CRISPR-Cas III-A Csm6 CARF Domain Is a Ring Nuclease Triggering Stepwise cA4 Cleavage with ApA>p Formation Terminating RNase Activity.

Type III-A CRISPR-Cas surveillance complexes containing multi-subunit Csm effector, guide, and target RNAs exhibit multiple activities, including formation of cyclic-oligoadenylates (cAn) from ATP and subsequent cAn-mediated cleavage of single-strand RNA (ssRNA) by the trans-acting Csm6 RNase. Our structure-function studies have focused on Thermococcus onnurineus Csm6 to deduce mechanistic insights into how cA4 binding to the Csm6 CARF domain triggers the RNase activity of the Csm6 HEPN domain and what factors contribute to regulation of RNA cleavage activity. We demonstrate that the Csm6 CARF domain is a ring nuclease, whereby bound cA4 is stepwise cleaved initially to ApApApA>p and subsequently to ApA>p in its CARF domain-binding pocket, with such cleavage bursts using a timer mechanism to regulate the RNase activity of the Csm6 HEPN domain. In addition, we establish T. onnurineus Csm6 as an adenosine-specific RNase and identify a histidine in the cA4 CARF-binding pocket involved in autoinhibitory regulation of RNase activity.

Refractive lensing of scintillating FRBs by subparsec cloudlets in the multiphase CGM.

We consider the refractive lensing effects of ionized cool ([Formula: see text]) gas cloudlets in the circumgalactic medium (CGM) of galaxies. In particular, we discuss the combined effects of lensing from these cloudlets and scintillation from plasma screens in the Milky Way interstellar medium (ISM). We show that, if the CGM comprises a mist of subparsec cloudlets with column densities of order [Formula: see text] (as predicted by [M. McCourt, S. P. Oh, R. O'Leary, A. M. Madigan, MNRAS 473, 5407-5431 (2018)]), then fast radio bursts (FRBs) whose sightlines pass within a virial radius of a CGM halo will may be lensed into tens of refractive images with a ∼10 ms scattering timescale. When these images are formed, they will be resolved by scintillating screens in the Milky Way ISM and will suppress the observed scintillation. We illustrate this effect in refractive lensing and argue that positive detections of FRB scintillation may constrain the properties of these cool-gas cloudlets, with current scintillation observation weakly disfavoring the cloudlet model. We propose that sheet-like geometries for the cool gas in the CGM can reconcile quasar absorption measurements (from which we infer the presence of the cool gas with structure on subparsec scales) and the unexpected lack of lensing signals from this gas thus far observed.

Single-Molecule Analysis Reveals Linked Cycles of RSC Chromatin Remodeling and Ace1p Transcription Factor Binding in Yeast.

It is unknown how the dynamic binding of transcription factors (TFs) is molecularly linked to chromatin remodeling and transcription. Using single-molecule tracking (SMT), we show that the chromatin remodeler RSC speeds up the search process of the TF Ace1p for its response elements (REs) at the CUP1 promoter. We quantified smFISH mRNA data using a gene bursting model and demonstrated that RSC regulates transcription bursts of CUP1 only by modulating TF occupancy but does not affect initiation and elongation rates. We show by SMT that RSC binds to activated promoters transiently, and based on MNase-seq data, that RSC does not affect the nucleosomal occupancy at CUP1. Therefore, transient binding of Ace1p and rapid bursts of transcription at CUP1 may be dependent on short repetitive cycles of nucleosome mobilization. This type of regulation reduces the transcriptional noise and ensures a homogeneous response of the cell population to heavy metal stress.

Random Tactile Noise Stimulation Reveals Beta-Rhythmic Impulse Response Function of the Somatosensory System.

Both passive tactile stimulation and motor actions result in dynamic changes in beta band (15-30 Hz Hz) oscillations over somatosensory cortex. Similar to alpha band (8-12 Hz) power decrease in the visual system, beta band power also decreases following stimulation of the somatosensory system. This relative suppression of α and ß oscillations is generally interpreted as an increase in cortical excitability. Here, next to traditional single-pulse stimuli, we used a random intensity continuous right index finger tactile stimulation (white noise), which enabled us to uncover an impulse response function of the somatosensory system. Contrary to previous findings, we demonstrate a burst-like initial increase rather than decrease of beta activity following white noise stimulation (human participants, N = 18, 8 female). These ß bursts, on average, lasted for 3 cycles, and their frequency was correlated with resonant frequency of somatosensory cortex, as measured by a multifrequency steady-state somatosensory evoked potential paradigm. Furthermore, beta band bursts shared spectro-temporal characteristics with evoked and resting-state ß oscillations. Together, our findings not only reveal a novel oscillatory signature of somatosensory processing that mimics the previously reported visual impulse response functions, but also point to a common oscillatory generator underlying spontaneous ß bursts in the absence of tactile stimulation and phase-locked ß bursts following stimulation, the frequency of which is determined by the resonance properties of the somatosensory system.SIGNIFICANCE STATEMENT The investigation of the transient nature of oscillations has gained great popularity in recent years. The findings of bursting activity, rather than sustained oscillations in the beta band, have provided important insights into its role in movement planning, working memory, inhibition, and reactivation of neural ensembles. In this study, we show that also in response to tactile stimulation the somatosensory system responds with ∼3 cycle oscillatory beta band bursts, whose spectro-temporal characteristics are shared with evoked and resting-state beta band oscillatory signatures of the somatosensory system. As similar bursts have been observed in the visual domain, these oscillatory signatures might reflect an important supramodal mechanism in sensory processing.

Brain-heart interaction disruption in major depressive disorder: disturbed rhythm modulation of the cardiac cycle on brain transient theta bursts.

Brain neurons support arousal and cognitive activity in the form of spectral transient bursts and cooperate with the peripheral nervous system to adapt to the surrounding environment. However, the temporal dynamics of brain-heart interactions have not been confirmed, and the mechanism of brain-heart interactions in major depressive disorder (MDD) remains unclear. This study aimed to provide direct evidence for brain-heart synchronization in temporal dynamics and clarify the mechanism of brain-heart interaction disruption in MDD. Eight-minute resting-state (closed eyes) electroencephalograph and electrocardiogram signals were acquired simultaneously. The Jaccard index (JI) was used to measure the temporal synchronization between cortical theta transient bursts and cardiac cycle activity (diastole and systole) in 90 MDD patients and 44 healthy controls (HCs) at rest. The deviation JI was used to reflect the equilibrium of brain activity between diastole and systole. The results showed that the diastole JI was higher than the systole JI in both the HC and MDD groups; compared to HCs, the deviation JI attenuated at F4, F6, FC2, and FC4 in the MDD patients. The eccentric deviation JI was negatively correlated with the despair factor scores of the HAMD, and after 4 weeks of antidepressant treatment, the eccentric deviation JI was positively correlated with the despair factor scores of the HAMD. It was concluded that brain-heart synchronization existed in the theta band in healthy individuals and that disturbed rhythm modulation of the cardiac cycle on brain transient theta bursts at right frontoparietal sites led to brain-heart interaction disruption in MDD.

Generation and propagation of bursts of activity in the developing basal ganglia.

The neonatal brain is characterized by intermittent bursts of oscillatory activity interspersed by relative silence. Although well-characterized for many cortical areas, to what extent these propagate and interact with subcortical brain areas is largely unknown. Here, early network activity was recorded from the developing basal ganglia, including motor/somatosensory cortex, dorsal striatum, and intralaminar thalamus, during the first postnatal weeks in mice. An unsupervised detection and classification method revealed two main classes of bursting activity, namely spindle bursts and nested gamma spindle bursts, characterized by oscillatory activity at ~ 10 and ~ 30 Hz frequencies, respectively. These were reliably identified across all three brain regions and exhibited region-specific differences in their structural, spectral, and developmental characteristics. Bursts of the same type often co-occurred in different brain regions and coherence and cross-correlation analyses reveal dynamic developmental changes in their interactions. The strongest interactions were seen for cortex and striatum, from the first postnatal week onwards, and cortex appeared to drive burst events in subcortical regions. Together, these results provide the first detailed description of early network activity within the developing basal ganglia and suggest that cortex is one of the main drivers of activity in downstream nuclei during this postnatal period.

Using occipital ⍺-bursts to modulate behavior in real-time.

Pre-stimulus endogenous neural activity can influence the processing of upcoming sensory input and subsequent behavioral reactions. Despite it is known that spontaneous oscillatory activity mostly appears in stochastic bursts, typical approaches based on trial averaging fail to capture this. We aimed at relating spontaneous oscillatory bursts in the alpha band (8-13 Hz) to visual detection behavior, via an electroencephalography-based brain-computer interface (BCI) that allowed for burst-triggered stimulus presentation in real-time. According to alpha theories, we hypothesized that visual targets presented during alpha-bursts should lead to slower responses and higher miss rates, whereas targets presented in the absence of bursts (low alpha activity) should lead to faster responses and higher false alarm rates. Our findings support the role of bursts of alpha oscillations in visual perception and exemplify how real-time BCI systems can be used as a test bench for brain-behavioral theories.

Ion-channel degeneracy and heterogeneities in the emergence of complex spike bursts in CA3 pyramidal neurons.

Complex spike bursting (CSB) is a characteristic electrophysiological signature exhibited by several neuronal subtypes and has been implicated in neural plasticity, learning, perception, anaesthesia and active sensing. Here, we address how pronounced intrinsic and synaptic heterogeneities affect CSB, with hippocampal CA3 pyramidal neurons (CA3PNs), where CSB emergence and heterogeneities are well characterized, as a substrate. We randomly generated 12,000 unique models and found 236 valid models that satisfied 11 characteristic CA3PN measurements. These morphologically and biophysically realistic valid models accounted for gating kinetics and somatodendritic expression profiles of 10 active ion channels. This heterogeneous population of valid models was endowed with broad distributions of underlying parameters showing weak pairwise correlations. We found two functional subclasses of valid models, intrinsically bursting and regular spiking, with significant differences in the expression of calcium and calcium-activated potassium conductances. We triggered CSB in all 236 models through different intrinsic or synaptic protocols and observed considerable heterogeneity in CSB propensity and properties spanning models and protocols. Finally, we used virtual knockout analyses and showed that synergistic interactions between intrinsic and synaptic mechanisms regulated CSB emergence and dynamics. Specifically, although there was a dominance of calcium and calcium-activated potassium channels in the emergence of CSB, individual deletion of none of the several ion channels or N-methyl-d-aspartate receptors resulted in the complete elimination of CSB across all models. Together, our analyses critically implicate ion-channel degeneracy in the robust emergence of CSB and other characteristic signatures of CA3PNs, despite pronounced heterogeneities in underlying intrinsic and synaptic properties. KEY POINTS: An unbiased stochastic search algorithm yielded a heterogeneous population of morphologically and biophysically realistic CA3 pyramidal neuronal models matching several signature electrophysiological characteristics. Two functional subclasses of valid models were identified with intrinsically bursting (IB) and regular spiking (RS) characteristics, which exhibited differential localization within the parametric space with linear and non-linear dimension reduction analyses. Calcium and calcium-activated potassium channels distinguished IB from RS models, apart from playing dominant roles in the emergence of complex spike bursting (CSB). The impact of deleting individual ion channels or N-methyl-d-aspartate receptors was variable across different models and differential for each channel/receptor, pointing to ion-channel degeneracy in the emergence of CSB. Biological heterogeneities across different neurons of the same subtype, ion-channel degeneracy and state-dependent changes (involving activity-dependent plasticity, pathology, and neuromodulation of intrinsic and synaptic properties) need to be considered carefully in assessing the propensity and dynamics of CSB in different neuronal subtypes.

Channel HCN4 mutation R666Q associated with sporadic arrhythmia decreases channel electrophysiological function and increases protein degradation.

Mutations in the hyperpolarization-activated nucleotide-gated channel 4 (HCN4) are known to be associated with arrhythmias in which QT prolongation (delayed ventricular repolarization) is rare. Here, we identified a HCN4 mutation, HCN4-R666Q, in two sporadic arrhythmia patients with sinus bradycardia, QT prolongation, and short bursts of ventricular tachycardia. To determine the functional effect of the mutation, we conducted clinical, genetic, and functional analyses using whole-cell voltage-clamp, qPCR, Western blot, confocal microscopy, and co-immunoprecipitation. The mean current density of HEK293T cells transfected with HCN4-R666Q was lower in 24 to 36 h after transfection and was much lower in 36 to 48 h after transfection relative to cells transfected with wildtype HCN4. Additionally, we determined that the HCN4-R666Q mutant was more susceptible to ubiquitin-proteasome system-mediated protein degradation than wildtype HCN4. This decreased current density for HCN4-R666Q could be partly rescued by treatment with a proteasome inhibitor. Therefore, we conclude that HCN4-R666Q had an effect on HCN4 function in two aspects, including decreasing the current density of the channel as a biophysical effect and weakening its protein stability. Our findings provide new insights into the pathogenesis of the HCN4-R666Q mutation.

Using convolutional dictionary learning to detect task-related neuromagnetic transients and ageing trends in a large open-access dataset.

Human neuromagnetic activity is characterised by a complex combination of transient bursts with varying spatial and temporal characteristics. The characteristics of these transient bursts change during task performance and normal ageing in ways that can inform about underlying cortical sources. Many methods have been proposed to detect transient bursts, with the most successful ones being those that employ multi-channel, data-driven approaches to minimize bias in the detection procedure. There has been little research, however, into the application of these data-driven methods to large datasets for group-level analyses. In the current work, we apply a data-driven convolutional dictionary learning (CDL) approach to detect neuromagnetic transient bursts in a large group of healthy participants from the Cam-CAN dataset. CDL was used to extract repeating spatiotemporal motifs in 538 participants between the ages of 18-88 during a sensorimotor task. Motifs were then clustered across participants based on similarity, and relevant task-related clusters were analysed for age-related trends in their spatiotemporal characteristics. Seven task-related motifs resembling known transient burst types were identified through this analysis, including beta, mu, and alpha type bursts. All burst types showed positive trends in their activation levels with age that could be explained by increasing burst rate with age. This work validated the data-driven CDL approach for transient burst detection on a large dataset and identified robust information about the complex characteristics of human brain signals and how they change with age.

'Rinse and Replace': Boosting T Cell Turnover To Reduce HIV-1 Reservoirs.

Latent HIV-1 persists indefinitely during antiretroviral therapy (ART) as an integrated silent genome in long-lived memory CD4+ T cells. In untreated infections, immune activation increases the turnover of intrinsically long-lived provirus-containing CD4+ T cells. Those are 'washed out' as a result of their activation, which when coupled to viral protein expression can facilitate local inflammation and recruitment of uninfected cells to activation sites, causing latently infected cells to compete for survival. De novo infection can counter this washout. During ART, inflammation and CD4+ T cell activation wane, resulting in reduced cell turnover and a persistent reservoir. We propose accelerating reservoir washout during ART by triggering sequential waves of polyclonal CD4+ T cell activation while simultaneously enhancing virus protein expression. Reservoir reduction as an adjunct to other therapies might achieve lifelong viral control.

Characteristics of constrained turbulent transport in flux-driven toroidal plasmas.

We study the dynamics of turbulence transport subject to a constraint on the profile formation and relaxation, dominated by the ion temperature gradient modes, within the framework of adiabatic electron response using a flux-driven global gyro-kinetic toroidal code, GKNET. We observe exponentially constrained profiles, with two different scale lengths, that are spatially constant in each region in higher input power regimes. The profiles are smoothly connected in the knee region located at [Formula: see text] of the minor radius, outside which the gradient is steepened and shows a weak confinement improvement. Based on the probability density function analysis of heat flux eddies, the power law demonstrates a dependence on the eddy size S, as [Formula: see text], which distinguishes events into diffusive and non-diffusive parts including the validation of quasi-linear hypotheses. Radially localized avalanches and global bursts, which exhibit different spatial scales, play central roles in giving rise to constrained profiles on an equal footing. It is also found that the [Formula: see text] shear layers are initiated by the global bursts, which evolve downward on a slow time scale across the knee region and play a role in adjusting the profile by increasing the gradient. This article is part of a discussion meeting issue 'H-mode transition and pedestal studies in fusion plasmas'.

Clinical burden related to oral corticosteroid treatment of severe asthma in Spain: LEVANTE study.

BACKGROUND: Severe asthma treatment with oral corticosteroids (OCS) added to inhaled corticosteroids and a long-acting ß2-agonist (ICS-LABA) may result in more treatment burden and increased adverse effects. OBJECTIVE AND METHODS: This ambispective multicenter observational study aimed at describing the clinical burden in patients with severe asthma on stable high-dose ICS-LABA who received OCS during ≥6 months (maintenance group) or ≥2 cycles in the previous 12 months (bursts group). Data collection comprised a retrospective 12-month baseline period and 2 follow-up visits at 3 and 6 months. RESULTS: Eighty-nine patients were evaluable (30 on maintenance, 59 on bursts). At baseline, mean (SD) daily prednisone equivalent exposure in the total population was 24.6 (14.7) mg: 13.8 (9.4) mg on maintenance and 29.9 (14.3) mg on bursts. During the 6-month follow-up period, mean (SD) daily dose in the total cohort was 22.5 (18.8) mg: 17.2 (18.6) mg on maintenance and 28.4 (20.6) mg on bursts. The overall annual severe exacerbations rate during the 12-month baseline period was 2.05 per patient-year and 1.5 per patient-year over the 6-month follow-up, and frequency of hospitalizations and emergency department visits were similar on both maintenance and bursts use. CONCLUSIONS: Results show a suboptimal control of severe asthma despite such high doses of OCS and persistence of disease burden regardless of the prescribing pattern in maintenance or bursts. There is therapeutic inertia to continue using OCS despite the increased risk of adverse effects and the availability of biologics.

The structure underlying core affect and perceived affective qualities of human vocal bursts.

Vocal bursts are non-linguistic affectively-laden sounds with a crucial function in human communication, yet their affective structure is still debated. Studies showed that ratings of valence and arousal follow a V-shaped relationship in several kinds of stimuli: high arousal ratings are more likely to go on a par with very negative or very positive valence. Across two studies, we asked participants to listen to 1,008 vocal bursts and judge both how they felt when listening to the sound (i.e. core affect condition), and how the speaker felt when producing it (i.e. perception of affective quality condition). We show that a V-shaped fit outperforms a linear model in explaining the valence-arousal relationship across conditions and studies, even after equating the number of exemplars across emotion categories. Also, although subjective experience can be significantly predicted using affective quality ratings, core affect scores are significantly lower in arousal, less extreme in valence, more variable between individuals, and less reproducible between studies. Nonetheless, stimuli rated with opposite valence between conditions range from 11% (study 1) to 17% (study 2). Lastly, we demonstrate that ambiguity in valence (i.e. high between-participants variability) explains violations of the V-shape and relates to higher arousal.

Two-Photon-Excited Single-Molecule Fluorescence Enhanced by Gold Nanorod Dimers.

We demonstrate two-photon-excited single-molecule fluorescence enhancement by single end-to-end self-assembled gold nanorod dimers. We employed biotinylated streptavidin as the molecular linker, which connected two gold nanorods in end-to-end fashion. The typical size of streptavidin of around 5 nm separates the gold nanorods with gaps suitable for the access of fresh dyes in aqueous solution, yet small enough to give very high two-photon fluorescence enhancement. Simulations show that enhancements of more than 7 orders of magnitude can be achieved for two-photon-excited fluorescence in the plasmonic hot spots. With such high enhancements, we successfully detect two-photon-excited fluorescence for a common organic dye (ATTO 610) at the single-molecule, single-nanoparticle level.

Volume of ß-Bursts, But Not Their Rate, Predicts Successful Response Inhibition.

In humans, impaired response inhibition is characteristic of a wide range of psychiatric diseases and of normal aging. It is hypothesized that the right inferior frontal cortex (rIFC) plays a key role by inhibiting the motor cortex via the basal ganglia. The electroencephalography (EEG)-derived ß-rhythm (15-29 Hz) is thought to reflect communication within this network, with increased right frontal ß-power often observed before successful response inhibition. Recent literature suggests that averaging spectral power obscures the transient, burst-like nature of ß-activity. There is evidence that the rate of ß-bursts following a Stop signal is higher when a motor response is successfully inhibited. However, other characteristics of ß-burst events, and their topographical properties, have not yet been examined. Here, we used a large human (male and female) EEG Stop Signal task (SST) dataset (n = 218) to examine averaged normalized ß-power, ß-burst rate, and ß-burst "volume" (which we defined as burst duration × frequency span × amplitude). We first sought to optimize the ß-burst detection method. In order to find predictors across the whole scalp, and with high temporal precision, we then used machine learning to (1) classify successful versus failed stopping and to (2) predict individual stop signal reaction time (SSRT). ß-burst volume was significantly more predictive of successful and fast stopping than ß-burst rate and normalized ß-power. The classification model generalized to an external dataset (n = 201). We suggest ß-burst volume is a sensitive and reliable measure for investigation of human response inhibition.SIGNIFICANCE STATEMENT The electroencephalography (EEG)-derived ß-rhythm (15-29 Hz) is associated with the ability to inhibit ongoing actions. In this study, we sought to identify the specific characteristics of ß-activity that contribute to successful and fast inhibition. In order to search for the most relevant features of ß-activity, across the whole scalp and with high temporal precision, we employed machine learning on two large datasets. Spatial and temporal features of ß-burst "volume" (duration × frequency span × amplitude) predicted response inhibition outcomes in our data significantly better than ß-burst rate and normalized ß-power. These findings suggest that multidimensional measures of ß-bursts, such as burst volume, can add to our understanding of human response inhibition.

Microstates and power envelope hidden Markov modeling probe bursting brain activity at different timescales.

State modeling of whole-brain electroencephalography (EEG) or magnetoencephalography (MEG) allows to investigate transient, recurring neurodynamical events. Two widely-used techniques are the microstate analysis of EEG signals and hidden Markov modeling (HMM) of MEG power envelopes. Both reportedly lead to similar state lifetimes on the 100 ms timescale, suggesting a common neural basis. To investigate whether microstates and power envelope HMM states describe the same neural dynamics, we used simultaneous MEG/EEG recordings at rest and compared the spatial signature and temporal activation dynamics of microstates and power envelope HMM states obtained separately from EEG and MEG. Results showed that microstates and power envelope HMM states differ both spatially and temporally. Microstates reflect sharp events of neural synchronization, whereas power envelope HMM states disclose network-level activity with 100-200 ms lifetimes. Further, MEG microstates do not correspond to the canonical EEG microstates but are better interpreted as split HMM states. On the other hand, both MEG and EEG HMM states involve the (de)activation of similar functional networks. Microstate analysis and power envelope HMM thus appear sensitive to neural events occurring over different spatial and temporal scales. As such, they represent complementary approaches to explore the fast, sub-second scale bursting electrophysiological dynamics in spontaneous human brain activity.

Transient beta modulates decision thresholds during human action-stopping.

Action-stopping in humans involves bursts of beta oscillations in prefrontal-basal ganglia regions. To determine the functional role of these beta bursts we took advantage of the Race Model framework describing action-stopping. We incorporated beta bursts in three race model variants, each implementing a different functional contribution of beta to action-stopping. In these variants, we hypothesized that a transient increase in beta could (1) modulate decision thresholds, (2) change stop accumulation rates, or (3) promote the interaction between the Stop and the Go process. We then tested the model predictions using EEG recordings in humans performing a Stop-signal task. We found that the model variant in which beta increased decision thresholds for a brief period of time best explained the empirical data. The model parameters fitted to the empirical data indicated that beta bursts involve a stronger decision threshold modulation for the Go process than for the Stop process. This suggests that prefrontal beta influences stopping by temporarily holding the response from execution. Our study further suggests that human action-stopping could be multi-staged with the beta acting as a pause, increasing the response threshold for the Stop process to modulate behavior successfully. Overall, our approach of introducing transient oscillations into the race model and testing against human electrophysiological data provides a novel account of the puzzle of prefrontal beta in executive control.

Cortical network formation based on subthalamic beta bursts in Parkinson's disease.

Recent evidence suggests that beta bursts in subthalamic nucleus (STN) play an important role in Parkinsonian pathophysiology. We studied the spatio-temporal relationship between STN beta bursts and cortical activity in 26 Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery. Postoperatively, we simultaneously recorded STN local field potentials (LFP) from externalized DBS leads and cortical activity using whole-brain magnetoencephalography. Event-related magnetic fields (ERF) were averaged time-locked to STN beta bursts and subjected to source localization. Our results demonstrate that ERF exhibiting activity significantly different from baseline activity were localized within areas functionally related to associative, limbic, and motor systems as well as regions pertinent for visual and language processing. Our data suggest that STN beta bursts are involved in network formation between STN and cortex. This interaction is in line with the idea of parallel processing within the basal ganglia-cortex loop, specifically within the functional subsystems of the STN (i.e., associative, limbic, motor, and the related cortical areas). ERFs within visual and language-related cortical areas indicate involvement of beta bursts in STN-cortex networks beyond the associative, limbic, and motor loops. In sum, our results highlight the involvement of STN beta bursts in the formation of multiple STN - cortex loops in patients with PD.

The modulatory effect of self-paced and cued motor execution on subthalamic beta-bursts in Parkinson's disease: Evidence from deep brain recordings in humans.

Deep brain stimulation (DBS) electrodes provide an unparalleled window to record and investigate neuronal activity right at the core of pathological brain circuits. In Parkinson's disease (PD), basal ganglia beta-oscillatory activity (13-35 Hz) seems to play an outstanding role. Conventional DBS, which globally suppresses beta-activity, does not meet the requirements of a targeted treatment approach given the intricate interplay of physiological and pathological effects of beta-frequencies. Here, we wanted to characterise the local field potential (LFP) in the subthalamic nucleus (STN) in terms of beta-burst prevalence, amplitude and length between movement and rest as well as during self-paced as compared to goal-directed motor control. Our electrophysiological recordings from externalised DBS-electrodes in nine patients with PD showed a marked decrease in beta-burst durations and prevalence during movement as compared to rest as well as shorter and less frequent beta-bursts during cued as compared to self-paced movements. These results underline the importance of beta-burst modulation in movement generation and are in line with the clinical observation that cued motor control is better preserved than self-paced movements. Furthermore, our findings motivate the use of adaptive DBS based on beta-bursts, which selectively trim longer beta-bursts, as it is more suitable and efficient over a range of motor behaviours than conventional DBS.