Phasic Bursts Research Articles

Effects of Locus Coeruleus Activation on n-Back Performance and Frontoparietal Activity.

Previous studies have linked working memory capacity to restricted hemodynamic responses within critical nodes of the frontoparietal network. Emerging evidence suggests a potential role of the locus coeruleus (LC) in modulating activation of key regions essential for working memory function. This study investigated this hypothesis by examining changes in BOLD signal within the LC and cortex during a parametrically designed verbal working memory task (n-back). fMRI revealed load-dependent task activation, with maximum activation of presumed LC neurons positively correlating with working memory capacity. Furthermore, increased hemodynamic responses in the superior parietal lobes and dorsolateral pFC corresponded with the magnitude of LC activation near working memory capacity limits. An exploratory functional connectivity analysis suggests improvements in working memory performance rely on negative functional connectivity between the LC and cortical regions not primarily involved in task completion. On the basis of previous evidence, this association may represent inhibitory input from cortical regions, enabling phasic bursts of activity from LC neurons, thereby facilitating enhanced cortical activation. This result may also indicate noradrenergic suppression of cortical regions that are not crucial for task completion, leading to enhanced network efficiency. These findings suggest a mechanism by which the LC may improve verbal working memory performance by facilitating enhanced activation in regions critical for visual working memory capacity and active maintenance, potentially enhancing network efficiency.

Examination of the relationship between masseter muscle activity during sleep and wakefulness measured by using a wearable electromyographic device.

Purpose This study aimed to measure masseter muscle activity throughout the day in outpatients suspected of having awake bruxism (AB) and/or sleep bruxism (SB) and examine the relationship between AB and SB by comparing muscle activity during daytime wakefulness and nighttime sleep.Methods Fifty outpatients with suspected SB and/or AB participated in this study. A single-channel wearable electromyogram (EMG) device was used for EMG recording. The selected EMG bursts were divided into bursts during sleep (S-bursts) and bursts during awake state (A-bursts). The number of bursts per hour, average burst duration, and ratio of burst peak value to maximum voluntary contraction were calculated for both the S- and A-bursts. These values of the S- and A-bursts were then compared, and the correlations between them were analyzed. Additionally, the ratios of phasic and tonic bursts in the S- and A-bursts were compared.Results The number of bursts per hour was significantly higher for A-bursts than for S-bursts. No significant correlation was found between the numbers of S- and A-bursts. The ratio of phasic bursts was large and that of tonic bursts was small in both the S- and A-bursts. A comparison of the S- and A-bursts showed that the S-bursts had a significantly lower ratio of phasic bursts and higher ratio of tonic bursts than the A-bursts.Conclusions The number of masseteric EMG bursts during wakefulness did not show any association with that during sleep. It became clear that sustained muscle activity was not dominant in AB.

Contemporary diagnostic visual and automated polysomnographic REM sleep without atonia thresholds in isolated REM sleep behavior disorder.

Accurate diagnosis of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is crucial due to its injury potential and neurological prognosis. We aimed to analyze visual and automated REM sleep without atonia (RSWA) diagnostic thresholds applicable in varying clinical presentations in a contemporary cohort of patients with iRBD using submentalis (SM) and individual bilateral flexor digitorum superficialis (FDS) and anterior tibialis electromyography limb recordings during polysomnography. We analyzed RSWA in 20 patients with iRBD and 20 age-, REM-, apnea-hypopnea index-matched controls between 2017 and 2022 for phasic burst durations, density of phasic, tonic, and "any" muscle activity (number of 3-second mini-epochs containing phasic or tonic muscle activity divided by the total number of REM sleep 3-second mini-epochs), and automated Ferri REM atonia index (RAI). Group RSWA metrics were comparatively analyzed. Receiver operating characteristic curves determined optimized area under the curve (AUC) and maximized specificity and sensitivity diagnostic iRBD RSWA thresholds. All mean RSWA metrics were higher in patients with iRBD than in controls (P < .05), except for selected anterior tibialis measures. Optimized, maximal specificity AUC diagnostic cutoffs for coprimary outcomes were: SM "any" 6.5%, 14.0% (AUC = 92.5%) and combined SM+FDS "any" 15.1%, 27.4% (AUC = 95.8%), while SM burst durations were 0.72, and 0.72 seconds (AUC 90.2%) and FDS RAI = 0.930, 0.888 (AUC 92.8%). This study provides evidence for current quantitative RSWA diagnostic thresholds in chin and individual 4 limb muscles applicable in different iRBD clinical settings and confirms the key value of SM or SM+FDS to assure accurate iRBD diagnosis. Evolving iRBD recognition underscores the necessity of continuous assessment with future large, prospective, well-harmonized, multicenter polysomnographic analyses. Leclair-Visonneau L, Feemster JC, Bibi N, etal. Contemporary diagnostic visual and automated polysomnographic REM sleep without atonia thresholds in isolated REM sleep behavior disorder. J Clin Sleep Med. 2024;20(2):279-291.

Wavelet-Based Bracketing, Time–Frequency Beta Burst Detection: New Insights in Parkinson's Disease

Studies have shown that beta band activity is not tonically elevated but comprises exaggerated phasic bursts of varying durations and magnitudes, for Parkinson's disease (PD) patients. Current methods for detecting beta bursts target a single frequency peak in beta band, potentially ignoring bursts in the wider beta band. In this study, we propose a new robust framework for beta burst identification across wide frequency ranges. Chronic local field potential at-rest recordings were obtained from seven PD patients implanted with Medtronic SenSight™ deep brain stimulation (DBS) electrodes. The proposed method uses wavelet decomposition to compute the time–frequency spectrum and identifies bursts spanning multiple frequency bins by thresholding, offering an additional burst measure, ∆f, that captures the width of a burst in the frequency domain. Analysis included calculating burst duration, magnitude, and ∆f and evaluating the distribution and likelihood of bursts between the low beta (13–20 Hz) and high beta (21–35 Hz). Finally, the results of the analysis were correlated to motor impairment (MDS-UPDRS III) med off scores. We found that low beta bursts with longer durations and larger width in the frequency domain (∆f) were positively correlated, while high beta bursts with longer durations and larger ∆f were negatively correlated with motor impairment. The proposed method, finding clear differences between bursting behavior in high and low beta bands, has clearly demonstrated the importance of considering wide frequency bands for beta burst behavior with implications for closed-loop DBS paradigms.

A medullary hub for controlling REM sleep and pontine waves

Rapid-eye-movement (REM) sleep is a distinct behavioral state associated with vivid dreaming and memory processing. Phasic bursts of electrical activity, measurable as spike-like pontine (P)-waves, are a hallmark of REM sleep implicated in memory consolidation. However, the brainstem circuits regulating P-waves, and their interactions with circuits generating REM sleep, remain largely unknown. Here, we show that an excitatory population of dorsomedial medulla (dmM) neurons expressing corticotropin-releasing-hormone (CRH) regulates both REM sleep and P-waves in mice. Calcium imaging showed that dmM CRH neurons are selectively activated during REM sleep and recruited during P-waves, and opto- and chemogenetic experiments revealed that this population promotes REM sleep. Chemogenetic manipulation also induced prolonged changes in P-wave frequency, while brief optogenetic activation reliably triggered P-waves along with transiently accelerated theta oscillations in the electroencephalogram (EEG). Together, these findings anatomically and functionally delineate a common medullary hub for the regulation of both REM sleep and P-waves.

0044 Thalamocortical functional connectivity increases during REM sleep sawtooth waves

Abstract Introduction Whereas sawtooth waves have been described as phasic bursts of slow oscillations in the scalp EEG during rapid-eye-movement (REM) sleep sixty years ago, little is known about their generators and functional role. Stereo-electroencephalography recordings (SEEG) performed for presurgical evaluation in drug-resistant focal epilepsy have allowed to demonstrate a peculiar slow activity in the thalamic medial pulvinar nucleus during REM sleep, contrasting with the fast desynchronized cortical activity. However, the link between this slow thalamic activity and sawtooth waves remains unexplored. Here, we used combined polysomnography and SEEG to investigate the dynamics of thalamic activity and thalamocortical functional connectivity at the time of scalp EEG sawtooth waves. Methods Night sleep recordings from six patients investigated with SEEG including thalamic recording in the Epilepsy Department of Lyon University Hospital were analyzed. Sawtooth waves were visually detected in the scalp EEG and compared with control segments selected in REM sleep. Thalamic SEEG and cortical EEG spectral power as well as thalamo-cortical functional connectivity assessed by the phase locking value were compared between sawtooth waves and control segments using paired t-tests. The effect size was assessed with Cohen’s d. Results A significant increase in the delta-theta (2-5 Hz, p&amp;lt; 0.003, d=0.31) and gamma (30-100 Hz, p&amp;lt; 0.003, d=0.31) power bands was found in posterior nuclei of the thalamus at the time of scalp-detected sawtooth waves. Functional thalamocortical connectivity in the 2-5 Hz band was enhanced during sawtooth waves as compared to control segments, with the thalamus driving the cortex (p&amp;lt; 0.001; d=0.84, average +/- SD time lag: 23 +/- 22 ms). Conclusion Our results provide evidence that sawtooth waves involve not only cortical areas but also the thalamus, suggesting a relation with ponto-geniculo-occipital waves. They may hence represent phasic brainstem-triggered short windows of an increased thalamocortical dialogue during REM sleep. Support (if any) B.F was supported by the Natural Sciences and Engineering Research Council of Canada RGPIN2020-04127 and RGPAS-2020-00021, and by the Fonds de Recherche du Québec–Santé 2021-2025 Salary Award “Chercheur-boursier clinicien Senior”. T.A. was supported by the “Healthy Brains, Healthy Lives initiative at McGill University” from the Canada First Research Excellence Fund and Fonds de recherche du Québec 2021-2022.

β Bursting in the Retrosplenial Cortex Is a Neurophysiological Correlate of Environmental Novelty Which Is Disrupted in a Mouse Model of Alzheimer's Disease.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer's disease (AD). In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of AD-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials (LFPs) were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of β (20-30 Hz) oscillations (β bursts), which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of β bursts. Additionally, θ-α/β cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during β bursts. Finally, excessive β bursting was seen in J20 mice, including increased β bursting during novelty and familiarity, yet a loss of coupling between β bursts and spiking activity. These findings support the concept that β bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.SIGNIFICANCE STATEMENT The retrosplenial cortex (RSC) is thought to be involved in the formation, recall and consolidation of contextual memory. The discovery of bursts of β oscillations in this region, which are associated with increased neuronal spiking and strongly upregulated while mice explore novel environments, provides a potential mechanism for the activation of neuronal ensembles, which may underlie the formation of cortical representations of context. Excessive β bursting in the RSC of J20 mice, a mouse model of Alzheimer's disease (AD), alongside the disassociation of β bursting from neuronal spiking, may underlie spatial memory impairments previously shown in these mice. These findings introduce a novel neurophysiological correlate of spatial learning and memory, and a potentially new form of AD-related cortical dysfunction.

0555 Isolated REM Sleep Without Atonia Following COVID-19 Infection: A Case-Control Study

IntroductionREM sleep without atonia (RSWA) is the neurophysiological substrate of REM sleep behavior disorder (RBD), a form of prodromal parkinsonism in most older adults. Isolated RSWA (without clinical RBD) elevation was demonstrated recently in older adults following SARS-CoV2 (COVID-19) infection, but comparison to controls was not reported. We aimed to comparatively analyze RSWA between patients with previous COVID-19 infection and COVID-19 negative controls.Methods25 patients with previous COVID-19 infection were compared to 25 age-sex matched controls who tested negative for COVID-19 prior to polysomnography. Patients receiving medications known to increase RSWA were excluded. We reviewed medical records to determine clinical features and quantitatively analyzed RSWA in the submentalis (SM) and anterior tibialis (AT) muscles for phasic, tonic, and “any” muscle activity, phasic burst duration, and the automated REM atonia index. Non-parametric analyses compared clinical and polysomnographic features between groups, with combined SM and AT RSWA as the defined primary outcome. The comparative frequency of COVID-19 positive cases and COVID-19 negative controls who met or exceeded proposed isolated RSWA thresholds was also determined.ResultsCOVID-19 patients had significantly greater RSWA than COVID-19 negative controls in the combined SM and AT muscles (p = 0.00076). Most other RSWA metrics were also higher in COVID-19 patients than controls (p<0.03), except tonic muscle activity, phasic burst durations, and RAI. Isolated RSWA occurred more frequently in COVID-19 (9 patients, 36%) than controls (3, 12%; p>0.05). No patients had a clinical history or polysomnographic evidence for parasomnia behavior or a primary neurological condition.ConclusionQuantitative RSWA amounts were comparatively greater in COVID-19 patients than in COVID-19 tested-negative controls, suggesting association of previous COVID-19 infection with central nervous system brainstem dysfunction in the region of the dorsal pons and/or ventromedial medulla. Further prospective studies are needed to determine whether RSWA is a predisposing influence to, or consequence of, COVID-19 infection in these patients, and whether COVID-19 survivors might harbor neurodegenerative risk or disease markers.Support (If Any)

0557 Diagnostic Visual and Automated Polysomnagraphic REM Sleep Without Atonia Thresholds in Isolated REM Sleep Behavior Disorder 2.0

Abstract Introduction Accurate, early diagnosis of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is crucial given its injury potential and neurological prognosis. We aimed to analyze visual and automated REM sleep without atonia (RSWA) diagnostic thresholds in a current cohort of iRBD patients using submentalis (SM) and individual four limb electromyography (EMG) recordings, including bilateral flexor digitorum superificialis (FDS) and anterior tibialis (AT) during polysomnography. Methods We analyzed RSWA in 20 iRBD patients and 20 age-sex-AHI matched controls who underwent polysomnography between 2017-2021 for phasic burst durations, phasic, tonic, and "any" muscle activity, and automated REM atonia index (RAI). Group RSWA metrics were analyzed with non-parametric comparisons, logistic regression, and receiver operating characteristic (ROC) curves to determine optimal diagnostic cutoff thresholds for iRBD. Correlation explored associative relationships between RSWA metrics, and principal components analysis (PCA) defined determinants of RSWA metric variance. Results All mean RSWA metrics were higher in iRBD patients than controls (p&amp;lt;0.05), except for left and bilateral AT phasic density and duration. RSWA(phasic%, AUC; "any"%, AUC) cutoffs were: SM (6.5%, AUC=90.2; 6.5%, AUC=92.5); L FDS (7.3%, AUC=95.8; 7.3%, AUC=95.8%); R FDS (5.4%, AUC=93.5; 5.8%, AUC=93.2%); Bilateral FDS (10.7%, AUC=96; 15.3%, AUC=95.8); L AT (6.7%, AUC=74.5; 6.7%, AUC=74.8%); R AT (4.7%, AUC=76.8; 4.7%, AUC=76.8%); Bilateral AT (7.5%, AUC=77.5; 7.5%, AUC=77.5%), combined SM/FDS (15.0%, AUC=95.5; 15.1%; AUC=95.8), combined SM/AT (16.5%, AUC=85.8; 21.0%; AUC=88.8),tonic (0.5%; AUC=85.9), and RAI (0.90; AUC=91.4). Phasic burst duration cutoffs were: SM=0.7s (AUC=90.2), L FDS=0.5 s (AUC=83.2), R FDS=0.6 (AUC=85.2), L AT=0.3 s (AUC=65.0) and R AT=0.4 s (AUC=77.0). PCA demonstrated that FDS and combined SM/FDS and SM/AT RSWA metrics best explained RSWA variance and differentiated controls from RBD, while SM and AT alone were less explanatory. Conclusion This study provides evidence for quantitative RSWA diagnostic thresholds applicable in current iRBD populations, and confirms the key importance of FDS to assure accurate iRBD diagnosis. Interestingly, these RSWA diagnostic thresholds are lower than previously determined thresholds, suggesting secular trends toward earlier iRBD detection and heterogeneous disease duration relative to polysomnography acquisition, underscoring the necessity of future large scale prospective, multicenter polysomnographic analyses to determine definitive iRBD diagnostic RSWA thresholds. Support (If Any)

Precise and Pervasive Phasic Bursting in Locus Coeruleus during Maternal Behavior in Mice.

The noradrenergic locus coeruleus (LC) mediates key aspects of arousal, memory, and cognition in structured tasks, but its contribution to naturalistic behavior remains unclear. LC activity is thought to multiplex distinct signals by superimposing sustained ("tonic") firing patterns reflecting global brain states, such as arousal and anxiety, and rapidly fluctuating ("phasic") bursts signaling discrete behaviorally significant events. Manipulations of the LC noradrenergic system broadly impair social behavior, but the temporal structure of LC firing and its relationship to social interaction is unknown. One possibility is that tonic firing may increase in the presence of social partners; it is also possible that phasic bursts may accompany specific social events. We used chronic in vivo electrophysiology and fiber photometry to measure single-unit and population neural activity in LC of freely behaving mice during their interactions with pups. We find that pup retrieval elicits remarkably precise phasic activity in LC that cannot be attributed merely to sensory stimuli, motor activity, or reward. Correlation of LC activity with retrieval events shows that phasic events are most closely related to specific subsequent behaviors. The reliability and magnitude of phasic responses strongly suggest that these events are coordinated across LC and broadcast noradrenaline (NA) release throughout the brain. We also observed slow changes in tonic firing when females performed distinct maternal behaviors such as nest building and pup grooming. We therefore propose that LC signals state changes during sustained interactions and contributes to goal-directed action selection during social behavior with globally broadcast NA release.SIGNIFICANCE STATEMENT Locus coeruleus (LC) releases noradrenaline (NA) brain wide, influencing many cognitive, emotional, and physiological processes. Multifunctionality of LC is maintained by multiplexing NA signaling via brief "phasic" patterns of bursting and slowly changing "tonic" firing. Manipulations of NA impair social behavior, yet the structure of LC activity with respect to specific social events is unknown. We measured LC activity in mice freely interacting with pups. We find that pup retrieval elicits precisely timed and pervasive phasic activation of LC that anticipates specific behaviors. We also found that LC neurons exhibited slow fluctuations in firing during sustained behaviors. We propose that LC simultaneously contributes to goal-directed social action selection with globally broadcast NA release and signals social state changes with increased tonic firing.

The ascending arousal system shapes neural dynamics to mediate awareness of cognitive states

Models of cognitive function typically focus on the cerebral cortex and hence overlook functional links to subcortical structures. This view does not consider the role of the highly-conserved ascending arousal system’s role and the computational capacities it provides the brain. We test the hypothesis that the ascending arousal system modulates cortical neural gain to alter the low-dimensional energy landscape of cortical dynamics. Here we use spontaneous functional magnetic resonance imaging data to study phasic bursts in both locus coeruleus and basal forebrain, demonstrating precise time-locked relationships between brainstem activity, low-dimensional energy landscapes, network topology, and spatiotemporal travelling waves. We extend our analysis to a cohort of experienced meditators and demonstrate locus coeruleus-mediated network dynamics were associated with internal shifts in conscious awareness. Together, these results present a view of brain organization that highlights the ascending arousal system’s role in shaping both the dynamics of the cerebral cortex and conscious awareness.

Hypothalamic Dopamine Neurons Control Sensorimotor Behavior by Modulating Brainstem Premotor Nuclei in Zebrafish

Dopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. Although there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here, we demonstrate that tyrosine-hydroxylase-2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal-fluid-contacting DA nuclei surrounding the 3rd ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.

A Dopamine-Gated Nucleus Accumbens Circuit for Cognitive Map Reification

Animals navigate environment based on cognitive map built upon spatial cues and desired outcomes. However, how the goal representation stems from spatial information and outcomes, and its causal role in action control, remain elusive. Here we show that ‘where-to-escape’ relies on the cognitive map formulated by shelter experience. Dopamine (DA) neurons in the ventral tegmental area (VTA) exhibit valence encodings and the phasic burst stimulations of VTADA neurons sufficiently generate latent goal memory. Converging DA and excitatory inputs from VTA and hippocampus (HPC), respectively, onto the nucleus accumbens (NAc) is required for goal memory formation, integrating spatial value with the place. Tracking cellular dynamics of NAc neurons reveals emerging ensembles representing shelter positions. Targeting functionally-selective neuronal ensemble guides movements towards the goal location, regardless of the animal’s position. Thus, our findings reveal a neural basis of goal memory-to-action instantiation, demonstrating the feasibility of cognitive action tracing in space and time.

Discharge and Role of GABA Pontomesencephalic Neurons in Cortical Activity and Sleep-Wake States Examined by Optogenetics and Juxtacellular Recordings in Mice.

The cholinergic neurons in the pontomesencephalic tegmentum have been shown to discharge in association with and promote cortical activation during active or attentive waking and paradoxical or rapid eye movement sleep. However, GABA neurons lie intermingled with the cholinergic neurons and may contribute to or oppose this activity and role. Here we investigated in vitro and in vivo the properties, activities, and role of GABA neurons within the laterodorsal tegmental and sublaterodorsal tegmental nuclei (LDT/SubLDT) using male and female transgenic mice expressing channelrhodopsin-(ChR2)-EYFP in vesicular GABA transporter (VGAT)-expressing neurons. Presumed GABA (pGABA) neurons were identified by response to photostimulation and verified by immunohistochemical staining following juxtacellular labeling in vivo pGABA neurons were found to be fast-firing neurons with the capacity to burst when depolarized from a hyperpolarized membrane potential. When stimulated in vivo in urethane-anesthetized or unanesthetized mice, the pGABA neurons fired repetitively at relatively fast rates (∼40 Hz) during a continuous light pulse or phasically in bursts (>100 Hz) when driven by rhythmic light pulses at theta (4 or 8 Hz) frequencies. pNon-GABA, which likely included cholinergic, neurons were inhibited during each light pulse to discharge rhythmically in antiphase to the pGABA neurons. The reciprocal rhythmic bursting by the pGABA and pNon-GABA neurons drove rhythmic theta activity in the EEG. Such phasic bursting by GABA neurons also occurred in WT mice in association with theta activity during attentive waking and paradoxical sleep.SIGNIFICANCE STATEMENT Neurons in the pontomesencephalic tegmentum, particularly cholinergic neurons, play an important role in cortical activation, which occurs during active or attentive waking and paradoxical or rapid eye movement sleep. Yet the cholinergic neurons lie intermingled with GABA neurons, which could play a similar or opposing role. Optogenetic stimulation and recording of these GABA neurons in mice revealed that they can discharge in rhythmic bursts at theta frequencies and drive theta activity in limbic cortex. Such phasic burst firing also occurs during natural attentive waking and paradoxical sleep in association with theta activity and could serve to enhance sensory-motor processing and memory consolidation during these states.

Daytime masticatory muscle electromyography biofeedback regulates the phasic component of sleep bruxism.

Electromyography (EMG) biofeedback (BF) training is potentially an effective cognitive-behavioural approach to regulate bruxism. This study examined sleep bruxism regulation by daytime clenching control using a single-channel auditory EMG BF device. Seventeen male subjects (mean age, 24.4±3.1years; mean±SD) with self-reported awake/sleep bruxism were recruited and divided into a BF (n=10) and a control (CO) group (n=7). All subjects underwent four EMG recording sessions during both daytime and sleep over 3weeks. During the daytime, in week 2, the BF group received feedback alert signals when excessive EMG activity with certain burst duration was detected while the subjects performed regular daily activities. The CO group underwent EMG recording sessions without receiving any alerts of parafunctional activity. The number of phasic burst events during sleep was compared between the BF and CO groups. While the number of phasic EMG events was not significantly different between the BF and CO groups at baseline, significantly smaller phasic events were observed in the BF compared to the CO group at the follow-up session (week 3) (P=.006, Tukey's HSD). Since daytime BF training is aimed at raising awareness of awake bruxism, it does not interrupt the sleep sequence or involve associated side effects. The present results suggest that EMG BF targeting fortonic EMG events during the daytime can be an effective method to regulate phasic EMG events during sleep.

Frequency- and State-Dependent Network Effects of Electrical Stimulation Targeting the Ventral Tegmental Area in Macaques.

The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic system underlying adaptive behavior. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity. Artificial perturbations of the VTA, through electrical or optogenetic stimulation methods, generate different and sometimes even contrasting behavioral outcomes depending on stimulation parameters such as frequency, amplitude, and pulse width. Here, we investigate the global functional effects of electrical stimulation frequency (10, 20, 50, and 100 Hz) of the VTA in rhesus monkeys. We stimulated 2 animals with chronic electrodes, either awake or anesthetized, while concurrently acquiring whole-brain functional magnetic resonance imaging (fMRI) signals. In the awake state, activity as a function of stimulation frequency followed an inverted U-shape in many cortical and subcortical structures, with highest activity observed at 20 and 50 Hz and lower activity at 10 and 100 Hz. Under anesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10 Hz stimulation, but decreased linearly as a function of higher stimulation frequencies. A speculative explanation for the remarkable frequency dependence of stimulation-induced fMRI activity is that the VTA makes use of different frequency channels to communicate with different postsynaptic sites.

Quantitative analyses of jaw-opening muscle activity during the active phase of jaw-closing muscles in sleep bruxism.

Rhythmic masticatory muscle activity (RMMA), which is defined as three or more consecutive phasic bursts, accounts for a large part of sleep bruxism (SB). RMMA is thought to be characterized by co-contraction, a jaw muscle activity in which jaw-opening muscles contract during the active phase of jaw-closing muscles, which is different from that during mastication. However, there has been limited information about co-contraction. The aim of the present study was to clarify the amplitudes and patterns of jaw-opening muscle activity during the active phase of jaw-closing muscles in RMMA. Data from 14 healthy volunteers with bruxism, which was diagnosed by using polysomnographic recording with audio-video, were analysed. RMMA with electromyographic amplitudes of more than two times the baseline amplitude was selected. From the selected RMMA, burst groups consisting of five or more consecutive phasic bursts, including tonic bursts, were selected for analyses. Electromyographic activities during gum chewing were also recorded before sleeping. The minimum, maximum and average value of the amplitudes of jaw-opening muscle activity during the active phase of jaw-closing muscles were calculated. Jaw-opening muscle activity during the active phase of jaw-closing muscles in RMMA was closer to the baseline than that in gum chewing. The minimum, maximum and average values of amplitudes of jaw-opening muscle activity during the phase were significantly smaller than those of gum chewing. Contrary to our hypothesis prior to the study, the obtained results suggested that the pattern of electromyogram activity of jaw-opening and jaw-closing muscles in RMMA was not necessarily co-contraction.

Commonly Abused Drugs Differentially Increase the Frequency and Amplitude of Accumbal Transient Dopamine Release Events

The rewarding and reinforcing effects of abused drugs are thought to be mediated by their ability to increase brain dopamine levels. The canon holds that all drugs of abuse increase dopamine release in a brain region called the nucleus accumbens (NAc) but, due to the temporal constraints of previously available neurochemical techniques, it remains unknown how distinct drugs of abuse alter dopamine release in real time. A real time assessment is important due to the nature by which dopamine neurons fire. In awake and behaving rats, dopamine neurons fire in two distinct patterns. At ‘rest,’ dopamine neurons fire in a low‐frequency pacemaker fashion that is thought to produce a tone on high‐affinity dopamine receptors in the NAc. When presented with motivationally relevant stimuli, dopamine neurons fire in high‐frequency bursts. The phasic bursts of dopamine neural activity contribute to the generation of subsecond release events in the NAc that are sufficient in concentration to occupy low‐affinity dopamine receptors. As the activation of these low‐affinity receptors is thought to be particularly important in strengthening action‐outcome associations, we are especially interested in investigating how drugs of abuse alter their patterns of release. Fast‐scan cyclic voltammetry (FSCV) allows for the detection of dopamine release events with a temporal resolution of milliseconds, making it an ideal tool with which to examine how drugs of abuse alter transient dopamine release events in real time. We obtain two primary dependent measures of dopamine release, the frequency at which they occur and the total concentration of each event.Here, we are using FSCV to compare how different drugs of abuse alter the frequency and amplitude of dopamine release events in the awake and behaving rat. Drugs of investigation include: ethanol, diazepam, zolpidem, WIN55,212‐2, methamphetamine, methylenedioxymethamphetamine (MDMA) and heroin. Preliminary data show that the sedative‐hypnotics ethanol, diazepam and zolpidem all increase the frequency but decrease the amplitude of dopamine release events; although the ethanol amplitude effect is biphasic. Heroin, the synthetic cannabinoid WIN55,212‐2, and the psychostimulant methamphetamine increase both the frequency and amplitude of dopamine release events. The psychostimulant and tryptamine psychedelic MDMA increases the amplitude of dopamine release events but not their frequency. Together, these data reveal that the effects of abused drugs on transient dopamine release events varies across drug classes.Support or Funding InformationFunding for this work was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBOThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting.

Appropriate modification of behavior in response to our dynamic environment is essential for adaptation and survival. This adaptability allows organisms to maximize the utility of behavior-related energy expenditure. Modern theories of locus coeruleus (LC) function implicate a pivotal role for the noradrenergic nucleus in mediating switches between focused behavior during periods of high utility (exploit) versus disengagement of behavior and exploration of other, more rewarding opportunities. Two modes of activity in LC neurons have been characterized as elements in an Adaptive Gain Theory (AGT) of LC function. In this theory, during periods of accurate and focused behavior, LC neurons exhibit task-related phasic bursts. However, as behavioral utility wanes, phasic activity is suppressed and baseline (tonic) impulse activity increases to facilitate exploration. Our experiments sought to exogenously induce an elevated pattern of activity in LC neurons and their medial prefrontal cortical (mPFC) targets to test the tenets of the AGT. This theory posits that tonic activation immediately following a rule change should increase exploration and thereby improve performance on a set-shifting task. Indeed, DREADD mediated stimulation of LC terminals within mPFC decreased trials to reach criterion. However, this effect resulted from improved application of the new rule once the original rule is jettisoned rather than earlier disengagement from the old, ineffective strategy. Such improvements were not seen with global manipulation of LC, consistent with the view that LC-mediated exploration involves specific sub-circuits targeting mPFC. These findings extend our understanding of the role of LC in PFC and flexible behavior.

Frequency and state-dependent effects of VTA electrical stimulation on whole brain fMRI activity

Event Abstract Back to Event Frequency and state-dependent effects of VTA electrical stimulation on whole brain fMRI activity Sjoerd Murris1*, John Arsenault1, 2 and Wim Vanduffel1, 2, 3 1 Department of Neurosciences, KU Leuven, Belgium 2 Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, United States 3 Harvard Medical School, United States The Ventral Tegmental Area (VTA) and neighbouring Substantia Nigra are integral structures at the heart of the dopamine system, underlying adaptive behaviour. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity, possibly supporting diverse cognitive functionss1. Artificial perturbations of the VTA through electrical and optogenetic stimulation methods generate different and sometimes even contrasting behavioural outcomes depending on stimulation parameters such as frequency, amplitude and pulse width2–4. Here we investigate the brain-wide functional effects of electrical stimulation frequency (10, 20, 50 and 100 Hz) of the VTA of two rhesus macaques implanted with chronic electrodes5. We stimulated both animals while measuring brain-wide fMRI signal changes during a passive fixation task or under anaesthesia. In the awake state, activity in many cortical and subcortical structures followed an inverted u-shape as a function of stimulation frequency, with highest evoked activity when stimulating at 20 and 50 Hz and less activity at 10 and 100 Hz. In addition, we tested whether the state of the animals had an effect on stimulation-induced network activity by performing the same experiment under ketamine-induced anaesthesia. Under anaesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10Hz stimulation, but became negative and decreased linearly as a function of higher stimulation frequencies. In conclusion, brain wide network effects induced by electrical stimulation of the VTA are to a large degree frequency and state-dependent. The remarkably different stimulation-induced amplitudes and patterns of fMRI activity may explain varying and even opposing behavioural effects observed using Deep Brain Stimulation in patients. In addition, they call for a careful design and interpretation of electrical microstimulation procedures in fundamental research. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Acknowledgements This work received funding from KU Leuven C14/17/109; Hercules II funds; Fonds Wetenschappelijk Onderzoek-Vlaanderen G0D5817N, G090714N and Odysseus G0007.12; and the European Union's Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement No 785907 (Human Brain Project SGA2).