Early Rise and Persistent Inhibition of Electromyography during Failed Stopping.

Reactively canceling movements is a vital feature of the motor system to ensure safety. This behavior can be studied in the laboratory using the stop-signal task. There remains ambiguity about whether a "point-of-no-return" exists, after which a response cannot be aborted. A separate question concerns whether motor system inhibition associated with attempted stopping persists when stopping is unsuccessful. We address these two questions using electromyography (EMG) in two stop-signal task experiments. Experiment 1 (n = 24) involved simple right and left index finger responses in separate task blocks. Experiment 2 (n = 28) involved a response choice between the right index and pinky fingers. To evaluate the approximate point of no return, we measured EMG in responding fingers during the 100 msec preceding the stop signal and observed significantly greater EMG amplitudes during failed than successful stopping in both experiments. Thus, EMG before the stop signal differentiated success, regardless of whether there was a response choice. To address whether motor inhibition persists after failed stopping, we assessed EMG peak-to-offset durations and slopes (i.e., rate of EMG decline) for go, failed stop, and successful stop (partial response) trials. EMG peak-to-offset was shorter and steeper for failed stopping compared to go and successful stop partial response trials, suggesting motor inhibition persists even when failing to stop. These findings indicate EMG is sensitive to a "transition zone" at which the relative likelihood of stop failure versus success inverts and also suggest peak-to-offset time of response-related EMG activity during failed stopping reflects stopping-related inhibition.

Interhemispheric inhibition between dorsal premotor and primary motor cortices is released during preparation of unimanual but not bimanual movements.

Previous research applying transcranial magnetic stimulation during unimanual reaction time tasks indicates a transient change in the inhibitory influence of the dorsal premotor cortex over the contralateral primary motor cortex shortly after the presentation of an imperative stimulus. The degree of interhemispheric inhibition from the dorsal premotor cortex to the contralateral primary motor cortex shifts depending on whether the targeted effector representation in the primary motor cortex is selected for movement. Further, the timing of changes in inhibition covaries with the selection demands of the reaction time task. Less is known about modulation of dorsal premotor to primary motor cortex interhemispheric inhibition during the preparation of bimanual movements. In this study, we used a dual coil transcranial magnetic stimulation to measure dorsal premotor to primary motor cortex interhemispheric inhibition between both hemispheres during unimanual and bimanual simple reaction time trials. Interhemispheric inhibition was measured early and late in the 'pre-movement period' (defined as the period immediately after the onset of the imperative stimulus and before the beginning of voluntary muscle activity). We discovered that interhemispheric inhibition was more facilitatory early in the pre-movement period compared with late in the pre-movement period during unimanual reaction time trials. In contrast, interhemispheric inhibition was unchanged throughout the pre-movement period during symmetrical bimanual reaction time trials. These results suggest that there is greater interaction between the dorsal premotor cortex and contralateral primary motor cortex during the preparation of unimanual actions compared to bimanual actions.

Inhibition for gain modulation in the motor system.

Signatures of inhibition within the cortico-spinal pathway are frequently observed during action preparation in humans. Popular theoretical and computational models highlight a critical role for inhibition as the suppressor of motor system output, e.g., to withhold undesired action tendencies or to stop ongoing movements. However, inhibition frequently serves a modulatory role in non-motor systems. For example, in vision and somatosensory systems, inhibition can adjust the relationships between input and output, a computation referred to as gain modulation. Inhibition may modulate gain within the motor system as well. Changes in cortico-spinal inhibition observed during human behavior can reflect adjustments in motor system gain and may be sensitive to latent behavioral states. This review summarizes roles for inhibition in gain modulation, drawing principally on evidence from non-motor systems, and examines the hypothesis that homologous functions operate in the animal and human motor systems to facilitate action preparation.

A Single Mechanism for Global and Selective Response Inhibition under the Influence of Motor Preparation.

In our everyday behavior, we frequently cancel one movement while continuing others. Two competing models have been suggested for the cancellation of such specific actions: (1) the abrupt engagement of a unitary global inhibitory mechanism followed by reinitiation of the continuing actions; or (2) a balance between distinct global and selective inhibitory mechanisms. To evaluate these models, we examined behavioral and physiological markers of proactive control, motor preparation, and response inhibition using a combination of behavioral task performance measures, electromyography, electroencephalography, and motor evoked potentials elicited with transcranial magnetic stimulation. Healthy human participants of either sex performed two versions of a stop signal task with cues incorporating proactive control: a unimanual task involving the initiation and inhibition of a single response, and a bimanual task involving the selective stopping of one of two prepared responses. Stopping latencies, motor evoked potentials, and frontal ß power (13-20 Hz) did not differ between the unimanual and bimanual tasks. However, evidence for selective proactive control before stopping was manifest in the bimanual condition as changes in corticomotor excitability, µ (9-14 Hz), and ß (15-25 Hz) oscillations over sensorimotor cortex. Together, our results favor the recruitment of a single inhibitory stopping mechanism with the net behavioral output depending on the levels of action-specific motor preparation.SIGNIFICANCE STATEMENT Response inhibition is a core function of cognitive flexibility and movement control. Previous research has suggested separate mechanisms for selective and global inhibition, yet the evidence is inconclusive. Another line of research has examined the influence of preparation for action stopping, or what is called proactive control, on stopping performance, yet the neural mechanisms underlying this interaction are unknown. We combined transcranial magnetic stimulation, electroencephalography, electromyography, and behavioral measures to compare selective and global inhibition models and to investigate markers of proactive control. The results favor a single inhibitory mechanism over separate selective and global mechanisms but indicate a vital role for preceding motor activity in determining whether and which actions will be stopped.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Response preparation involves a release of intracortical inhibition in task-irrelevant muscles.

Action preparation involves widespread modulation of motor system excitability, but the precise mechanisms are unknown. In this study, we investigated whether intracortical inhibition changes in task-irrelevant muscle representations during action preparation. We used transcranial magnetic stimulation (TMS) combined with electromyography in healthy human adults to measure motor-evoked potentials (MEPs) and cortical silent periods (CSPs) in task-irrelevant muscles during the preparatory period of simple delayed response tasks. In experiment 1, participants responded with the left index finger in one task condition and the right index finger in another task condition, whereas MEPs and CSPs were measured from the contralateral nonresponding and tonically contracted index finger. During experiment 2, participants responded with the right pinky finger whereas MEPs and CSPs were measured from the tonically contracted left index finger. In both experiments, MEPs and CSPs were compared between the task preparatory period and a resting intertrial baseline. The CSP duration during response preparation decreased from baseline in every case. A laterality difference was also observed in experiment 1, with a greater CSP reduction during the preparation of left finger responses compared to right finger responses. Despite reductions in CSP duration, consistent with a release of intracortical inhibition, MEP amplitudes were smaller during action preparation when accounting for background levels of muscle activity, consistent with earlier studies that reported decreased corticospinal excitability. These findings indicate that intracortical inhibition associated with task-irrelevant muscles is transiently released during action preparation and implicate a novel mechanism for the controlled and coordinated release of motor cortex inhibition.NEW & NOTEWORTHY In this study, we observed the first evidence of a release of intracortical inhibition in task-irrelevant muscle representations during response preparation. We applied transcranial magnetic stimulation to elicit cortical silent periods in task-irrelevant muscles during response preparation, and observed a consistent decrease in the silent period duration relative to a resting baseline. These findings address the question of whether cortical mechanisms underlie widespread modulation in motor excitability during response preparation.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

The Neural Specificity of Movement Preparation During Actual and Imagined Movements.

Current theories consider motor imagery, the mental representation of action, to have considerable functional overlap with the processes involved in actual movement preparation and execution. To test the neural specificity of motor imagery, we conducted a series of 3 experiments using transcranial magnetic stimulation (TMS). We compared changes in corticospinal excitability as people prepared and implemented actual or imagined movements, using a delayed response task in which a cue indicated the forthcoming response. TMS pulses, used to elicit motor-evoked responses in the first dorsal interosseous muscle of the right hand, were applied before and after an imperative signal, allowing us to probe the state of excitability during movement preparation and implementation. Similar to previous work, excitability increased in the agonist muscle during the implementation of an actual or imagined movement. Interestingly, preparing an imagined movement engaged similar inhibitory processes as that observed during actual movement, although the degree of inhibition was less selective in the imagery conditions. These changes in corticospinal excitability were specific to actual/imagined movement preparation, as no modulation was observed when preparing and generating images of cued visual objects. Taken together, inhibition is a signature of how actions are prepared, whether they are imagined or actually executed.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

Planning face, hand, and leg movements: anatomical constraints on preparatory inhibition.

Motor-evoked potentials (MEPs), elicited by transcranial magnetic stimulation (TMS) over the motor cortex, are reduced during the preparatory period in delayed response tasks. In this study we examined how MEP suppression varies as a function of the anatomical organization of the motor cortex. MEPs were recorded from a left index muscle while participants prepared a hand or leg movement in experiment 1 or prepared an eye or mouth movement in experiment 2. In this manner, we assessed if the level of MEP suppression in a hand muscle varied as a function of the anatomical distance between the agonist for the forthcoming movement and the muscle targeted by TMS. MEP suppression was attenuated when the cued effector was anatomically distant from the hand (e.g., leg or facial movement compared with finger movement). A similar effect was observed in experiment 3 in which MEPs were recorded from a muscle in the leg and the forthcoming movement involved the upper limb or face. These results demonstrate an important constraint on preparatory inhibition: it is sufficiently broad to be manifest in a muscle that is not involved in the task, but it is not global, showing a marked attenuation when the agonist muscle belongs to a different segment of the body. NEW & NOTEWORTHY Using transcranial magnetic stimulation, we examined changes in corticospinal excitability as people prepared to move. Consistent with previous work, we observed a reduction in excitability during the preparatory period, an effect observed in both task-relevant and task-irrelevant muscles. However, this preparatory inhibition is anatomically constrained, attenuated in muscles belonging to a different body segment than the agonist of the forthcoming movement.

Individual Differences in Resting Corticospinal Excitability Are Correlated with Reaction Time and GABA Content in Motor Cortex.

Individuals differ in the intrinsic excitability of their corticospinal pathways and, perhaps more generally, their entire nervous system. At present, we have little understanding of the mechanisms underlying these differences and how variation in intrinsic excitability relates to behavior. Here, we examined the relationship between individual differences in intrinsic corticospinal excitability, local cortical GABA levels, and reaction time (RT) in a group of 20 healthy human adults. We measured corticospinal excitability at rest with transcranial magnetic stimulation, local concentrations of basal GABA with magnetic resonance spectroscopy, and RT with a behavioral task. All measurements were repeated in two separate sessions, and tests of reliability confirmed the presence of stable individual differences. There was a negative correlation between corticospinal excitability and RT, such that larger motor-evoked potentials (MEPs) measured at rest were associated with faster RTs. Interestingly, larger MEPs were associated with higher levels of GABA in M1, but not in three other cortical regions. Together, these results suggest that individuals with more excitable corticospinal pathways are faster to initiate planned responses and have higher levels of GABA within M1, possibly to compensate for a more excitable motor system.SIGNIFICANCE STATEMENT This study brings together physiological, behavioral, and neurochemical evidence to examine variability in the excitability of the human motor system. Previous work has focused on state-based factors (e.g., preparedness, uncertainty), with little attention given to the influence of inherent stable characteristics. Here, we examined how the excitability of the motor system relates to reaction time and the regional content of the inhibitory neurotransmitter GABA. Importantly, motor pathway excitability and GABA concentrations were measured at rest, outside a task context, providing assays of intrinsic properties of the individuals. Individuals with more excitable motor pathways had faster reaction times and, paradoxically, higher concentrations of GABA. We propose that greater GABA capacity in the motor cortex counteracts an intrinsically more excitable motor system.

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Influence of Delay Period Duration on Inhibitory Processes for Response Preparation.

In this study, we examined the dynamics of inhibitory preparatory processes, using a delayed response task in which a cue signaled a left or right index finger (Experiment 1) or hand (Experiment 2) movement in advance of an imperative signal. In Experiment 1, we varied the duration of the delay period (200, 500, and 900 ms). When transcranial magnetic stimulation (TMS) was applied 100 ms before the imperative, motor evoked potentials (MEPs) elicited in the first dorsal interosseous were strongly inhibited. For delays of 500 ms or longer, this inhibition was greater when the targeted muscle was selected compared with when it was not selected. In contrast, the magnitude of inhibition just after the cue was inversely related to the duration of the delay period, and the difference between the selected and nonselected conditions was attenuated. In Experiment 2, TMS and peripheral nerve stimulation procedures were used during a 300-ms delay period. MEPs in the flexor carpi radialis for both selected and nonselected conditions were inhibited, but without any change in the H-reflex. Taken together, these results reveal the dual influence of temporal constraints associated with anticipation and urgency on inhibitory processes recruited during response preparation.

Nonspecific Inhibition of the Motor System during Response Preparation.

Motor system excitability is transiently inhibited during the preparation of responses. Previous studies have attributed this inhibition to the operation of two mechanisms, one hypothesized to help resolve competition between alternative response options, and the other to prevent premature response initiation. By this view, inhibition should be restricted to task-relevant muscles. Although this prediction is supported in one previous study (Duque et al., 2010), studies of stopping ongoing actions suggest that some forms of motor inhibition may be widespread (Badry et al., 2009). This motivated us to conduct a series of transcranial magnetic stimulation (TMS) experiments to examine in detail the specificity of preparatory inhibition in humans. Motor-evoked potentials were inhibited in task-irrelevant muscles during response preparation, even when the muscles were contralateral and not homologous to the responding effector. Inhibition was also observed in both choice and simple response task conditions, with and without a preparatory interval. Control experiments ruled out that this inhibition is due to expectancy of TMS or a possible need to cancel the prepared response. These findings suggest that motor inhibition during response preparation broadly influences the motor system and likely reflects a process that occurs whenever a response is selected. We propose a reinterpretation of the functional significance of preparatory inhibition, one by which inhibition reduces noise to enhance signal processing and modulates the gain of a selected response. SIGNIFICANCE STATEMENT: Motor preparation entails the recruitment of excitatory and inhibitory neural mechanisms. The current experiments address the specificity of inhibitory mechanisms, asking whether preparatory inhibition affects task-irrelevant muscles. Participants prepared a finger movement to be executed at the end of a short delay period. Transcranial magnetic stimulation over primary motor cortex provided an assay of corticospinal excitability. Consistent with earlier work, the agonist muscle for the forthcoming response was inhibited during the preparatory period. Moreover, this inhibition was evident in task-irrelevant muscles, although the magnitude of inhibition depended on whether the response was fixed or involved a choice. These results implicate a broadly tuned inhibitory mechanism that facilitates response preparation, perhaps by lowering background activity before response initiation.

Individual differences in GABA content are reliable but are not uniform across the human cortex.

1H magnetic resonance spectroscopy (MRS) provides a powerful tool to measure gamma-aminobutyric acid (GABA), the principle inhibitory neurotransmitter in the human brain. We asked whether individual differences in MRS estimates of GABA are uniform across the cortex or vary between regions. In two sessions, resting GABA concentrations in the lateral prefrontal, sensorimotor, dorsal premotor, and occipital cortices were measured in twenty-eight healthy individuals. GABA estimates within each region were stable across weeks, with low coefficients of variation. Despite this stability, the GABA estimates were not correlated between regions. In contrast, the percentage of brain tissue per volume, a control measure, was correlated between the three anterior regions. These results provide an interesting dissociation between an anatomical measure of individual differences and a neurochemical measure. The different patterns of anatomy and GABA concentrations have implications for understanding regional variation in the molecular topography of the brain in health and disease.

Inhibition during response preparation is sensitive to response complexity.

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors.

Cholinergic enhancement of functional networks in older adults with mild cognitive impairment.

OBJECTIVE: The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group. METHODS: We conducted a 3-month, double-blind, placebo-controlled study on the effects of donepezil in 27 older adults with mild memory deficits. Participants completed a delayed recognition memory task. Functional magnetic resonance imaging (fMRI) scans were collected at baseline prior to treatment and at 3-month follow-up while subjects were on a 10mg daily dose of donepezil or placebo. RESULTS: Donepezil treatment significantly enhanced the response time for face and scene memory probes when compared to the placebo group. A group-by-visit interaction was identified for the functional network connectivity of the left fusiform face area (FFA) with the hippocampus and inferior frontal junction, such that the treatment group showed increased connectivity over time when compared to the placebo group. Additionally, the enhanced functional network connectivity of the FFA and hippocampus significantly predicted memory response time at 3-month follow-up in the treatment group. INTERPRETATION: These findings suggest that increased cholinergic transmission improves goal-directed neural processing and cognitive ability and may serve to facilitate communication across functionally-connected attention and memory networks. Longitudinal fMRI is a useful method for elucidating the neural changes associated with pharmacological modulation and is a potential tool for monitoring intervention efficacy in clinical trials.

Failures to launch preclude response inhibition.

Neural analyses of response inhibition rely on separating trials with and without a behavioral response. Can researchers be sure the absence of a behavioral outcome equates to the presence of inhibitory control? We emphasize advancing response inhibition research by utilizing peripheral measures of response progress to define behavioral stopping contrasts.

PMd and action preparation: bridging insights between TMS and single neuron research.

Transcranial magnetic stimulation (TMS) research has furthered understanding of human dorsal premotor cortex (PMd) function due to its unrivalled ability to measure the inhibitory and facilitatory influences of PMd over the primary motor cortex (M1) in a temporally precise manner. TMS research indicates that PMd transiently modulates inhibitory output to effector representations within M1 during motor preparation, with the direction of modulation depending on which effectors are selected for response, and the timing of modulations co-varying with task selection demands. In this review, we critically assess this literature in the context of a dynamical systems approach used to model nonhuman primate (NHP) PMd/M1 single-neuron recordings during action preparation. Through this process, we identify gaps in the literature and propose future experiments.

Deep brain stimulation of the subthalamic nucleus alters the cortical profile of response inhibition in the beta frequency band: a scalp EEG study in Parkinson's disease.

Stopping an initiated response could be implemented by a fronto-basal-ganglia circuit, including the right inferior frontal cortex (rIFC) and the subthalamic nucleus (STN). Intracranial recording studies in humans reveal an increase in beta-band power (approximately 16-20 Hz) within the rIFC and STN when a response is stopped. This suggests that the beta-band could be important for communication in this network. If this is the case, then altering one region should affect the electrophysiological response at the other. We addressed this hypothesis by recording scalp EEG during a stop task while modulating STN activity with deep brain stimulation. We studied 15 human patients with Parkinson's disease and 15 matched healthy control subjects. Behaviorally, patients OFF stimulation were slower than controls to stop their response. Moreover, stopping speed was improved for ON compared to OFF stimulation. For scalp EEG, there was greater beta power, around the time of stopping, for patients ON compared to OFF stimulation. This effect was stronger over the right compared to left frontal cortex, consistent with the putative right lateralization of the stopping network. Thus, deep brain stimulation of the STN improved behavioral stopping performance and increased the beta-band response over the right frontal cortex. These results complement other evidence for a structurally connected functional circuit between right frontal cortex and the basal ganglia. The results also suggest that deep brain stimulation of the STN may improve task performance by increasing the fidelity of information transfer within a fronto-basal-ganglia circuit.