Fronto-subthalamic phase synchronization and cross-frequency coupling during conflict processing.

Growing evidence suggests that both the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) play crucial roles in conflict processing, but how these two structures coordinate their activities remains poorly understood. We simultaneously recorded electroencephalogram from the mPFC and local field potentials from the STN using deep brain stimulation electrodes in 13 Parkinson's disease patients while they performed a Stroop task. Both mPFC and STN showed significant increases in theta activities (2-8 Hz) in incongruent trials compared to the congruent trials. The theta activity in incongruent trials also demonstrated significantly increased phase synchronization between mPFC and STN. Furthermore, the amplitude of gamma oscillation was modulated by the phase of theta activity at the STN in incongruent trials. Such theta-gamma phase-amplitude coupling (PAC) was much stronger for incongruent trials with faster reaction times than those with slower reaction times. Elevated theta-gamma PAC in the STN provides a novel mechanism by which the STN may operationalize its proposed "hold-your-horses" role. The co-occurrence of mPFC-STN theta phase synchronization and STN theta-gamma PAC reflects a neural substrate for fronto-subthalamic communication during conflict processing. More broadly, it may be a general mechanism for neuronal interactions in the cortico-basal ganglia circuits via a combination of long-range, within-frequency phase synchronization and local cross-frequency PAC.

Event-related deep brain stimulation of the subthalamic nucleus affects conflict processing.

OBJECTIVE: Many lines of evidence suggest that response conflict recruits brain regions in the cortical-basal ganglia system. Within the basal ganglia, deep brain recordings from the subthalamic nucleus (STN) have shown that conflict triggers a transient increase in low-frequency oscillations (LFOs; 2-8Hz). Here, we deployed a new method of delivering short trains of event-related deep brain stimulation (DBS) to the STN to test the causal role of the STN and its associated circuits in conflict-related processing. METHODS: In a double-blind design, we stimulated the STN in patients with Parkinson disease by locking brief trains of DBS to specific periods of the trial within a Stroop task. RESULTS: Stimulation had a specific effect on conflict compared to nonconflict trials by relatively speeding responses on conflict trials (ie, reducing the Stroop effect, defined as the difference in reaction time between conflict and nonconflict trials) when it was delivered in the preresponse period in the preparation phase. Stimulation also increased errors when it was delivered early in the response window. This latter result corresponded to the timing of the conflict-induced increase in LFOs observed in the absence of stimulation but was not directly related to the reduction in the Stroop effect. INTERPRETATION: These results support the theory that the time of LFO increase recorded from the STN corresponds to a conflict-processing function. They also provide one of the first demonstrations of event-related DBS of the STN in humans during a cognitive control paradigm. Ann Neurol 2018;84:515-526.

Establishing a Right Frontal Beta Signature for Stopping Action in Scalp EEG: Implications for Testing Inhibitory Control in Other Task Contexts.

Many studies have examined the rapid stopping of action as a proxy of human self-control. Several methods have shown that a critical focus for stopping is the right inferior frontal cortex. Moreover, electrocorticography studies have shown beta band power increases in the right inferior frontal cortex and in the BG for successful versus failed stop trials, before the time of stopping elapses, perhaps underpinning a prefrontal-BG network for inhibitory control. Here, we tested whether the same signature might be visible in scalp electroencephalography (EEG)-which would open important avenues for using this signature in studies of the recruitment and timing of prefrontal inhibitory control. We used independent component analysis and time-frequency approaches to analyze EEG from three different cohorts of healthy young volunteers (48 participants in total) performing versions of the standard stop signal task. We identified a spectral power increase in the band 13-20 Hz that occurs after the stop signal, but before the time of stopping elapses, with a right frontal topography in the EEG. This right frontal beta band increase was significantly larger for successful compared with failed stops in two of the three studies. We also tested the hypothesis that unexpected events recruit the same frontal system for stopping. Indeed, we show that the stopping-related right-lateralized frontal beta signature was also active after unexpected events (and we accordingly provide data and scripts for the method). These results validate a right frontal beta signature in the EEG as a temporally precise and functionally significant neural marker of the response inhibition process.

Modulation of cognitive cerebello-cerebral functional connectivity by lateral cerebellar continuous theta burst stimulation.

Network connectivity measured with resting state functional magnetic resonance imaging (rsfMRI) has revealed the contribution of distinct cerebellar lobules to an array of brain wide networks sub-serving motor and cognitive processes. As distinct cerebellar lobules form relatively accessible nodes of different brain networks, this raises the possibility for site-specific modulation of network connectivity using non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS). Continuous theta burst transcranial magnetic stimulation (cTBS) induces long-lasting inhibition of cortical areas. Although previous studies have shown that cTBS of the lateral cerebellum modulates motor cortical excitability and improves symptoms in several movement disorders, the effect on cognitive domains has not been examined. We explored the immediate effects of cTBS in a sham-controlled study on the strength of intrinsic functional connectivity between cerebellar and cortical motor and cognitive regions in 12 participants. Lateral cerebellar cTBS significantly decreased functional connectivity with frontal and parietal cognitive regions, while connectivity with motor regions remained unaltered. Sham stimulation had no effect on either motor or cognitive connectivity. These results show that inhibitory cerebellar stimulation reduces intrinsic functional connectivity between different cortical areas, in keeping with the known connectivity pattern of the cerebellum. The results highlight the plasticity of cerebello-cerebral networks and indicate for the first time that this functional connectivity can be downregulated using an inhibitory neurostimulation paradigm. This may shed light on the pathophysiology of network dysfunction and is a potential treatment for cognitive and movement disorders.

Stop-related subthalamic beta activity indexes global motor suppression in Parkinson's disease.

BACKGROUND: Rapid action stopping leads to global motor suppression. This is shown by studies using transcranial magnetic stimulation to measure corticospinal excitability of task-unrelated effectors (e.g., from the hand during speech stopping). We hypothesize that this global suppression relates to the STN of the basal ganglia. Several STN local field potential studies in PD patients have shown increased ß-band power during successful stopping. OBJECTIVES: Here, we aimed to test whether this STN ß-band activity indexes global motor suppression measured by transcranial magnetic stimulation. METHODS: We studied 9 medicated PD patients (age, 47-67 years; mean, 55.8; 3 female) who were implanted with STN-DBS electrodes. Participants performed a vocal stop-signal task (i.e., they had to occasionally stop a vocal response) while we simultaneously recorded local field potentials from right STN and delivered transcranial magnetic stimulation to primary motor cortex to measure corticospinal excitability from a task-unrelated hand muscle (first dorsal interosseous). RESULTS: Replicating previous results, STN ß-band power was increased (P < 0.005) and corticospinal excitability was reduced (P = 0.024; global motor suppression) during successful stopping. As hypothesized, global motor suppression was greater for successful stop trials with higher STN ß-power (median split: P = 0.043), which was further evident in a negative correlation between single-trial STN ß-power and corticospinal excitability (mean, r = -0.176; P = 0.011). CONCLUSION: These findings link stopping-related global motor suppression to STN ß-band activity through simultaneous recordings of STN and corticospinal excitability. The results support models of basal ganglia function that propose the STN has broad motor suppressive effects. © 2016 International Parkinson and Movement Disorder Society.

Modulation of cerebello-cerebral resting state networks by site-specific stimulation.

Converging evidence from neuroimaging and neuromodulation literature suggests that the cerebellum plays a broad role in motor as well as cognitive processes through its participation in resting-state networks. A recent study by Halko et al. (J Neurosci 34: 12049-12056, 2014) demonstrates, for the first time, the ability to modulate functional connectivity of some of these distinct resting-state networks using site-specific repetitive transcranial magnetic stimulation (rTMS) of the cerebellum. In this Neuro Forum, we discuss and critically analyze this study, emphasizing important findings, potential therapeutic relevance, and areas worthy of further inquiry.

Robust Removal of Slow Artifactual Dynamics Induced by Deep Brain Stimulation in Local Field Potential Recordings Using SVD-Based Adaptive Filtering.

Deep brain stimulation (DBS) is widely used as a treatment option for patients with movement disorders. In addition to its clinical impact, DBS has been utilized in the field of cognitive neuroscience, wherein the answers to several fundamental questions underpinning the mechanisms of neuromodulation in decision making rely on the ways in which a burst of DBS pulses, usually delivered at a clinical frequency, i.e., 130 Hz, perturb participants' choices. It was observed that neural activities recorded during DBS were contaminated with large artifacts, which lasts for a few milliseconds, as well as a low-frequency (slow) signal (~1-2 Hz) that can persist for hundreds of milliseconds. While the focus of most of methods for removing DBS artifacts was on the former, the artifact removal capabilities of the slow signal have not been addressed. In this work, we propose a new method based on combining singular value decomposition (SVD) and normalized adaptive filtering to remove both large (fast) and slow artifacts in local field potentials, recorded during a cognitive task in which bursts of DBS were utilized. Using synthetic data, we show that our proposed algorithm outperforms four commonly used techniques in the literature, namely, (1) normalized least mean square adaptive filtering, (2) optimal FIR Wiener filtering, (3) Gaussian model matching, and (4) moving average. The algorithm's capabilities are further demonstrated by its ability to effectively remove DBS artifacts in local field potentials recorded from the subthalamic nucleus during a verbal Stroop task, highlighting its utility in real-world applications.

Stopping and slowing manual and spoken responses: Similar oscillatory signatures recorded from the subthalamic nucleus.

Response control in the forms of stopping and slowing responses is thought to be implemented by a frontal-subcortical network, which includes the subthalamic nucleus (STN). For manual control, stopping is linked to STN beta (13-30 Hz) and slowing responses are linked to lower frequencies (<12 Hz). Whether similar STN oscillatory activities are associated with the control of spoken responses is not clear. We studied 16 patients with STN LFP recordings during manual and vocal stop signal tasks in two experiments. We found increased beta activities for stopping spoken responses, similar to manual stopping. However, unlike manual stopping, stopping spoken responses elicited a right-lateralized beta power increase, which may be related to previously reported hyperactivity of right-sided motor control regions in stuttering. We additionally studied STN power changes associated with slowing responses in the same stop-signal tasks by comparing slower vs. faster go trials. Now, rather than beta, there was an alpha power increase after Go cues, which remained elevated only in slower Go trials in both the vocal and manual tasks. These data show that different types of response control are generalizable across effectors and relate to different frequencies recorded from the STN.

Beat-induced fluctuations in auditory cortical beta-band activity: using EEG to measure age-related changes.

People readily extract regularity in rhythmic auditory patterns, enabling prediction of the onset of the next beat. Recent magnetoencephalography (MEG) research suggests that such prediction is reflected by the entrainment of oscillatory networks in the brain to the tempo of the sequence. In particular, induced beta-band oscillatory activity from auditory cortex decreases after each beat onset and rebounds prior to the onset of the next beat across tempi in a predictive manner. The objective of the present study was to examine the development of such oscillatory activity by comparing electroencephalography (EEG) measures of beta-band fluctuations in 7-year-old children to adults. EEG was recorded while participants listened passively to isochronous tone sequences at three tempi (390, 585, and 780 ms for onset-to-onset interval). In adults, induced power in the high beta-band (20-25 Hz) decreased after each tone onset and rebounded prior to the onset of the next tone across tempo conditions, consistent with MEG findings. In children, a similar pattern was measured in the two slower tempo conditions, but was weaker in the fastest condition. The results indicate that the beta-band timing network works similarly in children, although there are age-related changes in consistency and the tempo range over which it operates.