Cortical oscillatory dysfunction in Parkinson disease during movement activation and inhibition.

Response activation and inhibition are functions fundamental to executive control that are disrupted in Parkinson disease (PD). We used magnetoencephalography to examine event related changes in oscillatory power amplitude, peak latency and frequency in cortical networks subserving these functions and identified abnormalities associated with PD. Participants (N = 18 PD, 18 control) performed a cue/target task that required initiation of an un-cued movement (activation) or inhibition of a cued movement. Reaction times were variable but similar across groups. Task related responses in gamma, alpha, and beta power were found across cortical networks including motor cortex, supplementary and pre- supplementary motor cortex, posterior parietal cortex, prefrontal cortex and anterior cingulate. PD-related changes in power and latency were noted most frequently in the beta band, however, abnormal power and delayed peak latency in the alpha band in the pre-supplementary motor area was suggestive of a compensatory mechanism. PD peak power was delayed in pre-supplementary motor area, motor cortex, and medial frontal gyrus only for activation, which is consistent with deficits in un-cued (as opposed to cued) movement initiation characteristic of PD.

Introduction

Response initiation and inhibition are functions fundamental to executive control that are disrupted in Parkinson disease (PD) [1-3]. Response initiation, sometimes referred to as ‘movement activation,’ refers to the process of eliciting a desired response, whereas response inhibition refers to the capacity to suppress inappropriate or irrelevant responses that are prepotent. People with PD often show deficits on standard neuropsychological tests of inhibition, such as the Stroop Test [4, 5], which is consistent with the idea that inhibition plays a role in automatic behaviors and action override, functions that are also disrupted in PD [6]. Furthermore, impairments in response activation and inhibition have been proposed to subserve some of the common motor signs of PD. For example, akinesia, or an inability to start movement [7-10] is consistent with a problem in movement activation [3]. Activation and inhibition are also associated with motor switching and sequencing, which are impaired in PD [3, 11]. However, deficits in response activation and inhibition associated with PD are complex and not fully understood. For instance, in PD, the latency to initiate movement can be shortened by the use of pre-movement external auditory or visual cueing such as walking in time to a metronome or walking paced by floor markers (e.g., [12-16]).

Many behavioral studies have shown that people with PD display deficits in both the activation and inhibition of motor responses [17-19]. Studies targeting components of responding traditionally use two types of tasks, the classic ‘Go Nogo’ tasks [20] and ‘stop-signal’ tasks [21]. Wu and colleagues [22] found that people with PD performing a Go Nogo task demonstrated increased reaction times for ‘Go’ trials and increased errors for both ‘Go’ and ‘Nogo’ trials as compared to controls. Franz and Miller [23] found that people with mild to moderate PD demonstrated abnormal force output during inhibition of ‘Nogo’ responses in comparison to controls, despite a lack of difference in mean reaction times between PD and control groups. Previously, we [1] also observed an absence of statistically significant reaction time differences between PD and control groups during movement activation and inhibition in PD (though variability was high) despite deterioration in spatial and temporal specificity of blood-oxygen-level-dependent imaging signal in cortical and subcortical regions of interest.

Anatomical evidence indicates that motor and cognitive function are subserved by anatomically segregated parallel circuits from the cerebral cortex to thalamus via the basal ganglia nuclei which form circuits with projections back to the cortex. Segregated parallel loops are thought to mediate distinct motor, cognitive, and limbic functions based on cortical targets [24-26]. For example, abnormalities in motor cortical activity observed in PD [27, 28] have been linked to loss of dopamine in the posterior putamen [29, 30]. Similarly, studies of executive dysfunction in PD suggest that loss of dopamine in the caudate results in abnormalities in activity in prefrontal cortex (PFC; [31-33] for review). This PFC-connected cognitive circuit has also been implicated in important aspects of both response activation and inhibition behaviors ([34] for review).

There is evidence in the electroencephalography (EEG) literature of delayed onset and decreased power in the event related responses for components of movement activation and inhibition in people with PD [35-39], though not all studies agree (see [40] for review). Furthermore, growing evidence suggests that parkinsonian impairments in motor and cognitive function are associated with dysregulated cortical oscillatory activity. Oscillatory activity is thought to reflect modulation of neuronal excitability in synchronously active neural assemblies [41, 42]. For example, using magnetoencephalography (MEG), a diffuse slowing of oscillatory activity at rest has been observed in people with PD, as well as increased beta band power over sensorimotor cortex at rest [43]. Such changes are reported early in disease progression, and can be measured regardless of disease duration, stage, severity, or medication level [44]. A number of studies demonstrate that in PD, global changes in oscillatory power are correlated with cognitive dysfunction as well (for a review, see [45-49]). Attenuated desynchronization of both beta band [22] and higher alpha band [50] EEG has been reported in people with PD during Go and Nogo trials [51]. However, few studies have brought to bear the superior temporal and spatial resolutions of MEG to elucidate the abnormalities in brain activity associated with movement activation and inhibition in PD.

Our goal was to examine PD-associated abnormalities in the magnitude and timing of oscillatory power in the basal ganglia thalamocortical circuit subserving response activation and inhibition. We tested the hypothesis that oscillatory activity in the frontal cortical regions subserving these functions had reduced event related power change and delayed onset in people with mild to moderate PD on dopamine replacement therapy compared to control participants. This hypothesis was based on previous work showing increased cortical resting state oscillatory synchronization and increased event related response latency in PD [35–40, 43, 52–54]. We used MEG, which combines high temporal precision and spatial resolution in the cortex to measure anatomical, at the level of the cortical field, region of interest, and physiological, specifically electrophysiological data. Unlike previous work, we matched motor output across trial types, allowing us to isolate the pre-movement processes of activation and inhibition to examine network dysfunction in PD.

Methods

Subjects

Individuals with PD were recruited from the movement disorders clinic at the UC Davis Medical Center. Clinical diagnosis of Parkinson disease was made according to Queen Square Brain Bank criteria [55] by a movement disorders neurologist and confirmed by review of medical records. Eighteen people with PD (4 female, 14 male) and 18 controls (8 female, 10 male) participated in this study. All participants were right-handed and PD participants had right side (of body) dominant PD, defined by side of initial symptom onset. Statistical power analysis based on Beste and colleagues [56] showed an amplitude difference between PD and control groups of about 8 ±2 μV in P300 peak amplitude for both compatible and incompatible Go trials. Using an alpha of 0.05 for a single comparison, a sample size of 18 per group yielded power of over 90% for an independent, 2 sample t-test comparing PD and control groups. Similar results were obtained from a power analysis of peak latency measures from the same study.

Inclusion criteria were male or female > 55 years old and fluent in English. Additional PD specific inclusion criteria were right-handed and right sided PD dominant onset. Exclusion criteria were history of severe head trauma based on patient report; significant uncorrected visual impairment; significant additional medical conditions known to affect cognitive function; history of substance or alcohol abuse; inability to understand informed consent, study purpose and procedures or other study materials involved in the research study; and women who were or might have been pregnant. Additional exclusion criteria included depression (Beck Depression Scale score >20; [57]), significant cognitive impairment (Mini-Mental State Exam <25; [58]), and excessive daytime sleepiness (Epworth Sleepiness Scale score >10; [59]). MRI specific exclusion criteria were significant claustrophobia or other identified problem making the MRI environment intolerable; body weight >300lbs; pacemakers, artificial limbs, or other implanted medical devices that contained metal; other metal objects, such as jewelry, piercings, braces, or internal prosthetics that were not MRI compatible and could not be removed based on pre-MRI screening form.

PD specific exclusion criteria were atypical PD, persistent tremor (score > 1 on UPDRS items 16, 20 or 21 for best on medication state), presence of motor fluctuations (score >1 on UPDRS items 36–39), or dyskinesia (score >1 on UPDRS items 32–34). Participants with PD were given the UPDRS on medication on a separate day from brain imaging. Written consent from each participant was obtained prior to the experiment and procedures were approved by the Institutional Review Board on Human Subjects Research at the University of California, Davis.

All patients had late onset (>55 years at time of diagnosis) idiopathic PD with a history of positive response to dopamine replacement therapy and no alterations in medication for 6 weeks prior to enrollment. PD participants took their prescribed medication in the morning prior to study participation and performed the experiment in their best ON medication state. Thus, PD participants performed the tasks while on levodopa with carbidopa, dopamine agonist, Amantadine, Monoamine Oxidase Type B inhibitors and/or Catechol-O-Methyl Transferase inhibitor treatment for Parkinson disease. Dopamine equivalency for each PD participant’s daily medications was calculated based on established conversion factors [60].

Activation inhibition task

Subjects were presented with a visual cue-target design task and required to respond to the target by pushing a button with one or both index fingers. Fiber optic button boxes (Photon Control, Inc. ) were held in both the left and right hands. Subjects were trained prior to entering the scanner to respond only to the target arrow(s) with their index fingers pressing hand-held button boxes. The training task consisted of a series of stimuli that contained 2 trials of each trial type. All subjects executed this trial run once before scanning following which they reported understanding the task. Stimuli were generated on a PC using Presentation software (www.neurobs.com/presentation). Stimuli were projected into the magnetically shielded room using a Christie Lx41 projector (Christine Digital, Cypress) onto a screen using a series of mirrors. Participants lay supine and their heads were padded to reduce movement.

On each trial, stimuli consisted of a visual fixation cross (a white + sign on a black background), which was present for the entire trial, and subjects were instructed to focus on this fixation point. A cue arrow appeared superimposed on the fixation cross, followed by a target arrow indicating the response to produce on a particular trial. The arrow cue (presented in orange) appeared for 200 ms followed by a delay interval that varied randomly between 600 and 1200 ms. The target arrow then appeared in the same central position (in blue) for 1000 ms. The inter-trial interval (ITI) was 2000–3000 ms (Fig 1A).

Fig 1

Trial timeline.

(A) Arrow cue timeline for a bilateral cue and unilateral target. (B) Example of arrow cue visual presentation to subjects. The examples are for bilateral or right-hand trials. Left-hand stimulus pattern was identical. Letters indicate cue and target type, B = bilateral, L = left, R = right.

Cue and target stimuli were pairs of either unidirectional arrows pointing to the left or right, or bidirectional (double-headed) arrows. Subjects were instructed to respond to the target arrow with either a unimanual (in the direction of a single-headed arrow) or bimanual (in the case of bidirectional arrows) button press. One of seven possible pairs of cue/target stimuli was presented: bilateral cue and bilateral target (cue = B, target = B), right cue and bilateral target (RB), left cue and bilateral target (LB), right cue and right target (RR), left cue and left target (LL), bilateral cue and right target (BR), or bilateral cue and left target (BL). These combinations were grouped into two trial types: matched trials, where the cue and target arrows were the same (RR, LL, and BB), and mismatched trials, where the cue and target arrows were mismatched (BR, BL, RB, and LB). The mismatched trials were further classified into two key types that represent distinct types of behavioral functions. In the first type, subjects were required to activate an un-cued button press movement, as in the case of RB and LB trials. For these trials, a unilateral cue followed by a bilateral target requires initiation of a response that is un-cued for one hand, the hand not indicated by the cue. This added response (not previously cued) requires movement activation of a non-activated/non-cued response. In the second type, which we called inhibition trials, subjects were required to inhibit a cued movement, as in the BR and BL trials. In this case, a bilateral response is cued, but subjects must inhibit the already cued response on the target trial, responding with a single hand. In each of the 7 trial types there were 120 trials during a 70-minute scan session (some examples of trial types are shown in Fig 1B). Trial types were presented in random order.

Behavioral data

Behavioral measures (reaction time and errors) were collected using ADC channels from voltage changes in the button box and extracted using CTF Data Editor software (https://www.ctf.com/products). Datasets were sorted by trial type (matched, mismatched: activation, mismatched: inhibition), and errors were detected by visually inspecting voltage changes in ADC channels. An error was defined as a unilateral button press of the incorrect button, a unilateral response when a bilateral response was required or a bilateral response when a unilateral response was required. Error trials were excluded from analysis. For epoching of data, target stimulus presentation was marked as 0 ms. Reaction time was calculated for correct trials as the time between the onset of the target arrow to the onset of the button press for each response.

Acquisition

Neuromagnetic activity was recorded in a magnetically shielded room using a whole-head biomagnetometer (CTF MEG, Coquitlam, Canada) with 275 first-order axial gradiometers and 27 reference sensors that enabled collection of synthetic third-order gradient data with improved signal-to-noise ratio. Coils at the nasion and 1 cm from the tragus, rostral to the left and right periauricular points in the direction of the nasion, were used to quantify head position relative to the sensor array. These points were later co-registered to the structural MRI through a multi-sphere head model. Scan sessions where head movement exceeded 5 mm within a run were discarded and repeated. Epochs of 3–6 seconds duration were acquired using a sampling rate of 1200 Hz.

For reconstructions of the MEG data in source space, a structural MRI scan was acquired on a 1.5 T GE Signa scanner using an MP-RAGE (multiplanar rapidly acquired gradient echo) imaging sequence with the following parameters: repetition time (TR), 7.87 s; echo time (TE), 2.69 ms; flip angle, 8 degrees; slices, 200; field of view, 256 mm; resolution, 1 x 1 x 1.2 mm.

Data for this study has been made publicly available under Creative Commons CC0 1.0 Universal (CC0 1.0) at https://doi.org/10.12751/g-node.nb35ss. The data is stored in BIDS format using the CTF *.ds filetype. It can be opened in either proprietary CTF software (Omega 2000) or open-source M/EEG software packages (NUTMEG, fieldtrip). The Fieldtrip website expands on the file format here: https://www.fieldtriptoolbox.org/getting_started/ctf/.

Analysis

Trials were corrected for noise and movement artifacts and error trials were discarded using DataEditor software (https://www.ctf.com/products). Noise and artifacts were identified visually by scanning trials for patterns caused by eye blinks, saccades, and head motion (MEG sensor amplitude exceeding 20 pT). Neural sources were estimated in the time-frequency domain using the Neurodynamic Utility Toolbox for MEG (NUTMEG; https://www.nitrc.org/projects/nutmeg/) across a shared computing cluster at the California Institute for Quantitative Biomedical Research (www.qb3.org). Changes in induced (non-phase locked) activity were estimated using an adaptive spatial filtering technique (lead field resolution = 5 mm), which effectively weights each source estimate (voxel) relative to the signal of the MEG sensors [61-63].

Source power for each voxel was determined by comparing the magnitude of the signal during an ‘active’ experimental time window versus a pre-stimulus baseline ‘control’ window [61, 64] using a noise-corrected pseudo-F statistic expressed in logarithmic units (decibels (dB); [61]). The data were stimulus-locked (target onset = 0 ms) followed by 25 ms time windows until 1112.5 ms post-target onset. Data were passed through a filter bank and partitioned into partially overlapping time windows of varying size (100, 150, 200, and 300 ms) optimized to capture spectral peaks in the MEG signal [61, 63, 65]. Twenty-five ms steps were then estimated in the alpha (8–12 Hz), beta (12–30 Hz), and gamma (30–55 Hz) bands.

Whole-brain reconstructions of oscillatory activity were co-registered with each individual’s structural MRI. Each reconstruction was spatially normalized by applying a transformation matrix derived from the normalization of the structural MRI to a standard T1 template brain (Montreal Neurological Institute; MNI305) using SPM2 (http://www.fil.ion.ucl.ac.uk/spm/software/spm2). Averages and variance maps were smoothed using a Gaussian kernel with a 20 mm3 width (full-width half-maximum) [63, 65]. Spatially normalized activation maps were entered into a group analysis using statistical non-parametric mapping (SnPM) [66], a statistical metric known to accommodate non-normally distributed MEG datasets [67]. Regions of interest (ROI) based on Brodmann nomenclature were derived from MNI coordinates in the normalized brain [68]. Permutation testing (2N possible combinations of negations) to assess significance were performed both within-group (one-sample t-test, mean difference between conditions) and between the control and PD groups (unpaired t-tests). Within group analyses were corrected for multiple comparisons at a familywise error rate cutoff of p<0.05. Between-group analysis was corrected with a false discovery rate threshold of p<0.05. For the gamma band, we began with a conservative (multiple comparison corrected) threshold of p<0.05 as a first step, with a more liberal threshold (significant at p<0.05, uncorrected) as a second step if significant effects were not observed at a conservative level. The details of this approach have been described elsewhere [61, 67, 69]. As we have noted previously [61], the reduced power inherent to higher frequency oscillations often require us to rely on more liberal thresholds with a concomitant increase in risk for type 1 error [61, 65].

Latency data was obtained from simple activation and inhibition trials (not contrasts). Onset and duration for each region of interest was determined by using the time frequency viewer to select the first and last 25 ms time window where the ROI was significant at its threshold. Between group differences in behavioral and latency data were evaluated using repeated measures analysis of variance (ANOVA) with post hoc analysis using a p value of 0.05.

Results

There were no significant differences across groups for age F(1, 35) = 0.65, p = 0.43 or years of education F(1,35) = 1.64, p = 0.21. Gender distribution was not significantly different across groups X2(1, 35) = 2, p = 0.16. Demographic data are presented in Table 1.

Table 1

Demographic data reported as mean and (SD) except for H&Y, which is the median.

M = male, F = female, UPDRS = Unified Parkinson Disease Rating Scale.

	N	Age (years)	Sex	Education (years)	UPDRS Total	UPDRS III	H&Y	Dopamine Equivalent (mg)	Disease Duration (years)	Age at Diagnosis (years)
PD	18	66.5 (8.0)	14M, 4F	15.4 (2.7)	32.7 (13.5)	20.4 (12.0)	2	462.5 (395)	4.8 (2.7)	61.6 (8.1)
Control	18	63.8 (8.7)	10M, 8F	14.0 (2.3)	na	na	na	na	na	na

Repeated measures ANOVA revealed that there were no significant differences in reaction times for either group or any trial type F(1,70) = 2.25, p = 0.14. Error rates were significantly higher in the PD group for all trials F(1,70) = 6.22, p = 0.015. The means and standard deviations for reaction times and error rate are reported in Tables 2 and 3.

Table 2

Reaction time (ms) for control, activation, and inhibition trials.

Values are mean reaction time (SD) in milliseconds (ms) from target presentation.

	Matched (ms)	Mismatched: Activation (ms)	Mismatched: Inhibition (ms)
CO	533.95 (104.12)	579.05 (99.38)	531.03 (84.58)
PD	570.60 (149.01)	599.21 (163.67)	586.06 (125.74)

Table 3

Error rate for control, activation, and inhibition trials.

Values are mean percentages (SD), calculated by number of incorrect trials / number of total trials. *p < .05.

	Matched*	Mismatched: Activation*	Mismatched: Inhibition*
CO	1.35% (3.23%)	1.72% (4.66%)	1.31% (3.16%)
PD	4.4%(7.55%)	3.7% (7.24%)	4.3% (7.92%)

Task based activity

In general we observed brain regions that showed statistically significant event related changes in oscillatory power (p<0.05, corrected for multiple comparisons at a familywise error rate; not shown) following response (button press) activation or inhibition that included Brodmann area 4 (motor cortex), lateral BA 6 (pre-supplementary motor area), medial BA 6 (supplementary motor area), BA 7 (posterior parietal cortex), BA 24 (anterior cingulate cortex), and BA 9/10 (medial and anterior prefrontal cortex, specifically medial and superior frontal gyrus). Areas 9 and 10 were reported together because activity frequently overlapped at the border between these two regions. Right- and left-hand trials both tested activation and inhibition in a similar fashion, and results from right- and left-hand trials were similar, so data from right-hand response trials were used to illustrate the results. Right-hand results were chosen because all subjects were right-handed with right side dominant disease. Right- and left-hand response MEG data were not combined because frontal and sensorimotor cortex results were not aligned due to crossed inputs from the two hands, while frontal lobe activation was independent of response hand.

Across all tasks (control subject matched trial data not shown), primary motor cortex, lateral pre-supplementary motor area, and posterior parietal cortex showed statistically significant decreases in power compared to baseline, while supplementary motor area and anterior cingulate cortex showed increases. In medial/ anterior prefrontal cortex, we observed both increases and decreases in power in multiple frequency bands and time points. Of interest here are results from 1) control subject motor planning (matched vs. mismatched trial contrasts for activation (Fig 2A) and inhibition (Fig 4A); and 2) difference in motor planning across disease groups (control vs. PD subject mismatched trials contrasts for activation (Fig 2B) and inhibition (Fig 4B). Significant PD associated power changes in specific frequency bands, latencies, and brain regions are described below.

Fig 2

Activation contrast analysis.

(A) Differences in peak intensity in the control group for mismatched activation trials versus matched control trials. (B) Differences in peak intensity during mismatched activation trials between the PD and control groups. MS = millisecond. Scale color bar represents power in arbitrary units. Peak activity indicates a significant change at p<0.05, corrected for multiple comparisons except for the gamma band. To identify gamma band activity, we used a more liberal threshold (significant at p<0.05, uncorrected). R = right hand, B = bilateral.

Activation contrast analysis (unilateral cue, bilateral target vs. bilateral cue, bilateral target)

For activation trials, subjects were presented with a unilateral cue and bilateral target; for example, right cue, bilateral target (RB), which required activation of a (un-cued) left-hand response. In control subjects, brain activity from these trials was compared to that from control trials matched for motor output that did not require response activation (BB, bilateral cue, bilateral target; Fig 2). The control group contrast analysis (Fig 2, left, false discovery rate corrected threshold of p<0.05) revealed peak increased power in the gamma band in left medial/ anterior prefrontal cortex at 337.5 ms. There was also a peak power increase in the alpha band in anterior cingulate cortex at 337.5 ms. In bilateral medial/ anterior prefrontal cortex, there were peaks in increased power in the beta band at 537.5 ms.

To identify differences in PD brain activity patterns following response activation (of a not previously cued response), we compared trials consisting of a unilateral cue and bilateral target in the control versus PD groups. The contrast analysis of mismatched activation trials in the PD group versus control group (RB PD vs. RB Control; Fig 2, right; false discovery rate corrected threshold of p<0.05) revealed a relative power increase in the beta band in the bilateral primary motor cortex that peaked at 387.5 ms. We identified a decrease in power in the alpha band in left supplementary motor area, a decrease in power in the beta band in the left medial/ anterior prefrontal cortex, both at 387.5 ms. In the beta band we also observed a decrease in power in posterior parietal cortex at 512.5 ms in the left hemisphere in the PD versus the control groups.

Repeated measures ANOVA of response latency data from both matched and mismatched (activation and inhibition) trials revealed that changes in power peaked at longer latencies in the PD group relative to those in the control group. For matched (BB) trials (Fig 3A), the PD group gamma band peak power change latency was delayed relative to controls in the left supplementary motor area (BA 6; t(34) = -2.595, p = 0.014), and in the beta band in left medial/ anterior prefrontal cortex (BA 9/10; t(34) = -2.201, p = 0.035). For mismatched activation trials (Fig 3B), peak changes in power also occurred at longer latencies for the PD group, but to differing degrees depending on the area, leading to a significant interaction between ROI and group (F(3.95, 134.26) = 4.504, p = 0.002). PD group peak latency was longer in the gamma band in left supplementary motor area (BA 6; t(34) = -2.595, p = 0.014) and in the beta band in left primary motor cortex (BA 4; t(34) = -2.377, p = 0.023). PD group peak latency was also longer in the alpha band in left medial/ anterior prefrontal cortex (BA 9/10; t(34) = 2.175, p = 0.037).

Fig 3

Activation latency.

(A) Onset and duration (gray and white bars) of power change in each ROI for the matched control trials. Latency of peak power change is indicated by solid black or white lines. (B) Onset and duration of power change in each ROI for the mismatched activation condition. Peak latency was significantly longer in the PD vs. control group: *p < 0.05.

Inhibition contrast analysis (bilateral cue, unilateral target vs. unilateral cue, unilateral target)

For response inhibition trials, subjects were presented with a bilateral cue and unilateral target; for example, bilateral cue, right target (BR), which required inhibition of a left-hand cued response. In control subjects, brain activity from these trials was compared to control trials matched for motor output that did not require response inhibition (RR, unilateral cue, unilateral target; Fig 4A).

Fig 4

Inhibition contrast analysis.

(A) Differences in peak power change in the control group for mismatched inhibition trials versus matched control trials. (B) Differences in peak power change during mismatched inhibition task between the PD and control groups. Conventions as in Fig 2.

Control group contrast analysis (Fig 4A) revealed statistically significant peak increased power (p<0.05, corrected for multiple comparisons at a familywise error rate) in the gamma band in medial supplementary motor area (BA 6) at 287.5 ms. Maximum decreased power was observed in the gamma band in left posterior parietal cortex (BA 7) at 337.5 ms, while peak increased power was found in the beta band in left medial/ anterior prefrontal cortex (BA 9/10) at 362.5 ms. We additionally observed maximum decreased power in the gamma band in right pre-supplementary motor area (BA 6) at 437.5 ms.

To identify differences in PD brain activity patterns following response inhibition, we compared control bilateral cue unilateral target trials to the same trials in the PD group. The contrast analysis of mismatched inhibition trials in the PD group versus the control group (Fig 4, right, false discovery rate corrected threshold of p<0.05) revealed bilateral decreases in beta power in medial/ anterior prefrontal cortex at 312.5 ms (maximum right hemisphere) and 362.5 ms (maximum left hemisphere) in PD that was not present in control data. Increased alpha band power was observed in left medial/ anterior prefrontal cortex in the PD compared to the control group with a peak latency of 387.5 ms. We saw increased power in PD compared to controls in the beta band in primary motor cortex with a peak latency of 387.5 ms. We also observed greater power decreases in the gamma band in the PD group compared to controls with peak latencies of 112.5 and 612.5 ms in contralateral pre-supplementary motor area, indicating delayed onset and termination of desynchronous activity in this region in the PD group (Fig 5B).

Fig 5

Inhibition latency.

(A) Onset and duration (gray and white bars) of power change in each ROI for the matched control trials. Latency of peak intensity is indicated by solid black or white lines. (B) Onset and duration of power change in each ROI for the mismatched inhibition condition. Peak latency was significantly longer in the PD vs. control group: *p < 0.05.

Repeated measures ANOVA of response latency data from both matched and mismatched trials revealed that changes in power peaked at a longer latencies in the PD group relative to those in the control group. We observed differences in peak latency between the PD group and the control group only for matched trials (RR; Fig 5A). PD group peak latency was longer in right medial/ anterior prefrontal cortex in the alpha band (t(34) = -3.213, p = 0.003) and in the beta band (t(34) = -3.327, p = 0.002). Variability was high in gamma latency in left lateral pre-supplementary motor area. There were no peak latency differences between groups in the mismatched inhibition trials (BR; Fig 5B).

Discussion

We tested the hypothesis that oscillatory activity in the frontal cortical regions underlying response activation and inhibition had reduced event related power change and delayed onset in PD compared to control participants. We extend previous work by providing cortical oscillatory power and latency data with ROI spatial resolution specific to motor planning, and describe abnormalities in the cortical activation and inhibition responses associated with PD. Despite similar reaction time performance, in PD motor cortex we found increased beta band synchronization and delayed peak latency in primary motor cortex as in previous studies (see [46] for review). We also found reduced event related power changes on correct trials throughout the frontal cortical regions subserving response activation and inhibition consistent with previous work (for review see [34, 70]). Peak latency was delayed in PD for movement activation across frequency bands and brain regions while inhibition data was not different across groups. Furthermore, the changes in location and oscillatory power change of response were consistent with the concept of a compensatory mechanism.

Anatomy and physiology of movement activation and inhibition in PD

We found a group of cortical regions subserving movement activation and inhibition that included prefrontal, cingulate and supplementary motor cortex. In the control group we found increased beta band power in the left medial frontal gyrus during inhibition of a cued movement. Left medial prefrontal cortex is thought to be involved in sustained attention [71-73], short term memory [74], perceptual decision making [75], and overriding automatic responses [76, 77], all of which are likely components of our task. In PD we observed that activation trials were associated with reduced alpha band power changes and delayed peak latency in prefrontal cortex. This region plays a role in the parallel inhibitory and excitatory regulation of neural activities associated with executive function (see [34] and [78] for a review) which are known to be disrupted in PD [79]. Furthermore, the left prefrontal cortex [80] and BA9 subserve error detection [76, 81, 82], and the inhibition response was attenuated in this region in people with PD. Damage to dorsomedial prefrontal cortex (anterior cingulate cortex and supplemental motor area) has also been linked to increased errors in Go Nogo paradigms [18]. Taken together, these findings suggest that increased error rate in PD may be related to abnormal activity in prefrontal cortex.

We also observed event related power changes in cingulate and supplementary motor cortex during movement activation and inhibition that appeared to be preserved in PD. The anterior cingulate, specifically the dorsal anterior cingulate or midcingulate cortex [83, 84], is functionally linked with the prefrontal cortex [85-87], and is likely to play a role in attention processing [53, 88], working memory [76, 89, 90], conflict [91-95], and error processing [96, 97]. While we found that event related alpha band power changes in the cingulate were preserved in PD, previous data from this region showed significantly higher levels of slow wave activity during resting conditions in people with PD [53, 54]. In fact, while Braak staging suggests that anterior cingulate involvement occurs in later stage PD [98], there is accumulating evidence of abnormalities in cortical thickness, cerebral blood flow, fractional anisotropy, dopamine-2 receptor binding and connectivity earlier in the disease (for review see [99]). Our contrasting findings may be related to the significant difference in experimental design and measurement modality across studies and to the impact of plastic compensatory brain changes [100] on functional measures like ours.

In medial supplementary motor area in the control group we observed increased gamma band power during inhibition of a cued movement that was preserved in PD. The role of the right pre-supplementary motor area in response inhibition has been well documented (e.g., [18, 81, 101–106]), and it has been established that the pre-supplementary motor area is involved in motor response inhibition [19, 97, 104, 107, 108], active during stop signal and ‘change of plan’ task paradigms [105] (see [109] for a review), and may be associated with decision making [110], mediation of attention and motor response activation [111]. The normal gamma band power changes may be related to the relatively healthy inhibition related peak power changes observed in PD. In contrast, we found decreased power and increased latency in the alpha band for activation in medial supplementary motor area in PD compared to controls. The link between supplementary motor area function and timing of motor planning such as anticipatory postural adjustments is impaired in PD [112]. It is interesting to note that motor responses were required for both activation and inhibition trials, the difference being that activation requires execution of an un-cued movement. Behavioral deficits specific to un-cued, as opposed to cued movement initiation are well documented in PD [12, 113–115], which is consistent with our data showing delayed peak latency in motor premotor and supplementary motor cortex for activation trials.

Frequency specific cortical oscillatory power

Magnetic and electrical signal synchronization and desynchronization are thought to reflect dynamic communication between spatially distributed brain regions [116, 117]. Oscillatory power at different frequencies has been associated with unique behavioral functions (for a review, see [118]). Power in the gamma band (33–60 Hz) reflects active engagement (i.e., in feature integration, attention, and movement preparation, depending on the cortical area) [119, 120]. In controls, changes in gamma band power for activation and inhibition networks [93, 121–124]. The pattern of gamma band activity was similar to the peripheral attention network described by Corbetta and colleagues [125], and appeared to be relatively intact in PD. We found no differences in gamma band power change amplitude or location in PD. However peak latency was delayed in several ROI’s, consistent with existing studies showing reduced speed of processing in PD [122, 126–128]. In contrast, inhibition related gamma band changes have been reported in the subthalamic nucleus in PD [129], particularly in response to failed inhibition trials [130]. and increased gamma desynchronization following a Go cue was positively correlated with reaction time in PD [130]. Cortical gamma activity is also modulated by thalamic alpha activity [131], and Yoo and colleagues [132] found that alpha-gamma coupling was higher in PD compared to controls.

Reduced power in the beta band frequencies has been associated with movement preparation and execution [7, 133–135] as well as cognitive control [118]. Changes in beta power prior to target onset have also been shown to correlate with reaction time in PD and healthy controls [133]. Furthermore, healthy adults show an increase in beta band power over the frontal cortex while inhibiting responses during a stop-signal task [101]. As in previous work [22, 133, 136, 137], changes in beta band power were common in PD. Reduced beta band desynchronization in motor and prefrontal cortex during activation and inhibition may be related to reported increased synchronization in this region at rest in PD [43]. Interestingly, Heideman and colleagues [135] examined PD associated power differences in beta band, differentiating event amplitude, duration, and interval time. They found that beta-state interval time between short-lived, high-amplitude events accounted for decreases in beta band power in averaged responses in PD.

Alpha band activity is increased in cortical areas not engaged in a task [118], and event related synchronization in the alpha band is associated with top down control of response inhibition [138]. Previous work has shown that power changes in the alpha band prior to target onset, which were attenuated in PD, were correlated with reaction time [139, 140]. Across frequencies, where control subjects showed decreased event related power, this decrease was attenuated in PD. For example, we found decreased alpha band power in PD compared to controls in the supplementary motor area and medial/ anterior prefrontal cortex for response activation and inhibition, respectively. Decreased power in the alpha band in the frontal lobe has been associated with executive dysfunction in PD [141]. As in our study, Perfetti and colleagues [139] showed decreased alpha power in fronto-parietal cortex in PD prior to the presentation of a target. The change in alpha band power from baseline was positively correlated with reaction time in a reaching task [139]. Again, the attenuated event related changes in power in PD may be related to increased synchronization in resting state alpha band activity [141].

Compensation

There is a well described lag between the onset of nigrostriatal nerve terminal degeneration and the onset of motor signs in PD [142, 143] that is consistent with a capacity to compensate. In our study, reaction time did not differ significantly between groups, while differences in power were apparent in the network subserving activation of a cued movement, indicating that behavior was preserved in the face of changing brain function. For example, the decrease in alpha power in supplementary motor area during PD activation could be interpreted as recruitment of this region as a compensatory mechanism. Similarly, Buhmann and colleagues [144, 145] observed differences in left dorsal premotor cortex fMRI activity between asymptomatic Parkin mutation carriers and healthy non-carriers who performed a finger to thumb opposition task. Changes in left lateral supplementary motor area were only observed in response to a reduced cue condition where subjects were required to select which finger to tap. In addition, compensatory changes in connectivity in this region have been reported [145]. Compensation, therefore, is a possible explanation for the changes in alpha activity we observed in supplementary motor area [145].

However, disentangling compensation from pathophysiology is difficult. The simultaneous abnormal peaks (387.5 ms) in medial prefrontal cortex, primary motor cortex and supplementary motor area in the alpha and beta bands in PD activation could result from a single widely connected pathological source of circuit dysfunction. For example, the subthalamic nucleus, which is known to be dysfunctional in PD [146], has shown power changes during both movement activation and inhibition in PD [129, 147, 148]. Conversely, the additional distributed activity in primary motor cortex and supplementary motor area could be related to compensation for failing dopaminergic innervation, which is also consistent with the relatively normal response activation reaction times in the PD group. In a recent review of MEG and PD studies, Boon and colleagues [46] report that dopamine replacement therapy or deep brain stimulation normalized beta band power and interregional coupling while alleviating motor symptoms. These authors [46] suggested that the increased beta band power and connectivity in PD was a compensatory mechanism which became redundant once dopamine replacement therapy was administered.

Another possible interpretation of the abnormal distribution of activity is a change is response strategy. While reaction time was similar across groups, errors were more frequent in the PD group, suggestive of a shift in speed/accuracy trade off, maintaining speed at the cost of accuracy. This adjustment may be related to the recruitment of additional brain areas as well. Thus, while our findings of additional cortical power changes in PD are consistent with circuit dysfunction involving premotor and prefrontal cortex, the lack of reaction time deficits or changes in the speed/accuracy trade off in conjunction with activity observed in regions not commonly associated with PD pathology, such as posterior parietal cortex, could represent compensatory activity, though again, it is difficult to definitively differentiate compensation and pathological disinhibition [149, 150].

Clinical relevance

Currently, the utility of MEG in clinical practice is limited [46, 153]. The clinical significance of common MEG findings, such as the link between whole brain resting state spectral slowing and cognitive impairment are not clear. There is also a lack of consistent and comprehensive data examining the impact of dopamine replacement therapy and DBS on MEG outputs in PD ([46] for review). However, in development of clinical treatment advances which include forms of neurostimulation, understanding the underlying neural dynamics is crucial. Our findings inform those aspects of understanding. For example, there may be clinical relevance to hypothesized association of changes in alpha-band activity in supplementary motor cortex with compensatory mechanisms [144, 145]. may be possible to facilitate the brain’s intact compensatory mechanisms using neuromodulatory interventions that boost alpha power in BA 6 [151, 152]. However the clinical implications of the current results, though potentially significant, remain largely a matter of speculation.

Our observation of more widespread abnormalities in the neural activity associated with movement activation, as compared to inhibition, is consistent with the general characterization of parkinsonism as, first and foremost, a disorder of movement and with the preferential vulnerability of dopaminergic innervation of the basal ganglia’s motor territories [153, 154]. Indeed, many of the classical cardinal signs of PD (e.g., akinesia, bradykinesia, postural instability) fall easily within the general category of impairments of motor activation [155]. Data on abnormal cortical activity may inform intervention strategies [156-158]. For example, cognitive neurorehabilitation targeting movement activation has shown some success [157, 158]. Future studies of neurorehabilitation using MEG could yield clinically significant insight into the plasticity subserving recovery of function. Impairments of movement inhibition, though clearly present in PD, were described only recently [2] and, arguably, make subtle and complex contributions to classic motor signs such as gait or intricate stepping abnormalities [156]. As in most complicated diseases, the picture of Parkinson’s disease becomes clearer with accumulation of evidence at all levels of the neural-cognitive system.

Limitations

Our ability to measure magnetic task based responses was limited to the cortex, specifically to tangential signals emanating from sulci [159, 160], because of the physics of MEG. Our sensors did not capture signal from subcortical structures such as the basal ganglia which clearly play an important role in response activation and inhibition [11, 27, 161, 162]. We did not evaluate the impact of dopamine replacement therapy on movement activation and inhibition though this response is significant [163, 164] (for review, see [165]). Our analysis of the gamma frequency band was conducted using an uncorrected p value. Despite our best efforts to reduce noise, for example enrolling only right-handed subjects with right side disease onset, gamma band activity was noisy, and the more stringent corrected p value yielded minimal consistent activation patterns. Thus our findings on gamma band activity have an increased susceptibility to Type 1 error, though no differences between PD and control participants were observed in the gamma band event related power changes. We did find changes in the location, amplitude, frequency and latency of response signals in optimally medicated PD participants. However disentangling the contribution of PD pathophysiology, network compensation and chronic, as opposed to the more natural event related sporadic fluctuations in dopamine is a daunting task that is key to understanding the disease mechanisms subserving PD.

Conclusions

Our findings are consistent with decreased event related power changes in the frontal cortex during movement activation and inhibition in PD. However the PD associated changes in the network subserving movement activation were widespread across frontal cortex and included motor regions, while those for inhibition were not as pronounced, though both trial types required a motor response. In addition, PD associated increases in peak latency were observed only in movement activation data, suggesting that deficits in movement production were more complex and potentially influential than deficits in inhibition. While difficult to dissociate from disease pathophysiology and medication effects, the changes in location and power of response were consistent with the concept of compensation following cell death in the substantia nigra.

22 Sep 2020

PONE-D-20-21985

Cortical Oscillatory Dysfunction in Early Parkinson Disease During Movement Activation and Inhibition

PLOS ONE

Dear Dr. Disbrow,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

One reviewer rejected your manuscript, but two reviewers indicated major revisions. I have decided to give you the opportunity to address the suggestions and answer the questions. Please address the comments of three reviewers adequately.

Please submit your revised manuscript by Nov 06 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Fabio A. Barbieri, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This work was supported by a grant to ED from the National Institute of Neurological Disorders and Stroke (RO1NS064040)."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript"

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript describes the effects on brain activity using MEG on response activation and inhibition in control and PD patients. The results show that different brain regions are impacted in control and PD. The study is purely correlative and does not provide a clear conceptual context to explain the results. The discussion is not well organized and difficult to read.

The manuscript is poorly written and very difficult to follow. The description of the tasks is confusing. For instance, in the methods, it says that in the RB and LB task, the subjects must press an un-cued button but the task seems to be cued because it is called RB and LB. The authors should clarify this because they use the word clue for BR and BL but they consider the task un-cued. In addition, there is no description in the methods on how the subjects enter their responses. It seems that they press a button with the right and/or left hand to choose their answers but this is not stated. In this context, results mention “right-hand trials” and left-hand trials” but the manuscript does not explain what this means. This is all the more confusing because on page 12 and 13 of the results, it is stated that “right- and left-hand trials were similar, so data from right-hand response trials were used to illustrate the results. Right-hand results were chosen because all subjects were right-handed with right side dominant disease. Right- and left-hand response MEG data were not combined because sensory and motor cortex results were not aligned due to crossed inputs from the two hands, while frontal lobe activation was independent of response hand”.

Reviewer #2: This is a very interesting study where the authors deeply discussed the cortical oscillatory dysfunction in early Parkinson's disease during movement activation and inhibition. I have some comments about this paper, and some suggestions too.

In general, the manuscript sounds very technical and scientific. However, some clinical statements were not clear. For example, in the title the authors declare that in this study, the participants were in early stage of PD. Can the authors please update the Hoehn and Yahr stages of which the participants were classified in their early stages?

I also suggest that the authors reduce the number of acronyms. Try to keep the acronyms to minimum.

A more detailed suggestion and review follows below:

Abstract

Page 2, line 48 – please, define SMA.

Introduction

Page 3, lines 53-54 – Please, give a reference to the statement made.

Page 3, line 60 – What motor signs of PD are you referring? Only akinesia, as cited in line 61? Please, be clearer about this statement.

Page 3, line 64 – Please state the “pre-movement external cueing” which are cited in the references 9-13. Such statement makes it easier for the reader.

Page 3, line 74 – I think the authors are referring to “Miller”, not colleagues here. If I am correct, please, change this.

Page 3, line 76 – Please, define BOLD.

Page 3, line 77 – Please, define RT.

Page 4, line 101 – Please, define UPDRS.

Methods

Subjects – Is this a powered sample, or 36 participants in total were chosen by convenience? Please make this statement.

Page 6, lines 120-122 – Please, cite the reference about clinical diagnosis of PD. In addition, were these participants diagnosed with idiopathic PD? Please, make it clear.

Page 6, line 127 – Please, define MRI.

Page 6, line 131 – Please, define MMSE.

Page 6, line 132 – Please, define ESS.

Page 6, line 133 – How did the authors define “severe tremor”? Did the authors use any tools for that? Please, make it clear.

Page 6, line 137 – Please, define COMT.

Page 9, line 193 – Please, define MR.

Page 10, line 234 – Instead of citing the references 47, 53, please state the details that justify the use of uncorrected multiple comparisons.

Page 10, line 235 – Please, define ROI.

Page 11, line 239 – Please, define ANOVA.

Discussion

Page 17, line 373 – Please, define ACC.

Page 17, line 386 – Please, define STN.

Page 18, line 410 – Please, define IFG.

Page 19, line 430 – Please, define PFC.

Page 21, line 470 – Please, define fMRI.

I missed 3 important keys in this manuscript: statement of limitations, clinical relevance and conclusion. In regards of limitations, can the authors define any limitation in this study? I understand the importance of these results to understand how PD affects movement control and inhibition, but can the authors work out the clinical relevance of these findings? Finally, a conclusion is indeed missing.

Table 1. Is there any statistical between groups for age and gender? Regardless of statistical difference, please state the p-values in the text, or table.

Did the authors use UPDRS total score? Please, present the part 3 scores as well. The authors mentioned in the discussion that no correlation was observed between UPDRS and cortical data. Have the authors observed any correlations using the motor score (part 3)? Why did the authors use UPDRS instead of MDS-UPDRS?

How was the dopamine equivalent calculated? Did authors use Levodopa equivalency daily dosage according to Tomlinson et al., 2010?

Reviewer #3: The authors' objectives were to examine PD-associated abnormalities in the magnitude and timing of oscillatory power in cortical networks subserving response activation and inhibition. The paper is interesting and contributes to the understanding of cortical networks subserving response activation and inhibition.

Major reviews:

What do the authors call early Parkinson disease? Table 1 shows that some patients have more than 8 years of illness.

The hypothesis needs further explanation.

How many attempts at practice have been made? Did PD participants and control have the same practice time? Could this have influenced the task's performance during testing?

Were patients evaluated ON or OFF? What does this interfere with the results?

Were the conditions randomized or presented in blocks? Was the task learned during the experiment?

Discuss the implications of having found differences in cortical activity despite the same task performance.

A Conclusion section would be important.

Minor review:

- Place the units in the tables

- what is the patients' H&Y?

- are the values in table 3 reported as mean and standard deviation?

- check the link to the page (http://www.sourcesignal.com/dataeditor.html) that is not working

- What was considered a wrong attempt?

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Daniel Boari Coelho

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

25 Jan 2021

We would like to thank the reviewers for the time and effort that they invested in reviewing this manuscript. All comments have been carefully considered and included in the revised manuscript.

Reviewer #1:

We understand the frustration expressed by Reviewer 1 that the manuscript is very difficult to follow. The data set is complex, including several trial types and response options with both the right and left hand, as well as temporal and spatial brain response data across multiple frequency bands. It has been challenging to sift through everything and distill it into a reader friendly format that captures all the findings. I would like to thank the reviewer again for his/her feedback, which is invaluable in clarifying the manuscript. Based on the reviewer’s comments we have added a summary of the results to the first paragraph of the discussion to make the material easier to digest. We have also edited the manuscript throughout for clarity, including removing background information that was not directly related

The description of the tasks is confusing. For instance, in the methods, it says that in the RB and LB task, the subjects must press an un-cued button but the task seems to be cued because it is called RB and LB. The authors should clarify this because they use the word clue for BR and BL but they consider the task un-cued.

The section describing the task, now called “Activation Inhibition Task” (starting on page 7, Line 157) has been revised to clarify the cued and un-cued/ activation vs. inhibition design.

In addition, there is no description in the methods on how the subjects enter their responses. It seems that they press a button with the right and/or left hand to choose their answers but this is not stated. In this context, results mention “right-hand trials” and left-hand trials” but the manuscript does not explain what this means.

In the original version, this information was contained in the last sentences of the (lengthy) description of the task. It has been moved to the first few sentences of the revised version, along with a more general description of the task: “Subjects were presented with a visual cue-target design task and required to respond to the target by pushing a button with one or both index fingers. Fiber optic button boxes (Photon Control, Inc. ) were held in both the left and right hands. Subjects were trained prior to entering the scanner to respond only to the target arrow(s) with their index fingers pressing hand-held button boxes.” (page 7 line 158)

This is all the more confusing because on page 12 and 13 of the results, it is stated that “right- and left-hand trials were similar, so data from right-hand response trials were used to illustrate the results. Right-hand results were chosen because all subjects were right-handed with right side dominant disease. Right- and left-hand response MEG data were not combined because sensory and motor cortex results were not aligned due to crossed inputs from the two hands, while frontal lobe activation was independent of response hand”.

To clarify this procedure we added the phrase “Right- and left-hand trials both tested activation and inhibition in a similar fashion, and results from right- and left-hand trials were similar, so data from right-hand response trials were used to illustrate the results. Right-hand results were chosen because all subjects were right-handed with right side dominant disease. This change, in combination with the clarification of the task description, should improve reader accessibility to the information.

Reviewer #2: This is a very interesting study where the authors deeply discussed the cortical oscillatory dysfunction in early Parkinson's disease during movement activation and inhibition. I have some comments about this paper, and some suggestions too.

In general, the manuscript sounds very technical and scientific. However, some clinical statements were not clear. For example, in the title the authors declare that in this study, the participants were in early stage of PD.

Can the authors please update the Hoehn and Yahr stages of which the participants were classified in their early stages?

The H & Y data has been added to table 1. In addition the word “early” has been removed from the title and the subject description.

I also suggest that the authors reduce the number of acronyms. Try to keep the acronyms to minimum.

We agree that there were too many acronyms. All acronyms were removed except for these relatively common ones:

ANOVA

EEG

fMRI

MRI

ROI

UPDRS

All acronyms are now spelled out the first time they are used.

Introduction

Page 3, lines 53-54 – Please, give a reference to the statement made.

On page 3, line 54 we have added references (Disbrow et al., 2013; Franz, 2006; Obeso et al., 2011) to the first sentence of the introduction for our statement “Response initiation and inhibition are functions fundamental to executive control that are disrupted in Parkinson disease (PD).”

Page 3, line 60 – What motor signs of PD are you referring? Only akinesia, as cited in line 61? Please, be clearer about this statement.

We clarified this point by qualifying the original statement:

“Furthermore, impairments in response activation and inhibition have been proposed to subserve some of the common motor signs of PD. For example, akinesia, or an inability to start movement [6-9] is consistent with a problem in movement activation [10].”

We also added another example: “Activation and inhibition are also associated with motor switching and sequencing, which are impaired in PD (Franz, 2006; Cools et al., 1984).” Page 3, Line 59-63.

Page 3, line 64 – Please state the “pre-movement external cueing” which are cited in the references 9-13. Such statement makes it easier for the reader.

Details have been added to this statement on page 3 lines 64-66: “However, deficits in response activation and inhibition associated with PD are complex and not fully understood. For instance, in PD, the latency to initiate movement can be shortened by the use of pre-movement external auditory or visual cueing such as walking with a metronome or use of floor markers (e.g., [12-16]).

Page 3, line 74 – I think the authors are referring to “Miller”, not colleagues here. If I am correct, please, change this.

This error has been corrected, the line, now on page 3 line 73 now reads: “Franz and Miller [23] found that people with mild to moderate PD demonstrated abnormal force output during movement activation of ‘Go’ responses, as well as problems inhibiting movement of ‘Nogo’ responses in comparison to controls, despite a lack of difference in mean reaction times between PD and control groups.”

Methods

Subjects – Is this a powered sample, or 36 participants in total were chosen by convenience? Please make this statement.

A power analysis has been added to PAGE 6: line 125 “Power analysis based on Beste et al. (2009; Fig. 2) showed an amplitude difference between PD and control groups of about 8 ±2 µV for both compatible and incompatible control trials for the P300 peak. With an alpha of 0.05 for a single comparison, a sample size of 18 per group yielded power of over 90%. “

Page 6, lines 120-122 – Please, cite the reference about clinical diagnosis of PD. In addition, were these participants diagnosed with idiopathic PD? Please, make it clear.

A reference about clinical diagnosis has been added to page 6; line 122. To clarify that all patients had idiopathic PD the following sentence was added to page 7: Line 144 “All patients had late onset (>55 years at time of diagnosis) idiopathic PD with a history of positive response to dopamine replacement therapy and no alterations in medication for 6 weeks prior to enrollment.”

Page 6, line 133 – How did the authors define “severe tremor”? Did the authors use any tools for that? Please, make it clear.

The term “severe” was replaced with “persistent,” referring to the fact that it was not well resolved with medication. Persistent tremor was defined as a score > 1 on items 16, 20 or 21 of UPDRS 3 evaluated on medication page 6: line 136).

Page 10, line 234 – Instead of citing the references 48, 54, please state the details that justify the use of uncorrected multiple comparisons.

We have edited this section (page 11; line 256-261) which now reads: Between-group analysis was corrected with a false discovery rate threshold of p<0.05. For the gamma band, we began with a conservative (multiple comparison corrected) threshold of p<0.05 as a first step, with a more liberal threshold (significant at p<0.05, uncorrected) as a second step if significant effects were not observed at a conservative level. The details of this approach have been described elsewhere [61,67,68]. As we have noted previously [61], the reduced power inherent to higher frequency oscillations often require us to rely on more liberal thresholds with a concomitant increase in risk for type 1 error [61,65].

The following statement has also been added to the limitations section (Page 27; line 633-638): “Despite our best efforts to reduce noise, for example enrolling only right-handed subjects with right side disease onset, gamma band activity was noisy, and the more stringent corrected p value yielded minimal consistent activation patterns. Thus our findings on gamma band activity have an increased susceptibility to Type 1 error, though no differences between PD and control participants were observed in the gamma band event related power changes.”

Discussion

I missed 3 important keys in this manuscript: statement of limitations, clinical relevance and conclusion. In regards of limitations, can the authors define any limitation in this study? I understand the importance of these results to understand how PD affects movement control and inhibition, but can the authors work out the clinical relevance of these findings?

Finally, a conclusion is indeed missing.

As suggested by the reviewer, sections for clinical relevance (Page 26; line 598), limitations (Page 27; line 626) and conclusions (Page 28; line 644) have been added to the manuscript.

Table 1. Is there any statistical between groups for age and gender? Regardless of statistical difference, please state the p-values in the text, or table.

Two sentences were added to the manuscript to provide this information (Page 7; line 142-144): “There were no differences across groups for age F(1, 35) = 0.65, p = 0.43. Gender distribution was not significantly different across groups X2(1, 35) = 2, p = 0.16.”

Did the authors use UPDRS total score? Please, present the part 3 scores as well. The authors mentioned in the discussion that no correlation was observed between UPDRS and cortical data. Have the authors observed any correlations using the motor score (part 3)? Why did the authors use UPDRS instead of MDS-UPDRS?

Both UPDRS total and part 3 are now included in the table. Correlation? The older version of the UPDRS was used because data collection began before the release of the NDS-UPDRS.

How was the dopamine equivalent calculated? Did authors use Levodopa equivalency daily dosage according to Tomlinson et al., 2010?

To clarify this point, the following statement was added (Page 7; line 151): “Dopamine equivalency for each PD participant’s daily medications was calculated based on conversion factors from Tomlinson et al., 2010.

Reviewer #3: The authors' objectives were to examine PD-associated abnormalities in the magnitude and timing of oscillatory power in cortical networks subserving response activation and inhibition. The paper is interesting and contributes to the understanding of cortical networks subserving response activation and inhibition.

Major reviews:

What do the authors call early Parkinson disease? Table 1 shows that some patients have more than 8 years of illness.

We agree that the word “early” is not accurate and it has been removed from the title and manuscript.

The hypothesis needs further explanation.

To better explain the rationale for our hypothesis, a paragraph on the underlying anatomy has been added to the introduction (Page 4; line 82-90). The introduction now summarizes existing research that motivated the anatomical, latency and frequency band power aspects of our hypothesis: “We tested the hypothesis that oscillatory activity in the frontal cortex subserving these functions had reduced power and delayed onset in PD compared to control participants.”

How many attempts at practice have been made? Did PD participants and control have the same practice time? Could this have influenced the task's performance during testing?

Training was minimal for both PD and control participants as the task was simple and easy to grasp. To clarify this point, we added details to the description of the training: “Subjects were trained prior to entering the scanner to respond only to the target arrow(s) with their index fingers pressing hand-held button boxes. Stimuli consisted of a series of stimuli that contained 2 trials of each trial type. All subjects executed this trial run once before scanning following which they reported understanding the task.” Page 7; line 159- page 8; line 165

Were patients evaluated ON or OFF? What does this interfere with the results?

To clarify that all study activities were preformed on medication, the statement about evaluation was changed to the following: “PD participants took their prescribed medication in the morning prior to study participation and performed the experiment in their best ON medication state.” (Page 7; line 146-148)

In addition, the following statement was added to indicate that the UPDRS was also performed on medication: “Participants with PD were given the Unified Parkinson Disease Rating Scale (UPDRS) on medication on a separate day from brain imaging.” (Page 6; line 138-139)

A statement about the impact of ON medication evaluation was added page 26; lines 601-603.

Were the conditions randomized or presented in blocks? Was the task learned during the experiment?

The statement, “Trial types were presented in random order” was added to end of the section describing the trials (Page 9; lines 195-196). Regarding learning, the task was very simple, and we did not observe an error pattern (fewer errors over time) that was indicative of learning.

Discuss the implications of having found differences in cortical activity despite the same task performance.

The discussion of the interpretation of differences in cortical activity with similar task performance have been expanded. The paragraph on the distribution of abnormal network activity in response to movement activation now includes a discussion of a pathological, compensatory and response strategy interpretation (Page 18; line 446). The possibility of compensation is also addressed in the discussion of frequency abnormalities (Page 25; line 565-579) and in the conclusions (page 28; line 645).

A Conclusion section would be important.

We agree, and a conclusions section has been added (Page 28; line 644).

Minor review:

- Place the units in the tables

Units have been placed in the tables

- what is the patients' H&Y?

Median H&Y has been added to Table 1

- are the values in table 3 reported as mean and standard deviation?

Yes, this information has been added to the legend.

- check the link to the page (http://www.sourcesignal.com/dataeditor.html) that is not working

The link has been updated. The correct link is (https://www.ctf.com/products).

- What was considered a wrong attempt?

An error was defined as a unilateral button press of the incorrect button, a unilateral response when a bilateral response was required or a bilateral response when a unilateral response was required. This definition was added to page 9, line 206.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

3 Mar 2021

PONE-D-20-21985R1

Cortical Oscillatory Dysfunction in Parkinson Disease During Movement Activation and Inhibition

PLOS ONE

Dear Dr. Disbrow,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Dear authors,

One reviewer indicated some aspects that you might improve the manuscript. I call attention to the discussion. I agree totally with the reviewer, and the discussion should be more straight writing, reducing its size. Please address all suggestions in the manuscript.

==============================

Please submit your revised manuscript by Apr 17 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Fabio A. Barbieri, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors improved the manuscript and addressed the concerns I raised. Although, there are some parts of the manuscript which the authors should carefully address.

Page 6: was there any inclusion and exclusion criteria for healthy controls? Please, state them.

Page 6, end of last paragraph: “Using an alpha of 0.05 for a single comparison, a sample size of 18 per group yielded power of over 90%”

What statistical test the authors refer to?

Page 12 end of last paragraph: “analysis of variance (ANOVA) with t-test post hoc analysis”.

The authors should correct this to “… (ANOVA) with post hoc analysis using a p value of 0.05”

Caption for Table 3. Please, replace “#” with the word “number” or “amount”.

The authors first introduced the ROI in the results section. I suggest the authors introduce the regions of interest in the methods section.

Why do the authors present p-values for only some of the differences, and not for all? Please, present p-values for all comparisons.

Discussion – The discussion is too large (8 pages) and somewhat repeat the results. The authors have been comparing their results with literature rather than deeply discussing the meaning of the results found in the study. Please, update the discussion making it more concise and easier to follow.

Please see the manuscript from Pelicioni and colleagues (2020) where they discuss how people with PD exhibit reduced cognitive and motor cortical activity when undertaking complex stepping tasks requiring inhibitory control. Even though the authors have written the clinical implication in their most updated version of the manuscript, I still think the paper has many technical aspects and not enough clinical implications, and how these results can be translated to the understanding of motor impairment (such as inhibition impairments) in people with PD.

Reference:

People With Parkinson’s Disease Exhibit Reduced Cognitive and Motor Cortical Activity When Undertaking Complex Stepping Tasks Requiring Inhibitory Control. PHS Pelicioni, SR Lord, Y Okubo, DL Sturnieks, JC Menant. Neurorehabilitation and Neural Repair 34 (12), 1088-1098

Reviewer #3: This resubmission is improved with the addition of necessary details in the Methods and a more fulsome Discussion.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: Yes: Daniel Boari Coelho

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

21 Jul 2021

We would like to thank the reviewers for their thoughtful comments on this manuscript. All suggestions have been incorporated into the latest version. Most notably, the discussion has been extensively edited based on reviewer comments to be more accessible. Specific responses are described below.

Page 6: was there any inclusion and exclusion criteria for healthy controls? Please, state them.

The inclusion and exclusion criteria for controls have been added on page 6, line 133.

Page 6, end of last paragraph: “Using an alpha of 0.05 for a single comparison, a sample size of 18 per group yielded power of over 90%” What statistical test the authors refer to?

The line now reads: Using an alpha of 0.05 for a single comparison, a sample size of 18 per group yielded power of over 90% for an independent, 2 sample t-test comparing PD and control groups. Similar results were obtained for a power analysis for latency measures.

Page 12 end of last paragraph: “analysis of variance (ANOVA) with t-test post hoc analysis”. The authors should correct this to “… (ANOVA) with post hoc analysis using a p value of 0.05”

The text has been changed as indicated.

Caption for Table 3. Please, replace “#” with the word “number” or “amount”.

The text has been changed as indicated.

The authors first introduced the ROI in the results section. I suggest the authors introduce the regions of interest in the methods section.

We have added the following sentence to the last paragraph of the introduction: “to measure anatomical, at the level of the cortical field region of interest, and physiological, specifically electrophysiological data.” A sentence about the ROI definition procedure and a reference have also been added to the methods on page 11, line 261. “Regions of interest (ROI) based on Brodmann nomenclature were derived from MNI coordinates in the normalized brain [68].”

Why do the authors present p-values for only some of the differences, and not for all? Please, present p-values for all comparisons.

The p values for the ANOVA’s were provided in the results while the p value for the NUTMEG analysis were provided in the methods, which, as indicated by the reviewer, was odd. The NUTMEG p values are now included in the results as well to clarify the statistics.

Discussion – The discussion is too large (8 pages) and somewhat repeat the results. The authors have been comparing their results with literature rather than deeply discussing the meaning of the results found in the study. Please, update the discussion making it more concise and easier to follow.

This comment was very helpful and the discussion has been extensively edited. The discussion has been reduced from just over 10 pages to 8 pages including additions suggested by reviewers. The discussion of previous work was reduced and put in context, making the discussion more concise and easier to follow. We also created a section on compensation (page 23, line 533) to improve the organization and flow of the discussion.

Please see the manuscript from Pelicioni and colleagues (2020) where they discuss how people with PD exhibit reduced cognitive and motor cortical activity when undertaking complex stepping tasks requiring inhibitory control. Even though the authors have written the clinical implication in their most updated version of the manuscript, I still think the paper has many technical aspects and not enough clinical implications, and how these results can be translated to the understanding of motor impairment (such as inhibition impairments) in people with PD.

We read the recommended reference with interest. The clinical significance section has been amended along the lines of this paper, including a reference to our work on neurorehabilitation of movement activation, and a modified statement about the clinical implications of inhibition deficits in PD. The end of the clinical implications section now reads: “Data on abnormal cortical activity may inform intervention strategies [156-158]. For example, cognitive neurorehabilitation targeting movement activation has shown some success [157,158]. Future studies of neurorehabilitation using MEG could yield clinically significant insight into the plasticity subserving recovery of function. Impairments of movement inhibition, though clearly present in PD, were described only recently [2] and, arguably, make subtle and complex contributions to classic motor signs such as gait or intricate stepping abnormalities [156]. As in most complicated diseases, the picture of Parkinson's disease becomes clearer with accumulation of evidence at all levels of the neural-cognitive system.”

Submitted filename: Response letter 06 04 21.docx

Click here for additional data file.

9 Sep 2021

Cortical Oscillatory Dysfunction in Parkinson Disease During Movement Activation and Inhibition

PONE-D-20-21985R2

Dear Dr. Disbrow,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Fabio Augusto Barbieri, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

15 Feb 2022

PONE-D-20-21985R2

Cortical Oscillatory Dysfunction in Parkinson Disease During Movement Activation and Inhibition

Dear Dr. Disbrow:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Fabio Augusto Barbieri

Academic Editor

PLOS ONE