Decision letter: Movement-related coupling of human subthalamic nucleus spikes to cortical gamma

Field: Neuroscience (Life Sciences)

Article Figures and data Abstract Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Cortico-basal ganglia interactions continuously shape the way we move. Ideas about how this circuit works are based largely on models those consider only firing rate as the mechanism of information transfer. A distinct feature of neural activity accompanying movement, however, is increased motor cortical and basal ganglia gamma synchrony. To investigate the relationship between neuronal firing in the basal ganglia and cortical gamma activity during movement, we analysed human ECoG and subthalamic nucleus (STN) unit activity during hand gripping. We found that fast reaction times were preceded by enhanced STN spike-to-cortical gamma phase coupling, indicating a role in motor preparation. Importantly, increased gamma phase coupling occurred independent of changes in mean STN firing rates, and the relative timing of STN spikes was offset by half a gamma cycle for ipsilateral vs. contralateral movements, indicating that relative spike timing is as relevant as firing rate for understanding cortico-basal ganglia information transfer. Introduction Oscillations in extracellular field potential recordings reflect the synchronous rhythmic activation of thousands of nearby neurons capturing a mixture of sub- and suprathreshold activity (Buzsáki et al., 2012). At the onset of contralateral movements, relatively narrow gamma-band oscillations (~60–90 Hz) appear in the human basal ganglia, thalamus and motor cortex (Brücke et al., 2008; Brücke et al., 2012; Brücke et al., 2013; Muthukumaraswamy, 2010; Jenkinson et al., 2013). The potential significance of these oscillations is illustrated by the fact that neural activity synchronizes strongly only when movements are actively initiated, but not during similar passive displacements (Liu et al., 2008; Muthukumaraswamy, 2010; Brücke et al., 2012). The Communication-through-Coherence theory describes how gamma synchrony can be a key feature of interregional interactions, with brief windows of increased excitability between longer periods of inhibition (Hasenstaub et al., 2005; Fries et al., 2007; Buzsáki and Wang, 2012) rendering neuronal communication effective, precise and selective (Fries, 2015). One consequence of synchronized spiking activity is that where multiple cells converge onto a postsynaptic neuron, volleys of near-coincident spikes are more likely to trigger action potentials downstream (Azouz and Gray, 2003; Harris et al., 2003; Gupta et al., 2016). Neural synchronization could thus potentially trigger the currently unknown cascade of network interactions enabling movement execution. Uncontrolled movements recorded during levodopa-induced dyskinesia in Parkinson’s disease are for example accompanied by excessive gamma synchrony between the STN and motor cortex (Swann et al., 2016). Gamma phase coupling between the STN LFP and motor cortex has also been shown during voluntary movements, with the former seemingly driving the latter (Williams et al., 2002; Litvak et al., 2012; Sharott et al., 2018). Moreover, dopaminergic medication enhances gamma synchrony in Parkinson’s disease (Litvak et al., 2012), suggesting it may be functionally relevant for restoring these patients’ ability to move. Previously, it has been shown that changes in STN spike rhythmicity and phase coupling to cortical oscillations (focusing on frequencies below the gamma range) can occur before movement onset in the absence of changes in average firing rates (Lipski et al., 2017b). The precise temporal pattern of basal ganglia spikes relative to cortical population activity thus seems critical for understanding how the basal ganglia can contribute to motor control. Yet, studies on neural correlates of movement preparation and execution in the basal ganglia have mostly focussed only on changes in firing rates (Anderson and Horak, 1985; Mink and Thach, 1991; Turner and Anderson, 1997; Seo et al., 2012; Arimura et al., 2013). Hence not much is known about the relationship between gamma coupling and gating of activity for motor control, despite rapidly growing knowledge about the relevance of temporally organized activity for visual processing (Fries, 2015) and working memory encoding (Bastos et al., 2018). We simultaneously recorded STN unit activity and electrocorticography from the motor cortex during isolated contra- or ipsilateral hand gripping movements to gain insights into mechanisms of cortico-basal ganglia communication that may be linked to gamma-rhythmic activity. Inspired by previous findings that have demonstrated strong correlation between movement kinematics and basal ganglia gamma-band activity (Brücke et al., 2012; Fischer et al., 2017; Lofredi et al., 2018), we aim to shed light on the underlying neurophysiological mechanism resulting in cortico-subcortical communication in the gamma band. Therefore, we set out to examine if STN spike-to-cortical gamma phase coupling can predict the timing or vigour of contralateral action initiation. Second, because only contra- and not ipsilateral movements are accompanied by strongly increased motor cortical gamma synchrony (Crone et al., 1998; Cheyne et al., 2008) and result in more discharge activity (Matsunami and Hamada, 1981), we further characterized and compared the relationship between the precise timing of STN spikes and the cortical gamma phase. More specifically, if the timing of STN spikes helps to enhance gamma oscillations exclusively during contralateral gripping, then spikes during ipsilateral gripping may be clustered around points that are opposite to the preferred phase found during contralateral gripping to prevent a coincidental boost in gamma synchrony. Results Cortical ECoG and STN single neuron spikes were recorded in Parkinson’s disease patients undergoing deep brain stimulation surgery. Patients performed a visually-cued gripping task in which they squeezed a handgrip with their left or right hand within 2 s after the Go cue for at least 100 ms (Figure 1). Our analysis included 28 spike recordings from 12 patients (12 single-unit and 16 multi-unit recordings), from which spike-phase coupling to lower frequencies have been described previously (Lipski et al., 2017b). Figure 1 Download asset Open asset Schematic of the trial events for a grip trial with the right hand. In trials requesting gripping with the left hand, the image of the hand would be displayed to the left of the traffic light. The initial cue was displayed as yellow traffic light, which served as GO cue when it turned green, on average 1.5 ± 0.4 s after its onset. The gripping movement had to occur within two seconds of the GO cue onset to count as valid trial. Upon gripping, a white bar representing the grip force would move up (see bottom right corner in the rightmost plot). Visual feedback was presented according to whether the movement was performed at least for 100 ms and within the correct window. Trial onsets were on average separated by 4.7s ± 1.2s. Gripping performance Average reaction times from the Go signal to the grip onset were 0.53 ± (SD) 0.21 s and 0.55 ± 0.18 s for contra- and ipsilateral grips, respectively (contra-ipsi: p=0.435, t27 = −0.8). The mean variability (SD) of RTs within each patient was 0.19 ± 0.09 s and 0.23 ± 0.12 s (contra-ipsi: p=0.050, t27 = −2.1). This variability in RTs allowed us to compare the extent of spike-to-gamma phase coupling between trials with fast and slow RTs by grouping trials with RTs below the median and trials with RTs above the median. The average RTs of these two sets were 0.39 ± 0.16 s and 0.68 ± 0.27 s for grips contralateral to the recorded STN and 0.38 ± 0.12 s and 0.72 ± 0.26 s for ipsilateral grips. The delay between the cue that instructed patients whether to perform the grip with the right or left hand and the Go signal did not differ significantly between short and long RT trials (difference in delay between long vs. short RT trials = 4 ms, p=0.116). We also performed median-splits according to grip peak force and peak yank (contralateral gripping peak force: 91 ± 65 N and 104 ± 71 N, peak yank: 0.39 ± 0.30 N/ms and 0.50 ± 0.36 N/ms). The average grip duration was 0.98 ± 0.45 s. Topography of STN spike-to-cortical gamma coupling First, we assessed if movement-related STN spike-to-cortical gamma coupling was specific to a region of primary motor cortex that has also been demonstrated to show the strongest movement-related gamma power increase in MEG recordings Figure 2B, adapted from Cheyne et al. (2008). This MEG study has shown a contralateral gamma increase at highly specific spatial locations for individual limb movements, which was highly consistent over repeated measurements and sessions (Cheyne et al., 2008; Cheyne, 2013). Figure 2 with 1 supplement see all Download asset Open asset Cortical topography of STN spike-to-cortical gamma coupling and power changes. (A) ECoG strips were distributed mainly over precentral and parietal areas. ECoG coordinates from recordings performed in the left hemisphere were flipped in the x-axis to allow averaging across recordings performed in the left and right hemisphere. The maximum number of overlapping recordings was 18 (dark areas). (B) A magnetoencephalography study in healthy participants showed independently from our study that gamma oscillations at the onset of finger movements are focal to lateral motor cortex (Cheyne et al., 2008). (C) Gamma power increased most strongly over motor and somatosensory cortical areas during contralateral gripping. (D) Beta power decreased in spatially more widespread areas. (E) The left and right plots show the two sets of sites that showed the highest 60–80 Hz STN spike-to-cortical gamma coupling during contralateral and ipsilateral gripping, respectively. Each set includes one single site per recorded hemisphere (n = 28). These sites were chosen for further analyses. (F) As (E) but reduced to the sites showing significant gamma coupling −0.1–0.4 s around movement onset (α = 0.1 to show the location of a larger number of contacts). If several channels of one recording were significant, only the channel with the highest PLV was included. The contacts that showed significant gamma PLV during contralateral gripping were concentrated over precentral cortex. This hotspot corresponds well with the 60–90 Hz gamma source localized in MEG studies (Cheyne et al., 2008) shown in B). The significant contacts for ipsilateral gripping were scattered over a wider area. See also Figure 2—figure supplement 1. © 2008 Elsevier. Figure 2B is reprinted with permission from Cheyne et al. (2008) . It is not covered by the CC-BY 4.0 licence and further reproduction of this panel would need permission from the copyright holder. ECoG strips were distributed predominantly over precentral and parietal areas and were always located in the same hemisphere as the recorded STN (Figure 2A). Because other studies have already clearly demonstrated the presence of finely tuned gamma activity and coupling in cortex and the STN (Litvak et al., 2012: Figures 5 and 6; Cheyne et al., 2008), we took a hypothesis-driven approach and focussed specifically on analysing STN spike coupling with 60–80 Hz cortical gamma activity in a 500 ms window around movement onset. Cortical power in the 12–30 Hz beta and the 60–80 Hz gamma frequency bands was modulated at movement onset (−0.1–0.4 s around grip onset) in bipolar contact pairs situated predominantly in primary motor and sensory areas (Figure 2 C+D), which is in line with past ECoG studies (Ohara et al., 2000; Pfurtscheller et al., 2003). Note that gamma power increased specifically for contralateral and not ipsilateral movements. Within-subjects correlations between the magnitude of the relative power changes in the beta and gamma band at contralateral movement onset did not significantly differ from zero at the group level, suggesting that they were uncorrelated with each other (mean R = 0.05, p=0.785, Wilcoxon signed-rank test, n = 28). The bipolar contact pairs with the strongest cortical gamma phase coupling to STN spikes during contralateral gripping per spike recording were concentrated in lateral precentral gyrus (Figure 2E), a site, which corresponds strikingly well to the hotspot of 60–90 Hz gamma synchronization r in a previous MEG study that presumably identifies primary hand motor cortex Figure 2B, adapted from Cheyne et al. (2008). The spatial focus of coupling during contralateral gripping becomes even clearer when only the sites are displayed for which movement-related STN-spike-to-cortical gamma phase coupling reached significance relative to a permutation distribution (Figure 2F). The sites that showed significant coupling during ipsilateral gripping were more widely dispersed and were shifted toward somatosensory cortex. The significance tests in Figure 2F show that gamma coupling was higher relative to a pre-movement period and relative to shuffled data, confirming that the increase exclusively occurred at movement onset and was not already present at rest. Sites with the highest coupling during contralateral and ipsilateral gripping were separately selected for further analyses. Movement-related STN spike-to-cortical gamma coupling To evaluate changes in coupling across the whole task period and across multiple frequencies at the group-level, we employed a novel procedure that ensured that the time-frequency plots depict changes in the data locked to each task event. Each trial began with a Left/Right cue that was followed by a GO signal, movement onset and movement offset (Figure 1). To calculate coupling strength for multiple time points and make sure the values are comparable, the number of spikes going into the calculation should be kept constant for each point because smaller numbers would result in inflated coupling values. Intervals between events were divided into equidistant points for each trial so that the variability of these intervals across trials and subjects did not affect the accuracy of the data alignment around important task events. The windows centred around these points were scaled such that each window contained the same number of spikes to then compute the phase locking value (PLV) for this point (see Methods). Movement-related cortical power changes showed a broad power increase between 60–150 Hz (Figure 3B) that is typically observed in ECoG recordings. Such broad power increases can reflect both true oscillatory components as well as non-oscillatory broadband activity capturing short neural events (Ray and Maunsell, 2011). To focus on the 60–80 Hz oscillatory component of interest, we pre-selected the ECoG contacts with the highest PLV between 60–80 Hz over a −0.1–0.4 s period around movement onset (Figure 2E). Accordingly, STN firing was consistently phase-locked to cortical gamma at movement onset in these sites across all recordings (Figure 3A, n = 28). The significant cluster shows that coupling strength was higher than that obtained from a permutation distribution, which was generated by shuffling the association between STN spike trains and cortical LFP gamma phase time courses across trials, while keeping the respective individual trials intact. The cluster highlights that in the selected sites, above-chance coupling was relatively constrained to a narrow spectral window in the gamma band and centred narrowly in time on movement onset instead of being widespread, which would have been possible in principle, despite the selection criterion. Figure 3—figure supplement 2 shows the spike-triggered average of the 60–80 Hz filtered ECoG signal of three example recordings demonstrating clear locking around contralateral grip onset but not in a pre-movement period. During ipsilateral gripping, no significant clusters in coupling between STN spikes and the gamma phase of this pre-selected set of ECoG sites were found (Figure 3A, bottom row) and no significant gamma increase was present (Figure 3B). The cortical high-frequency activity (HFA, described in Methods) as a proxy of local discharge activity was also significantly higher during contra- versus ipsilateral gripping (Wilcoxon signed-rank test, n = 28, p=0.001). Figure 3 with 5 supplements see all Download asset Open asset STN spike-to-ECoG phase coupling and ECoG power during visually cued gripping. The top and bottom row show contra- and ipsilateral grip trials, respectively. To get comparable estimates of the coupling strength around each of the key trial events, we implemented an event-locked variable-window width PLV estimation procedure: Each interval between neighbouring task events was subdivided into equidistant points, which served as centre for a window within which the PLV was computed. The windows varied in width to encompass the same number of spikes for all time points for one recording. (A) The black outlines show significant clusters obtained with a cluster-based permutation procedure for multiple comparison correction (n = 28, p<0.05). Significant 60–80 Hz spike-to-cortical gamma phase coupling occurred at contralateral grip onset. The same cells also locked to beta after movement offset when cortical beta power rebounded. During ipsilateral gripping (bottom row), no significant clusters were found. (B) During contralateral gripping, cortical gamma power increased while beta power was significantly suppressed relative to the median power obtained from the whole recording. Ipsilateral gripping resulted in relatively reduced >120 Hz power after the grip was released. (C) Average firing rates across the 28 recordings showed no significant modulation to any of the task events. Error bars display standard errors. See also Figure 3—figure supplements 1–5. Figure 3—source data 1 Source data for Figure 3 showing contralateral grip trials. https://cdn.elifesciences.org/articles/51956/elife-51956-fig3-data1-v2.mat Download elife-51956-fig3-data1-v2.mat Figure 3—source data 2 Source data for Figure 3 showing ipsilateral grip trials. https://cdn.elifesciences.org/articles/51956/elife-51956-fig3-data2-v2.mat Download elife-51956-fig3-data2-v2.mat The average firing rate at the group level did not change with any of the task events (Figure 3C). This was the case not only when computing average firing rates in 0.3 s long sliding windows as shown in Figure 3C, matching the average window length used to calculate the coupling strength, but also when examining instantaneous firing rates. Importantly, gamma coupling could be found in recordings of all response types, irrespective of whether firing rates remained stable (47%), increased (21%) or decreased (32%) (Figure 3—figure supplement 3, cells were classified as increasing or decreasing if a significant cluster occurred between the Go cue and movement offset; some additionally showed a significant decrease either before or after the movement). We evaluated firing relationships further by computing a correlation across recordings between firing rate changes at movement onset and coupling strength, which confirmed that no relationship was present (mean R = 0.01, p=0.969, see Figure 3—figure supplement 4A). The only cue-related change in firing characteristics observed on the group level was a reduction in the interspike interval coefficient of variation (Figure 3—figure supplement 4B). In summary, these results show that spatially and temporally specific STN-spike-to-cortical-gamma coupling can be detected at the onset of contralateral movement. We then extended our analyses to ECoG sites that showed the greatest spike-to-gamma coupling during ipsilateral gripping. In this set of sites, coupling also exceeded that obtained by a permutation distribution (Figure 3—figure supplement 5B Note that these sites were spatially more widely distributed and to be located to motor cortex (Figure ECoG In these sites, gamma coupling was also present during contralateral gripping (Figure 3—figure supplement 5B the coupling frequency to be higher than for the set of ECoG sites in which coupling was greatest for contralateral gripping. Gamma power increased and beta power decreased significantly after cluster-based permutation correction relative to the median power obtained from the whole recording only for contralateral grip trials (Figure 3—figure supplement if the initial cue an ipsilateral beta power was significantly the Go signal while power above Hz was significantly reduced (Figure 3—figure supplement we if the coupling strength the movement onset to reaction spike-to-gamma coupling reaction times To if reaction time were linked to in gamma coupling, we all trials and coupling separately for the two This analysis that reaction times were preceded by higher STN motor cortical LFP gamma coupling and that this was specific for contralateral gripping. The was present already at the time of the Go signal (Figure which occurred on average 0.39 s before grip onset in fast trials and s in trials with slow The windows for on average s around each point and the precise window length at the Go signal was ± ms and ± ms for fast and slow RT trials. even in trials with short the movement onset the window used for at the time of the Go signal, where a significant in coupling already was present = the in coupling be by movements in trials with short The at grip which shows that the coupling strength during the movement was comparable irrespective of whether RTs up to the movement were fast or To further this we also correlations between coupling and RTs in a s long window at the Go This confirmed at the group level that RTs were significantly when coupling strength was higher (mean R = t27 = Figure 4 with 2 supplements see all Download asset Open asset was significantly higher when reaction times were (A) The cluster shows that in those trials, in which RTs were fast as by a median gamma coupling in the contralateral hemisphere was already significantly higher after the Go signal, about 500 ms before movement onset. (B) Average cortical gamma power to be higher and signal beta power lower in contralateral grip trials with reaction however, these did not cluster-based multiple comparison See also Figure supplements 1 and such correlation was present between RTs and firing rates (mean R = t27 = and of the firing characteristics between trials with fast and slow RTs (Figure supplement 1). trials were according to peak yank or peak grip no significant were found (Figure supplement Note that primary motor cortical gamma power also to be higher when reaction times were the was not significant (Figure 4B). we also found that the in coupling was spatially as it was not present in ECoG sites that showed the greatest coupling during ipsilateral gripping. STN spiking is modulated relative to the cortical gamma phase for individual pairs of STN spike and cortical ECoG recordings as a of coupling strength not a of the of the preferred phase across recordings. As only the length of the average phase is used to calculate how strongly or the phase values information about the preferred phase is To out across spikes were consistently more at points of the gamma cycle and at we the spiking relative to the cortical gamma phase. It would be to a consistent phase and significant modulation of spiking if PLV coupling was a of analysis the of ECoG contacts). were within a −0.1–0.4 s window around movement onset for gamma phase To whether the resulting were significantly we a 4 2 contralateral vs. The resulted in a significant = and no significant = = Figure 5 shows that spiking were significantly and modulated during contralateral vs. and ipsilateral gripping vs. This significant modulation shows that the preferred and for spiking were relatively consistent across despite the ECoG sites used to the gamma phase were selected according to the highest coupling irrespective of the preferred phase. Figure 5 with 4 supplements see all Download asset Open asset STN spiking is modulated relative to the phase of cortical The top shows how spiking during contralateral grip onset with the gamma phase. show significant between phase was relatively reduced in during contralateral gripping. It was significantly lower than during ipsilateral gripping (bottom Wilcoxon signed-rank test, The of the plots the median and show the and show the and are data points this See also Figure supplements The spiking in was significantly lower during contralateral compared to ipsilateral gripping (Wilcoxon signed-rank test, n = 28, and the in was higher = not significant if for the multiple the number of to instead of resulted in a similar significant modulation within contra- and ipsilateral grip trials (Figure supplement however, of the showed a significant between contra- and ipsilateral gripping with this the or the for gamma obtained from primary motor cortical ECoG sites were for gamma obtained from the other set of sites highest coupling during ipsilateral are shown in Figure supplement This distinct modulation of spiking according to the phase of gamma is and may a mechanism that enhances cortical gamma which were more during contralateral gripping (Figure If STN spikes that occur at one phase of the cortical gamma cycle contribute to cortical gamma for contralateral movements, then during ipsilateral movements of gamma could be if spikes would occur at the opposite phase The if such a in spike timing was This analysis was also by the above in spiking between contra- and ipsilateral gripping observed at a specific phase of the gamma The preferred gamma phase of STN spikes between contra- and ipsilateral movements To if the timing of STN spikes relative to the cortical gamma phase between contra- and ipsilateral grip trials, we the gamma phase from the primary motor cortical ECoG sites and the or phase with STN spikes for both trial To recordings where estimation of the average phase may have been we by only recordings in which gamma coupling was significant at movement onset in Figure 2F). We found in this (n = that the preferred gamma phase significantly between contra- and ipsilateral grip trials by (mean offset = Figure A more selection included all recordings in which the phase value of coupling exceeded zero (see Methods). In the larger set (n = which is potentially more individual phase estimates may be the preferred phase was offset by (Figure mean offset = from a an offset of showed as the significant phase was only present around movement onset (Figure where coupling was This analysis thus confirmed that spikes locked to opposite points of the gamma cycle on whether the selected motor response was contralateral or ipsilateral to the recorded hemisphere. Figure Download asset Open asset