and STN implants placed within the same surgery. From this patient, we recorded data from unilateral thalamus and bilateral STN. Administration of dopaminergic medication was withheld for over 8 hr before DBS surgery for all patients. Two participants’ data were excluded from analyses based on behavioral performance, leaving a sample of 21 participants (nine female, mean age: 67 years, age range: 52–78). Information regarding handedness, symptom laterality, and motor symptom severity for participants included in analyses can be found in the table included in Supplementary file 1. When available, pre-operative Unified Parkinson’s disease rating scale (UPDRS; Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease, 2003) part III motor examination total scores are included for PD patient participants and Fahn-Tolosa tremor scale scores (Fahn et al., 1993) are included for essential tremor patient participants. UPDRS scores are presented as totals of 33 scored items with possible scores of 0–4, and Fahn-Tolosa scores are presented as a total of 21 scored items, with a possible score of 0–4. These experimental protocols were approved by the University of Iowa’s Institutional Review Board (#201402720).

Data collection procedure

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Participants signed a written informed consent document during a clinic visit prior to surgery. Data collection for this study took place during awake bilateral DBS lead implantation surgery. Before surgery began, participants practiced the behavioral task. During surgery, two recording sessions took place. Following placement of bilateral subgaleal 4-contact electrode strips (Ad-Tech, Inc) directed posteriorly from the burr holes at the coronal suture so as to sit over SMC, a short recording session (a functional localizer) was used to confirm correct placement of the strip electrodes. Participants performed a short, 40-trial version of the SST that did not include any stop-signals (i.e. it was purely a two-alternative forced-choice reaction time task). These data were analyzed immediately in the operating room and the electrode lead placement was changed if the initial placement did not reveal the typical signature of SMC activity during movement execution (described subsequently in the ‘Analyzing local field potentials’ section). Then, after the DBS leads (3387, Medtronic, Inc, Minneapolis, MN) were successfully implanted into the bilateral subcortical sites (STN or VIM) using framed indirect stereotactic targeting refined by standard confirmatory physiologic testing (Gross et al., 2006; Geraedts et al., 2019; Malinova et al., 2020). STN localization was confirmed with multi-electrode simultaneous microelectrode recordings to define the dorsal and ventral borders following by multiple sessions of macrostimulation testing of efficacy as well as side effects. VIM localization was confirmed with macrostimulation to achieve tremor reduction efficacy as well as transient contralateral hand paresthesias. Routine post-operative brain imaging was not performed for these participants, but estimated exemplars of recording locations are shown in Figure 3—figure supplement 4. Following successful target localization and lead placements, a second recording session took place, which contained the main experiment (see next section).

Behavioral paradigm

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Participants completed an auditory SST (see Figure 3—figure supplement 1) in the operating room while recordings were collected. Task stimuli were played through in-ear headphones (ER4 SR model with ER38-14F foam buds, Etymotic Research, Elk Grove Village, IL, USA) connected to a Dell laptop running Fedora, using the PsychToolbox package (version 3; Brainard, 1997) in MATLAB (MathWorks, Natick, MA). Participants responded using two USB response buttons held in the hands (Kinesis Savant Elite 2, Kinesis, Bothell, WA). Participants heard a 100ms long, 500 Hz sine wave tone cuing a response (the go signal) every 4 s. Half of the go signals were presented in each ear (in random order); participants were instructed to respond with the button that indicated the side to which the tone was presented. (If the tone was presented in the left ear, the participants pressed the left button, and vice versa.) Participants had 2 s to respond to the tone, after which the task proceeded to a 2 s inter-trial interval.

On one-third of trials, participants heard a second, 1500 Hz tone (the stop signal) presented in both ears, cuing patients to try to stop their response. The delay between the go and stop signal, the stop-signal delay (SSD), was adjusted throughout the task to ideally converge on a stopping accuracy of 50%. Initial SSD was set to 250ms and adjusted in 50ms increments for each hand – subtracting 50ms following failed stops and adding 50ms following successful stops. To prevent proactive strategies, participants were instructed that it was equally important to (1) respond as fast as possible and (2) try to cancel movements successfully when the stop-signal occurred. The pre-surgical practice with the experiment consisted of one block of 30 trials (10 stop). The main task and recording block following macroelectrode lead placement included four blocks of 48 trials (16 stop). Between each block of the main task, the participants rested as needed and received feedback on their performance if necessary.

Local field potential recordings

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Local field potentials (LFPs) were recorded from the thalamus or STN using the four macroelectrode contacts on each DBS lead and from two four-, six-, or eight-contact strip electrodes placed in the subgaleal space over SMC (Ad-Tech, Oak Creek, WI; 10 mm spacing center-to-center, 3 mm exposed contact diameter).

The neurosurgeon (JDWG) inserted the strip electrodes into the subgaleal space posterior to the stereotactic burr hole at the coronal suture, para-sagitally in direction and anterior-posterior in alignment to cover the precentral gyrus. Estimations of the most posterior electrode were ~6 cm posterior to the coronal suture, which is consistent with a posterior placement covering precentral gyrus and SMC (Park et al., 2007; Rivet et al., 2004). We used the same electrode placement procedure for an identical recording set-up described in Wessel et al., 2019. LFP recordings were made on a Tucker-Davis technologies (Alachua, FL) system, using a RA16PA 16-Channel Medusa pre-amplifier and a RA16LI head-stage. The sampling rate for recording was 24 Hz or 2 Hz, with a low-pass filter of 7.5 kHz on the hardware side. Stimulus onsets were marked in the recording using a TTL pulse from a USB Data Acquisition Device (USB-1208FS, Measurement Computing, Norton, MA) triggered by the stimulus presentation laptop.

Preprocessing local field potentials

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Preprocessing and analysis of LFP data were conducted using custom MATLAB scripts. Data and analysis code for this study can be found on Dryad at https://datadryad.org/stash/dataset/doi:10.5061/dryad.gf1vhhmq0 (Diesburg et al., 2021). Electrical line noise from the operating room environment was filtered from the data using EEGLAB’s (Delorme and Makeig, 2004) cleanline function after which the recordings were down-sampled to 1000 Hz for analysis. Then, the recordings were visually inspected for any artifacts. Any 1 s segment of the recording containing an artifact was removed from the data.

Analyzing local field potentials

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Electrode pairs were converted to bipolar montages, resulting in three bipolar recordings from each side of the subcortical location. We conducted LFP analyses using ventral-most (contacts 0 and 1) and dorsal-most (contacts 2 and 3) bipolar arrays in thalamus and the bipolar array in the STN which included the greatest number of β bursts over the entire recording. We utilized the Medtronic lead labeling nomenclature such that contact 0 was the distal-most contact and positioned at the ventral border of each nucleus and contact three was the most proximal contact. Intercontact spacing was 1.5 mm. For thalamic DBS leads, placement of contacts 0 and 1 in the VIM were confirmed with clinical stimulation and testing in the operating room. Specifically, upper extremity tremor reduction was visible and low voltage (i.e. <2 V) paresthesias were achieved in the contralateral hand in all participants; these paresthesias were transient with test stimulation intensities up to 5 V. It is recognized that DBS electrodes placed via coronal / pre-coronal entry points typically span the border of VIM and Vop (Krack et al., 2002), making it likely based on these trajectories that LFP recordings from macroelectrodes capture both thalamic regions. Moreover, it is also likely that even recording electrodes that were not on the border between nuclei were nonetheless recording activity from both due to volume conduction.

Broadband event-related spectral perturbation (ERSP) plots of go-locked activity were made using a window of 100ms before stimulus onset to 1500ms following stimulus onset. A baseline window of 500ms to 200ms before stimulus onset was used to perform baseline corrections. Data were converted to time-frequency series using the filter-hilbert method: a Hilbert transform was applied to data filtered at specific frequencies (1–50 Hz) with a window of 0.5 Hz below and above that frequency using symmetric 2-way least-squares finite impulse response filters. The analytic signal was extracted by computing the squared absolute value of the complex signal.

Following localization, go-signal-locked ERSP plots were created for each bipolar array on the two subgaleal strips and visually inspected. One of the researchers in the OR (DAD) visually checked these ERSP plots for a visible, circumscribed decrease in average β band amplitude, a signature of movement-related activity in SMC (such as was observed by Pfurtscheller and Lopes da Silva, 1999). If no β suppression was observed in any bipolar array on one or both strips, those strip electrodes were replaced for more optimal positioning. Repositioning of one strip electrode was required in two of the 21 participants and repositioning of both was required in one participant.

β burst quantification

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β burst detection was performed using the same procedure as in Wessel, 2020 and Shin et al., 2017. Data from each bipolar electrode array were convolved with a complex Morlet wavelet constructed using the following equation:

wt,f=A exp-t22σt2 exp2iπ ft,

with σ= m2πf , A= 1σt 2π , and m = 7 (cycles) for each frequency in the β band (15–29 Hz). This β range was chosen based on foundational studies of cortical β bursts during movement (Sherman et al., 2016; Shin et al., 2017). The absolute value of the resulting complex data was squared to yield time-frequency power estimates. The resulting time-frequency data were epoched around events of interest (go and stop signals) with a window of 500ms before stimulus onset to 1000ms after stimulus onset. β bursts were classified by identifying local maxima in the trial-by-trial time-frequency data that exceeded six times the median of the time-frequency power for that specific array across the recording and that lasted at least two β cycles. In other words, the timing of a β burst was quantified only once at its center, at the time of maximal power within its frequency band. β burst frequency was defined as the frequency value at which maximum amplitude was quantified. β burst duration was the time in milliseconds during the search window where the amplitude at burst frequency exceeded the 6xmedian threshold cutoff.

Lagged coherence

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We quantified lagged phase coherence using the approach described in Fransen et al., 2015. Analyses were conducted with the FieldTrip software package (Oostenveld et al., 2011) using four cycles and frequencies between 8 and 35 Hz (i.e. the β band and surrounding frequencies). Data used in the computation included epoched data from both go and stop trials at all recorded locations.

Statistical analysis

Behavioral analysis

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Two participants’ data were excluded from analysis because they performed below chance accuracy (50%) on go trials or did not perform the task correctly during the main task. Participants included in the final analysis were 9 STN DBS patients, 11 thalamic DBS patients, and 1 participant with both thalamic and STN DBS. With the exception of the two key analyses that made use of the simultaneous recording of STN and thalamus (i.e. quantifying bursts in subcortical regions between SSD and SSRT, and comparing latencies of bursts in STN and thalamus in the single-subject analysis), the patient with both regions recorded was only included in one of the sample groups – in other words, the participant with data from both STN and thalamus only contributed data to the STN group for most statistical comparisons. Individual task blocks within participants were excluded from analysis if mean accuracy on go trials during a block was less than 60%, or if participants did not successfully stop on at least one stop trial. Based on these criteria, six of the 21 participants had one block of four excluded from behavioral and LFP analysis. Mean accuracies for stop and go trials were extracted for each subject. Go trials were considered incorrect if participants pressed the wrong button or missed responding before the 2 s deadline. Mean RTs for failed stop and successful go trials were extracted for each subject, and SSRT was calculated using the integration method with go omission replacement (Verbruggen et al., 2019). Differences in average accuracy and RT measures between STN and thalamic implant patient groups were tested using two-sample t-tests.

Temporal progression of β bursts

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In analyses of the temporal progression of β bursts, we included data from both hemispheres of subcortical sites. This approach is supported by findings that STN has a bilateral representation during movement execution (Alegre et al., 2005; Devos et al., 2006). Data from SMC was only included from sites contralateral to the correct trial. We quantified counts of bursts across all trials of the same type, binned by burst latency with respect to stimulus (go or stop signal) onset latency, in bins of 100ms from stimulus onset to 900ms following stimulus onset. For matched go trials, β burst latency was calculated with respect to the SSD set in the staircase for that trial. We also quantified bursts during a pre-stop signal baseline to ensure that there were no differences between burst rates across conditions before the stop-signal by summing bursts in the 100ms before SSD and averaging by the total number of trials.

For the analysis in which bursts were time-locked to β bursts at another recording site, the analysis was constrained to bursts within 500ms following the stop-signal (or 500ms following SSD for matched-go trials) in order to assess bursts that would reasonably contribute to movement cancellation based on average sample SSRT (474ms; Table 1). We calculated the latency difference between the first subcortical burst following the stop signal and all bursts in SMC during the same trial. This analysis was also repeated with the reverse ‘directionality’, analyzing subcortical burst rates time-locked to SMC β bursts in the same manner.

Permutation-based statistics were used to evaluate statistical significance. Specifically, two-way repeated measures ANOVAs were calculated with factors of TIMEPOINT and TRIAL TYPE. ANOVAs were bootstrapped by comparing resulting F values for each factor to null distributions of F values from 10,000 tests with data labels randomized. True F values were considered significant if they were greater than the F value at the 95th percentile of the null distribution and p < 0.05. Pairwise differences between trial types at specific time points were calculated using t-tests with Bonferroni-Holm corrections for multiple comparisons.

Calculating bursts in SSD-SSRT period

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To calculate subcortical burst rate differences between failed and successful stops and matched go trials in the SSD-SSRT delay, we quantified the total number of bursts between trial-specific SSD and the participant’s average SSRT (in other words, between time of SSD and SSD plus SSRT). Matched go trials were split into fast and slow trials using a median split of participant-wise go RTs. The participant with both thalamic and STN recordings contributed both STN and thalamic recording data to this analysis.

Timing of β bursts at each subcortical recording site

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To delineate the relative timing of bursts at different sites during stop trials, we calculated the mean latency of first bursts with respect to both stop-signal onset and subject-wise SSRT at each recording location following stop-signal onset. These first bursts were quantified between stop-signal onset and one second following stop-signal onset. This analysis was also performed in the subject with STN and thalamic recordings. We conducted a between- and within- subjects ANOVA with a within-subject factor of TRIAL TYPE and between-subjects factor of SUBCORTICAL LOCATION to assess whether successful stops might be associated with a shorter delay between STN and thalamic bursts than failed stops.

Data availability

All data analyzed during this study and scripts used for analyses are available on Dryad.

The following data sets were generated
    1. Diesburg DA
    2. Greenlee JDW
    3. Wessel JR
    (2021) Dryad Digital Repository
    Cortico-subcortical β burst dynamics underlying movement cancellation in humans.
    https://doi.org/10.5061/dryad.gf1vhhmq0

References

    1. Benabid AL
    2. Pollak P
    3. Seigneuret E
    4. Hoffmann D
    5. Gay E
    6. Perret J
    (1993)
    Acta Neurochirurgica. Supplementum
    39–44, Chronic VIM thalamic stimulation in Parkinson’s disease, essential tremor and extra-pyramidal dyskinesias, Acta Neurochirurgica. Supplementum, Vienna, Springer, 10.1007/978-3-7091-9297-9_8, 8109299.
    1. Fahn S
    2. Tolosa E
    3. Marín C
    (1993)
    Clinical rating scale for tremor
    Parkinson’s Disease and Movement Disorders 2:271–280.
    1. Schmidt R
    2. Berke JD
    (2017) A Pause-then-Cancel model of stopping: evidence from basal ganglia neurophysiology
    Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 372:20160202.
    https://doi.org/10.1098/rstb.2016.0202

Decision letter

  1. Nicole C Swann
    Reviewing Editor; University of Oregon, United States
  2. Richard B Ivry
    Senior Editor; University of California, Berkeley, United States
  3. Vignesh Muralidharan
    Reviewer; University of California, San Diego, United States
  4. Robert Schmidt
    Reviewer; University of Sheffield, United Kingdom

In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.

Decision letter after peer review:

Thank you for submitting your article "Cortico-subcortical β burst dynamics underlying movement cancellation in humans" for consideration by eLife. Your article has been reviewed by 3 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Richard Ivry as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Vignesh Muralidharan (Reviewer #2); Robert Schmidt (Reviewer #3).

The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.

Essential revisions:

In general, the reviewers were impressed with the manuscript – especially the novelty of the data. There were some concerns, especially with respect to the interpretation of results. These could be mitigated by some additional analyses. Below are more detailed comments.

1) A main conclusion is summarized in the 'fronto-basal ganglia network model for inhibitory control' in Figure 4, in which the thalamus sends the basal ganglia beta oscillations back to cortex. While this mechanism is of course possible, it does not seem to be supported by several results of the manuscript. In Figure 3 there is no indication of SMC beta bursts following the thalamus, which does not fit to their model. Although it is noted that the results for dorsal and ventral thalamus are remarkably similar, there seems to be several differences in key analyses. For example the timing of beta bursts and distinctions between trials types (Figure 2, right panels) seem to differ between ventral and dorsal thalamus (and actually precede STN, contradicting the model). Furthermore, only ventral, but not dorsal thalamus seems to have higher beta burst rates when stopping is successful (Figure 2, left). The key analysis of the relative timing using simultaneous recordings (Figure 4B) shows that beta in dorsal, but not ventral thalamus is later than in STN. The same analysis involving comparisons between the patient groups (Figure 4A) does not show any differences between STN and dorsal or ventral thalamus timing for the first burst, but only for the later beta that occurs after the SSRT (Figure 4A, right panel). However, as the model seems to rely on the very fast propagation of beta, it does not seem to be consistent with these results. Finally, the authors show a clear effect of TIMEPOINT in both these scenarios, but the comparison in the plots seem to be between trial types. Why was this was done as in both cases there wasn't a TIMEPOINT x TRIAL TYPE interaction? Shouldn't the comparison be across the different time-points, for instance the one before and the one after STN/thalamic burst to substantiate the claims of increased bursting of SMC after the sub-cortical nuclei?

2) In Figure 4, it is not clear (we might have missed this) what is the temporal window considered for getting the time of the first burst in STN and thalamus? The authors show the average first burst time occur in STN prior to the thalamus, providing support for the STN-thalamus part of the temporal model of stopping. If the first burst indexes recruitment of the inhibitory system via STN, could the authors also show the same average first burst time for the SMC. It would nice to see whether the model shown in Figure 4B extends till the SMC. Although they do this in Figure 3, that is in relation to STN bursts. If this does not pan out discuss why it is not the case, and what they might be capturing.

3) In Figure 1 several analyses are shown about beta decreasing during movement initiation. However, the plots seem to be aligned to the onset of the Go stimulus. Therefore, it is difficult to judge the time relation between the beta decrease and the initiation of the movement. Instead, or in addition, it would be helpful to see the data aligned to movement initiation, with a sufficient pre-event period, in order to see whether beta decreases during movement.

4) The timing of certain processes seemed a bit too late to fit in the temporal model of stopping. Keeping in mind that this is a patient population and the responses overall are slow and the SSRTs are also longer, the emergence of first beta activity in the STN seems to be close to SSRT (~400ms, Figure 4), whereas a robust signature of motor inhibition, the global motor suppression has been observed to happen much earlier (~140-150ms after stop-signal), which indexes the suppression of the motor cortex via inhibition exerted by the STN on thalamus. How do the authors reconcile those observations with their findings?

5) With respect to above point, in Figure 2, most of the changes in the beta burst rate seem to be happening after group average SSRT in both the STN and thalamic group and not prior to it. I appreciate that the authors acknowledge this lack of effect seen in the pre-SSRT burst rates which they suggest could because the individual variability in the SSRT has not been taken into account. I suggest that the authors repeat this analysis but time-lock the bursts to individual's SSRT (similarly in matched go trials) and see if they find out if the relationship comes out more robustly. Also, there is evidence of prefrontal burst times correlating with SSRT in previous studies (Jana et al. 2020) i.e. later bursts are associated with later SSRT. So, the authors could look at if the average time of the STN bursts (in successful stop trials) prior to the individual SSRT correlate with it, trying to explain this variability. Also in Figure 4B for single subject exemplar, could the authors also show the timing of the first burst in the STN and thalamus in relation to the SSRT (or mark it on the Figure), to see if the timing of sub-cortical regions is at least on average prior to it?

6) For many of the described results it is also important to consider how beta bursts relate to reaction times in Go trials. In Figure 1C average reaction times are determined for trials with and without beta oscillations. Depending on how this analysis is done, there is a potential problem due to counting beta bursts in time windows of different lengths. For trials with long reaction times, by definition, the time window between Go cue and movement response is longer than for trials with short reaction times. Therefore, even if beta bursts occur with a fixed probability at any time, it would result in a higher count of beta bursts in long reaction time trials, simply due to a longer time window considered. Thereby comparisons between groups of trials with and without beta bursts would be biased to yield long and short reaction times, respectively. This could be avoided by normalizing the burst count by the length of the time window (ie look at the burst rate instead). In any case, due to the potential relation between beta bursts and reaction time, it would be important to also consider Go trials with different reaction times for comparison with stop trials (Figure 2).

7) The SST has the inherent characteristic of comparing a motor to a non-motor output. When investigating beta activity this is obviously a problem if we want to discern "status quo" (Engel and Fries, 2010) from "inhibitory" signaling. In addition to comparing beta bursting from Go/Failed stop trials (movement) with successful strop trials (no movement), the authors could consider to compare beta burst rate during successful stopping with "rest" activity (here f.ex. during the inter-trial interval): Does beta bursting increase during stopping when compared to the "status quo" activity at rest? We note that the authors did perform compare results to pre-stop burst rates, but we were unclear if this baseline was immediately prior to the stop signal or during a resting period when no movement would be expected.

8) It would be intriguing to compare beta burst properties across SMC, thalamus, and STN, such beta burst wave shape and burst duration. Furthermore, it is referred to previous studies that had supported that beta seems to primarily occur in brief bursts (rather than slow, continuous power modulations). Due to the unique nature of this data set with simultaneous recordings from multiple sites in humans, it would be valuable to establish and verify these assumptions here, as the analyses done here seem to build on them.

9) In the Results the SSRT differences between groups seem quite large (>100ms), so it would be helpful to include the details on the statistical tests done to compare SSRT between thalamus and STN patients (even if differences are not statistically significant).

10) Although the main motivation of the paper is to look at beta bursts, it would be good if the authors also showed typical ERSP results from the STN and thalamus for the stop and go trials. Specifically, is there a relative change in beta power between the successful stop and matched go trials in the period between the stop-signal and SSRT, the difference ERSP will help. This might be confirmatory to the observation of the increased beta bursts seen during the successful stop.

11) Is there a lateralization of the findings? The literature often emphasizes the inhibitory network to be right hemispheric. It seems the authors averaged across hemispheres – it might be interesting to investigate whether there is a differential contribution of right and left, if possible.

12) To show that reported effects are frequency-specific, It could be interesting to add a control frequency (for instance. low frequency or gamma activity).

13) In the manuscript it is mentioned that response inhibition here is about cancelling already-initiated movements (e.g. "When already-initiated movements had to be cancelled…" in the impact statement). However, this does not seem to fit to the stop-signal task, especially with rather ballistic actions such as a button press. We assume that in most cases the action is stopped before any movement starts, and not e.g. while the finger is in the process of moving to make the button press (as that time window is very short for ballistic actions). Please clarify in the manuscript. Similarly, there are several statements about beta reflecting a "rapid re-instantiation of motor inhibition". It was not clear to me how this is concluded what it actually means (why 're'-instantiate?). Furthermore, it is stated that the findings have 'strong implications for many movement disorders' (eg in the Impact Statement). What are these implications, can they be spelled out? Similarly, in the Discussion it is stated that "this has major implications for emerging theories of movement cancellation". What are these implications?

14) In the explanation at the bottom of page 13, it is argued that the participant-specific SSRT accounts for the differences between analyses. Could the difference also simply be explained by one analysis involving (arbitrary) binning, while the other integrates differences across several bins into a single time window?

Reviewer #1:

In this study, the authors investigate the association between beta bursting and inhibitory processing in several motor circuit nodes (SMC with STN or VIM) of 21 patients with either PD or ET. They show that subcortical beta bursting is increased when stopping of initiated movements is successful. During successful stopping, specifically subthalamic beta bursts are preceding those in SMC. The authors claim that these results provide evidence for the role of beta bursts in conveying inhibitory signaling through the CBGTC-loop as well as for the directionality of this signaling (STN → VIM → SMC).

The paper is well written, results are presented in a clear way, figures are showing individual data points in comprehensive box-plots and the discussion is extensive and openly addresses limitations. The research question of an association between beta bursting and inhibitory processes as well as its directionality is intuitive and important. The presented data is valuable per se, as parallel cortico-subcortical intracranial recordings during task-performance in humans are rare.

While the authors address the limitations openly, I am still not entirely convinced that some of the claims are sufficiently backed up by the acquired data and current state of the literature. First, I am concerned by mixing different disease entities (PD and ET). I am not an expert in the field, but I think that there is an ongoing debate whether the dopamine-depleted state of PD is associated with alterations in response inhibition (for ex. Manza et al., 2017), which makes it difficult to present the PD-OFF state as "physiological". Second, it is unfortunate that there apparently has been no post-operative imaging in this cohort, as this would significantly help to undermine the claim of dorsal contact pairs capturing Vop instead of VIM activity. Third, I got the impression that the finding of directionality was slightly over-emphasized, given that thalamic bursting was not shown to precede SMC and that this would be a relevant pre-requisite for the hypothesis that subthalamic beta activity is conveyed through the thalamus to SMC.

Reviewer #2:

The paper explores the cortical-subcortical (basal-ganglia-thalamus- sensorimotor cortex) dynamics during human action-stopping, looking at transient beta (15-29Hz) events/bursts during stopping. The authors' findings support, especially at the sub-cortical level, the temporal model of stopping which implicates a frontal-basal-ganglia-thalamocortical circuitry during rapid action-stopping. The paper shows that beta bursts, a potential signature of inhibitory information flowing through this circuitry, occur earlier in the STN followed by the motor thalamus and sensorimotor cortex, fitting with the idea that STN is recruited first to inhibit the thalamus and thus movement. By recording simultaneous LFP from key nodes in the action-stopping network, the authors have high spatiotemporal resolution to investigate the dynamics in these regions which is a highlight of this study. Furthermore, by looking at the transient beta events in these regions they are able to estimate the exact time of beta activity and show timing specificity of sub-cortical nuclei during stopping.

Although the paper presents a good picture of the temporal model, there seems to be few caveats specifically regarding the beta burst time course, for instance most of the robust changes in the burst activity across trials seems to be happening after average stopping time (aka stop-signal reaction time) in both the STN and thalamus. In addition, the timing of first STN and thalamic beta burst also seems to be happening on an average close to and after SSRT respectively (~400-500ms). This seems a bit too late in respect to other metrics of motor inhibition, for instance the STN mediated motor suppression which seems to occur much earlier (~140-150ms in relation to a signal to stop). However, the authors show increased beta bursting in the sensorimotor cortex after STN beta bursts and higher number of bursts in sensorimotor cortex leading to slower reaction times, which is good demonstration of the potential role of the basal-ganglia-thalamocortical circuitry in aiding action stopping.

Reviewer #3:

In their manuscript "Cortico-subcortical β burst dynamics underlying movement cancellation in humans", Diesburg et al. examine beta oscillations in humans performing a stop-signal task. The beta oscillations are recorded in sensorimotor cortex (SMC) and either thalamus or subthalamic nucleus (STN; one patient has recordings in both subcortical sites) in patients with Parkinson's disease and Essential Tremor. The focus is on the relative timing of beta bursts with the suggestion that they propagate from STN over thalamus to SMC to mediate inhibitory control. Based on several analyses, it is stated that beta bursts increase when stopping is successful, and that STN beta bursts precede SMC beta bursts by up to 50ms. Furthermore some evidence is shown that STN beta also precedes thalamus. It is concluded that the recordings in humans support network models in which beta is quickly evoked by stop-signals and then propagated through cortical and subcortical loops.

A major strength of this paper is that it provides an important connection between previous studies with invasive recordings in non-human animals and human studies with non-invasive recordings. Thereby the manuscript achieves to connect findings about beta oscillations in the basal ganglia, thalamus and cortex. A (related) weakness of the paper is that the size of the data set is constrained due to the nature of the recordings (e.g. only one patient with simultaneous STN and thalamus recordings), and that some of the results rely on comparisons between different patient groups (with potentially different beta burst dynamics). These limitations are considered and addressed well by the authors by providing a comprehensive set of analyses. However, in some cases it is not clear whether the analyses and results support the statements and claims made.

https://doi.org/10.7554/eLife.70270.sa1

Author response

Essential revisions:

In general, the reviewers were impressed with the manuscript – especially the novelty of the data. There were some concerns, especially with respect to the interpretation of results. These could be mitigated by some additional analyses. Below are more detailed comments.

1) A main conclusion is summarized in the 'fronto-basal ganglia network model for inhibitory control' in Figure 4, in which the thalamus sends the basal ganglia beta oscillations back to cortex. While this mechanism is of course possible, it does not seem to be supported by several results of the manuscript. In Figure 3 there is no indication of SMC beta bursts following the thalamus, which does not fit to their model. Although it is noted that the results for dorsal and ventral thalamus are remarkably similar, there seems to be several differences in key analyses.

For example the timing of beta bursts and distinctions between trials types (Figure 2, right panels) seem to differ between ventral and dorsal thalamus (and actually precede STN, contradicting the model). Furthermore, only ventral, but not dorsal thalamus seems to have higher beta burst rates when stopping is successful (Figure 2, left). The key analysis of the relative timing using simultaneous recordings (Figure 4B) shows that beta in dorsal, but not ventral thalamus is later than in STN. The same analysis involving comparisons between the patient groups (Figure 4A) does not show any differences between STN and dorsal or ventral thalamus timing for the first burst, but only for the later beta that occurs after the SSRT (Figure 4A, right panel). However, as the model seems to rely on the very fast propagation of beta, it does not seem to be consistent with these results. Finally, the authors show a clear effect of TIMEPOINT in both these scenarios, but the comparison in the plots seem to be between trial types. Why was this was done as in both cases there wasn't a TIMEPOINT x TRIAL TYPE interaction? Shouldn't the comparison be across the different time-points, for instance the one before and the one after STN/thalamic burst to substantiate the claims of increased bursting of SMC after the sub-cortical nuclei?

The reviewers raise an excellent point. Indeed, the lack of SMC bursts following thalamic bursts was at first surprising to us as well. There is, of course, the possibility that the somewhat arbitrary time bins for this analysis obscure a potential effect. However, we do also have to take seriously the possibility of a true absence of such beta dynamics between Th and SMC. Indeed, while we show that rapid motor inhibition is signified by beta burst activity in STN and SMC (moreover in a sensible temporal sequence), it is very possible that Th-SMC communication does not take place via burst like beta activity. We have added a paragraph to our Discussion (on p. 28) expanding on this possibility.

“While our results support the view that beta bursts signify motor inhibition on the level of the basal ganglia, thalamus, and SMC, we did not find the same systematic temporal relationship between beta bursts in thalamus and in SMC that was found for STN and SMC – i.e., the ostensible subcortical start- and cortical endpoints of the cascade. et al.[…] In this scenario, the tight temporal relationship between the emergence of beta in STN and SMC during stopping would be merely an indirect effect of the fact that beta bursts signify the rapid re-instantiation of inhibition at both levels, rather than directly reflecting the propagation of beta commands through the entire basal ganglia-thalamus-SMC chain.”

Beyond this point, however, there are also a few misunderstandings about the results. These are (hopefully) addressed below and via changes to the revised manuscript. In detail, these are as follows:

“For example the timing of beta bursts and distinctions between trials types (Figure 2, right panels) seem to differ between ventral and dorsal thalamus (and actually precede STN, contradicting the model).”

It is true that the dorsal thalamus recordings in our sample did not contain differences in burst counts in the SSD-to-SSRT window. However, Figure 2 (now Figure 3) does not contain any information about relative timing between STN and thalamic bursts across the two groups. We suspect the reviewer is referring to the gray lines marked on the right panel, which simply show the average SSRT for STN and thalamic DBS patients, and do not indicate a particular time point at which beta bursts were plotted (they were counted between trial-wise SSD and individual subject SSRT). The only depiction of burst timing with respect to individual SSRT is shown in Figure 4 (now Figure 5), wherein thalamic bursts follow STN bursts on average. Please note that this is especially remarkable given that SSRTs were longer for our STN group on average than the thalamic group. We have edited the manuscript at several points on pages 17, 18, 23, and 24 to hopefully make this clearer.

“The same analysis involving comparisons between the patient groups (Figure 4A) does not show any differences between STN and dorsal or ventral thalamus timing for the first burst, but only for the later beta that occurs after the SSRT”.

Both panels in 4A (now Figure 5A) show the timing of the same beta bursts (the first bursts in a respective region during the SSD-SSRT period), but with different time locking. The left plot shows the first burst with respect to the stop-signal and the right one shows the first burst with respect to SSRT. The fact that burst timing significantly differs when the data are SSRT-locked speaks in favor of the proposition that stop-related beta bursts seem tightly linked to individual SSRT (and therefore the timing of each individual’s stopping process).

“Finally, the authors show a clear effect of TIMEPOINT in both these scenarios, but the comparison in the plots seem to be between trial types”

The reviewers are correct that Figures 2A and 3A (now Figures 3 and 4) do not display TIMEPOINT effects, and the significant comparisons in Figure 3A are effects of TRIAL TYPE on burst counts (panel A) or on burst rates (C). In Figure 3, after we found main effects of both TIMEPOINT and TRIAL TYPE for stimulus-locked burst rates, we used follow-up t-tests to determine at which time points comparisons between successful stop trials and other trials were significant. The reviewer is also correct that we only found a main effect of TIMEPOINT in the burst-locked analysis (shown in Figure 4), and no main effect of TRIAL TYPE or interaction effect. In that instance, we chose to conduct pairwise tests between trial types anyway, specifically because of our strong a priori hypothesis. Indeed, this analysis is essentially a repetition of the exact analysis from the Wessel 2020 J Neuro paper, except that the scalp-site FCz is replaced with the STN LFP. We’ve highlighted this decision in the text now on p. 19

We did not test for a TIMEPOINT effect in the analyses depicted in Figure 4 (now 5) – those analyses tested for effects of TRIAL TYPE and BURST LOCATION. We have added detail to all our Figure captions to be clearer about which comparisons are plotted. In panel C, the pairwise comparisons are follow-up tests comparing trial types at specific time bins, following up on significant omnibus effects of TRIAL TYPE (described on p. 14 of the Results section). In Figure 5, the significant comparisons shown in the Figure were effects of BURST LOCATION on average timing of first bursts following the stop signal.

We apologize for these misunderstandings and hope that these revisions have made things clearer.

2) In Figure 4, it is not clear (we might have missed this) what is the temporal window considered for getting the time of the first burst in STN and thalamus? The authors show the average first burst time occur in STN prior to the thalamus, providing support for the STN-thalamus part of the temporal model of stopping. If the first burst indexes recruitment of the inhibitory system via STN, could the authors also show the same average first burst time for the SMC. It would nice to see whether the model shown in Figure 4B extends till the SMC. Although they do this in Figure 3, that is in relation to STN bursts. If this does not pan out discuss why it is not the case, and what they might be capturing.

The window for obtaining the first bursts was one second from the stop-signal onset (or from SSD for go trials). We have added this detail to the figure caption and the Methods section.

In terms of the first-burst timing in SMC, we did not include those data in the figure on purpose. That’s because SMC produces a steady bursting of beta at baseline (Kilavik et al., 2013; Little et al., 2019). Importantly, this burst rate is upregulated when proactive control is exerted, such as in the stop-signal task (Soh et al., 2021). These proactive control-related bursts are impossible to distinguish from any event-related increases incurred by the stop-signal (which we were interested in in this study) – unless the data are plotted directly time-locked to beta bursts in other regions (c.f., Wessel 2020 J Neuro and Figure 4). Hence, it is impossible to know if an SMC burst was truly triggered by the stop-signal, or merely a reflection of a state of heightened proactive control. Instead, we believe that the analysis in which SMC activity is time-locked to bursts in subcortical areas (cf., Figure 4) is the best way to investigate SMC to test our hypothesis about subcortical-cortical communication. We hope the reviewers agree.

3) In Figure 1 several analyses are shown about beta decreasing during movement initiation. However, the plots seem to be aligned to the onset of the Go stimulus. Therefore, it is difficult to judge the time relation between the beta decrease and the initiation of the movement. Instead, or in addition, it would be helpful to see the data aligned to movement initiation, with a sufficient pre-event period, in order to see whether beta decreases during movement.

We agree. We have added a panel to Figure 1 including beta burst rates at individual time bins locked to responses.

4) The timing of certain processes seemed a bit too late to fit in the temporal model of stopping. Keeping in mind that this is a patient population and the responses overall are slow and the SSRTs are also longer, the emergence of first beta activity in the STN seems to be close to SSRT (~400ms, Figure 4), whereas a robust signature of motor inhibition, the global motor suppression has been observed to happen much earlier (~140-150ms after stop-signal), which indexes the suppression of the motor cortex via inhibition exerted by the STN on thalamus. How do the authors reconcile those observations with their findings?

Indeed, in healthy young participants, global motor suppression (indexed by MEPs or EMG) has been shown to occur around 140-150ms following the stop signal. However, the same has not been demonstrated in movement disorder patients, who have much longer SSRTs. Indeed, Jana et al. (2020) observed that SSRT measured using the classic integration method overestimated stopping measured in EMG traces by approximately 60ms. Therefore, we would argue that global motor suppression in our patient sample would be expected to occur approximately 60ms before SSRT as well, and not 150ms after the stop-signal. While the Stop+150ms timepoints and the SSRT-60ms timepoints are very close to one another in healthy humans, in our current population, they are much further apart.

However, it is important to note that STN bursts on average across the sample still do emerge before SSRT, which is an indication to us that the mechanism they index occurs in time to contribute to reactive cancellation, and perhaps even aligns with the SSRT-60ms timing that has been proposed based on healthy adults (cf., the new panel in Figure 3). Of course, in the absence of EMG measures, that is merely speculation.

5) With respect to above point, in Figure 2, most of the changes in the beta burst rate seem to be happening after group average SSRT in both the STN and thalamic group and not prior to it. I appreciate that the authors acknowledge this lack of effect seen in the pre-SSRT burst rates which they suggest could because the individual variability in the SSRT has not been taken into account. I suggest that the authors repeat this analysis but time-lock the bursts to individual's SSRT (similarly in matched go trials) and see if they find out if the relationship comes out more robustly. Also, there is evidence of prefrontal burst times correlating with SSRT in previous studies (Jana et al. 2020) i.e. later bursts are associated with later SSRT. So, the authors could look at if the average time of the STN bursts (in successful stop trials) prior to the individual SSRT correlate with it, trying to explain this variability. Also in Figure 4B for single subject exemplar, could the authors also show the timing of the first burst in the STN and thalamus in relation to the SSRT (or mark it on the Figure), to see if the timing of sub-cortical regions is at least on average prior to it?

Indeed, we believe that trial-type-wise differences in burst rates might not emerge at individual time bins because the true condition differences are tightly linked to subject-wise SSRT. We added plots of individual time bins locked to participant-wise SSRT to Figure 2 (now Figure 3) in the revised manuscript. Increased beta burst rates in the bin immediately preceding SSRT are indeed visible on this new figure, with significant differences seen between STN burst rates for successful stop and go trials in the 100ms preceding SSRT.

Furthermore, while we agree that cross subject correlations between behavior and beta bursts could be informative, we do not believe that our sample size is sufficient to validly allow for such analyses.

Lastly, we have added the single subject’s SSRT (304ms) to Figure 5. Because unlike for the full-sample analysis, all analyses here were performed on the same subject with the same SSRT, the stop- and SSRT-locked analyses and plots are identical.

6) For many of the described results it is also important to consider how beta bursts relate to reaction times in Go trials. In Figure 1C average reaction times are determined for trials with and without beta oscillations. Depending on how this analysis is done, there is a potential problem due to counting beta bursts in time windows of different lengths. For trials with long reaction times, by definition, the time window between Go cue and movement response is longer than for trials with short reaction times. Therefore, even if beta bursts occur with a fixed probability at any time, it would result in a higher count of beta bursts in long reaction time trials, simply due to a longer time window considered. Thereby comparisons between groups of trials with and without beta bursts would be biased to yield long and short reaction times, respectively. This could be avoided by normalizing the burst count by the length of the time window (ie look at the burst rate instead). In any case, due to the potential relation between beta bursts and reaction time, it would be important to also consider Go trials with different reaction times for comparison with stop trials (Figure 2).

First, we agree with the reviewers that there was indeed a systematic difference in search window size between these two trial types, which biased that analysis. Thank you for catching that aspect we had missed! Unfortunately, normalizing burst counts does not fully address this problem either, as time windows with zero bursts are more likely to occur for shorter detection windows / faster RT trials, but wouldn’t be susceptible to normalization (as 0 divided by anything is still 0). To try to address this concern somewhat, we repeated this analysis using a fixed time window of 500ms following the go signal (in all trials with RT > 500ms). While the results of this analysis are numerically in line with what Little and colleagues observed (increased RT in burst containing trials), they were not significant in our sample (though this is due to one participant who strongly deviates from the rest of sample, see (Author response image 1) ). Because these revised results are therefore inconclusive (neither indicative of a failed replication of the Little study, nor actually replicating it), we’ve removed them from the manuscript.

Author response image 1
Main effect of trial type (go + fail): F = 35.78, p <.0001; no main effect of burst presence: F = 0.13, p = .72; no interaction effect: F = 0.88, p = .36.

On the other point, we definitely agree that it is important to consider the different GoRT distribution when comparing subcortical bursts between successful/failed stop vs. go trials. Therefore, we have separated the matched go trials presented in Figure 3B into slow and fast go trials based on a median RT split, as is typical for this approach. Fast Go trials were then compared to failed stop trials and slow Go trials to successful stop trials. The main effects of trial type that were previously reported remained significant. At all recording locations, successful stop trials contain significantly more bursts in the SSD-SSRT window compared to slow go trials, and more bursts than failed stops in the STN and ventral thalamus. These results have been updated in Figure 3 and in the text.

7) The SST has the inherent characteristic of comparing a motor to a non-motor output. When investigating beta activity this is obviously a problem if we want to discern "status quo" (Engel and Fries, 2010) from "inhibitory" signaling. In addition to comparing beta bursting from Go/Failed stop trials (movement) with successful strop trials (no movement), the authors could consider to compare beta burst rate during successful stopping with "rest" activity (here f.ex. during the inter-trial interval): Does beta bursting increase during stopping when compared to the "status quo" activity at rest? We note that the authors did perform compare results to pre-stop burst rates, but we were unclear if this baseline was immediately prior to the stop signal or during a resting period when no movement would be expected.

We disagree with the argument that inhibitory signaling in purportedly inhibitory brain regions like the basal ganglia or M1 has to exceed baseline activity to signify inhibition. The baseline ‘status quo’ in the motoric regions of the basal ganglia and M1 in the absence of movement is inhibition (Uno and Yoshida, 1975; Di Chiara et al., 1979; Yoshida and Omata, 1979; DeLong and Georgopoulos, 1981). While it may be true that activity in control-related prefrontal regions that are not signaling inhibitory commands at baseline would have to show an above baseline increase, the same logic, to us, does not apply to the BG or M1.

Further, the addition of a pre-go-signal baseline (which has been added to Figure 3 and associated in-text results) supports this account. In line with our hypothesis that increasing beta burst rates during stopping reflect a re-instantiation of tonic inhibition present at rest, we see increased beta bursts in early post-stop-signal time bins compared to a pre-stop baseline (because beta bursts decrease during movement execution, signifying net-disinhibition), but no differences in burst rates when comparing to a pre-go baseline (when we assume tonic inhibition is being exerted). We have added these results on p. 16 of the Results section.

8) It would be intriguing to compare beta burst properties across SMC, thalamus, and STN, such beta burst wave shape and burst duration. Furthermore, it is referred to previous studies that had supported that beta seems to primarily occur in brief bursts (rather than slow, continuous power modulations). Due to the unique nature of this data set with simultaneous recordings from multiple sites in humans, it would be valuable to establish and verify these assumptions here, as the analyses done here seem to build on them.

In response to this valuable suggestion, we have extracted average beta burst duration and frequency of peak power for each recorded region. These values have been added to the Results section on p. 10 and a description of this analysis added to the Methods on p. 37.

To confirm the assumption that beta is indeed burst-like, we conducted a lagged coherence analysis. Lagged coherence (Fransen et al., 2015) provides an estimate of how much the phase of a signal predicts future phase at the same frequency. Signals that are oscillatory can be expected to predict their own phase many cycles in the future, while transient signals will have low lagged coherence several phases on. This is indeed what we observe in the 15-29Hz range at all our recording locations: lagged coherence decreases from 1-3 cycles, and at 3 cycles a trough in coherence is observed in the beta band compared to surrounding frequencies. This coherence trough is most pronounced in the SMC, while STN contains activity that is somewhat less “bursty” based on lagged coherence (we note in the text it is possible this could reflect the presence of pathologically long STN bursts in our patient sample). Beta activity in the thalamus seems to be the least burst-like and most sustained of all recording regions. We have added a new Figure (now Figure 2) with these results, an explanation of this approach in the Results section on p. 10, and a description of the methodology on page 38.

9) In the Results the SSRT differences between groups seem quite large (>100ms), so it would be helpful to include the details on the statistical tests done to compare SSRT between thalamus and STN patients (even if differences are not statistically significant).

We agree. The statistics for the other behavioral metric comparisons across groups have been added to the Results section on p. 7.

10) Although the main motivation of the paper is to look at beta bursts, it would be good if the authors also showed typical ERSP results from the STN and thalamus for the stop and go trials. Specifically, is there a relative change in beta power between the successful stop and matched go trials in the period between the stop-signal and SSRT, the difference ERSP will help. This might be confirmatory to the observation of the increased beta bursts seen during the successful stop.

Agreed. We have added ERSPs from STN and thalamus to Figure 2 (now Figure 3), plotting the difference in beta power between successful stop and go trials. There are clear increases in beta band power in STN and thalamus following the stop signal during stop trials.

11) Is there a lateralization of the findings? The literature often emphasizes the inhibitory network to be right hemispheric. It seems the authors averaged across hemispheres – it might be interesting to investigate whether there is a differential contribution of right and left, if possible.

Though the ventrolateral PFC aspects of the fronto-basal ganglia network (i.e., rIFC) are right-lateralized, we are not aware of intracranial research suggesting that the subcortical aspects are. Indeed, STN activity is bilateral during movement execution (Alegre et al., 2005; Devos et al., 2006). While we are aware of one fMRI study that suggests a lateralization on the level of STN (Aron and Poldrack, J Neuro 2006), that study was conducted at 3T, which does not have sufficient signal to noise ratio to reliably capture STN activity (de Hollander et al., Human Brain Mapping, 2017; Miletic et al., NeuroImage, 2020).

Therefore, we chose to pool subcortical bursts across hemispheres in the main manuscript. However, we have added the results separated by hemisphere in Supplement 3 to Figure 3.

12) To show that reported effects are frequency-specific, It could be interesting to add a control frequency (for instance. low frequency or gamma activity).

This is an interesting suggestion. Though gamma is probably burst-like, to our knowledge, however, it has not been shown that low frequencies are similarly burst-like compared to beta. Furthermore, the dominant models which informed our a priori hypothesis pertained specifically to beta. If the reviewers can point us to literature that has assessed bursts during movement execution or cancellation in other frequencies (so that a pre-existing approach can be adopted), we are willing to consider trying this.

However, based on our lagged coherence analysis (referenced above in response 8), there appears to be a peak of “burstiness” in the beta band that compared to the surrounding frequencies. We believe that the included lagged coherence analysis will help readers to compare “burstiness” of beta to neighboring frequency bands.

13) In the manuscript it is mentioned that response inhibition here is about cancelling already-initiated movements (e.g. "When already-initiated movements had to be cancelled…" in the impact statement). However, this does not seem to fit to the stop-signal task, especially with rather ballistic actions such as a button press. We assume that in most cases the action is stopped before any movement starts, and not e.g. while the finger is in the process of moving to make the button press (as that time window is very short for ballistic actions). Please clarify in the manuscript. Similarly, there are several statements about beta reflecting a "rapid re-instantiation of motor inhibition". It was not clear to me how this is concluded what it actually means (why 're'-instantiate?). Furthermore, it is stated that the findings have 'strong implications for many movement disorders' (eg in the Impact Statement). What are these implications, can they be spelled out? Similarly, in the Discussion it is stated that "this has major implications for emerging theories of movement cancellation". What are these implications?

First, we note that button presses in the stop-signal task are not ballistic (de Jong et al., 1990). However, we understand and appreciate the reviewer’s point that some successful stops may happen “earlier” in the brain or in the corticospinal motor system, before innervation reaches the peripheral muscle. Accordingly, we have changed the phrasing from “already-initiated” to “prepotent” on p. 4.

Second, because there is motor inhibition at baseline and the dominant models of motor control state that this baseline inhibition is reduced to enable movement, we consider the relative increase in beta burst rates after stop-signals to be a “re-instantiation” of the inhibition that is present at baseline.

Third, we agree that the implications for understanding of movement disorders and their treatment should be better spelled out. We have added to that paragraph on p. 29 of the Discussion to expand upon those implications.

14) In the explanation at the bottom of page 13, it is argued that the participant-specific SSRT accounts for the differences between analyses. Could the difference also simply be explained by one analysis involving (arbitrary) binning, while the other integrates differences across several bins into a single time window?

Indeed, we believe that artificially binning the data can account for the absence of findings in that analysis in several ways. One is the latency differences in processing indicated by differences in SSRT. Another are the (biologically meaningless) boundaries of the bins. Finally, it could be a difference in power of the binning-based analysis. For all of those reasons, we consider the analysis that considers the entire SSD-SSRT window (Figure 3B) to be the superior approach, as we note in the text.

https://doi.org/10.7554/eLife.70270.sa2

Article and author information

Author details

  1. Darcy A Diesburg

    Department of Psychological and Brain Sciences, University of Iowa, Iowa City, United States
    Contribution
    Conceptualization, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review and editing
    For correspondence
    darcy-diesburg@uiowa.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3489-7624
  2. Jeremy DW Greenlee

    1. Department of Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, United States
    2. Iowa Neuroscience Institute, University of Iowa, Iowa City, United States
    Contribution
    Conceptualization, Investigation, Methodology, Supervision, Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8481-8517
  3. Jan R Wessel

    1. Department of Psychological and Brain Sciences, University of Iowa, Iowa City, United States
    2. Iowa Neuroscience Institute, University of Iowa, Iowa City, United States
    3. Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, United States
    Contribution
    Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Software, Supervision, Writing – original draft, Writing – review and editing
    For correspondence
    jan-wessel@uiowa.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7298-6601

Funding

National Institutes of Health (T32GM108540)

  • Darcy A Diesburg

National Institutes of Health (R01NS117753)

  • Jan R Wessel

National Science Foundation (CAREER 1752355)

  • Jan R Wessel

Carver College of Medicine & Iowa Neuroscience Institute (Research Program of Excellence Funding)

  • Jeremy Greenlee
  • Jan R Wessel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Acknowledgements

The authors thank Haiming Chen for assistance with surgical recordings and the patient participants for volunteering their time. This research was funded by an NIH fellowship (T32GM108540) to DAD, Carver College of Medicine/Iowa Neuroscience Institute Research Program of Excellence funding to JDWG and JRW, and grants from the NIH (R01NS117753) and NSF (CAREER 1752355) to JRW.

Ethics

Human subjects: Research participants signed a written informed consent document during a clinic visit prior to surgery. Experimental protocols were approved by the University of Iowa's Institutional Review Board (#201402720).

Senior Editor

  1. Richard B Ivry, University of California, Berkeley, United States

Reviewing Editor

  1. Nicole C Swann, University of Oregon, United States

Reviewers

  1. Vignesh Muralidharan, University of California, San Diego, United States
  2. Robert Schmidt, University of Sheffield, United Kingdom

Publication history

  1. Received: May 11, 2021
  2. Accepted: December 6, 2021
  3. Accepted Manuscript published: December 7, 2021 (version 1)
  4. Version of Record published: December 21, 2021 (version 2)

Copyright

© 2021, Diesburg et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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