Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors.

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

Rapid synaptic and gamma rhythm signature of mouse critical period plasticity.

Early-life experience enduringly sculpts thalamocortical (TC) axons and sensory processing. Here, we identify the very first synaptic targets that initiate critical period plasticity, heralded by altered cortical oscillations. Monocular deprivation (MD) acutely induced a transient (<3 h) peak in EEG γ-power (~40 Hz) specifically within the visual cortex, but only when the critical period was open (juvenile mice or adults after dark-rearing, Lynx1-deletion, or diazepam-rescued GAD65-deficiency). Rapid TC input loss onto parvalbumin-expressing (PV) inhibitory interneurons (but not onto nearby pyramidal cells) was observed within hours of MD in a TC slice preserving the visual pathway - again once critical periods opened. Computational TC modeling of the emergent γ-rhythm in response to MD delineated a cortical interneuronal gamma (ING) rhythm in networks of PV-cells bearing gap junctions at the start of the critical period. The ING rhythm effectively dissociated thalamic input from cortical spiking, leading to rapid loss of previously strong TC-to-PV connections through standard spike-timing-dependent plasticity rules. As a consequence, previously silent TC-to-PV connections could strengthen on a slower timescale, capturing the gradually increasing γ-frequency and eventual fade-out over time. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after MD. Taken together, our findings reveal the initial synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe developmental trajectories.

Deep brain stimulation in the subthalamic nucleus for Parkinson's disease can restore dynamics of striatal networks.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson's disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma, and theta oscillations. These rhythms are essential to selection and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of behavioral deficits. Restoring the natural rhythms may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD and how DBS can restore normal beta, gamma, and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, found to preferentially target fast-spiking interneurons (FSI). We find that DBS in STN can normalize striatal medium spiny neuron activity by recruiting FSI dynamics and restoring the inhibitory potency of FSIs observed in normal conditions. We also find that DBS allows the reexpression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study highlights that DBS effects can go beyond regularizing BG output dynamics to restoring normal internal BG dynamics and the ability to regulate them. It also suggests how gamma and theta oscillations can be leveraged to supplement DBS treatment and enhance its effectiveness.

Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model.

Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brain stem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low-beta and slow rhythm, as well as their interactions. Our model suggests that propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta-frequency spiking in thalamus (C-state), whereas in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha colocalizes to the peak of the slow oscillation; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brain stem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state.NEW & NOTEWORTHY GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We constructed a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brain stem neuromodulation.

A Systematic Review of Pediatric Nonaccidental Burns: Protecting the Children Through Knowledge, Vigilance, and Prevention.

BACKGROUND: Inflicted burns on children are a particularly difficult medical and psychosocial issue. Pediatric nonaccidental burns (PNABs) are unfortunately relatively common. In our study, we aim to present the key findings on PNABs with the intention of raising awareness, improving early, and recognizing accurately by identifying red flags, developing triage tools, and establishing prevention strategies for this sensitive issue. METHODS: A computerized literature search was conducted on PubMed, Google Scholar, and Cochrane for articles published until November 2020. The online screening process was performed by 3 independent reviewers with the Covidence tool against set inclusion/exclusion criteria. The protocol was reported using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol. The study was registered with the International Prospective Register of Systematic Reviews (PROSPERO). RESULTS: A total of 12 studies were included for analysis. Scald burns via forced immersion accounted for the majority of reported PNABs affecting both feet and hands. Complications included wound infection, sepsis, requiring systemic antibiotics, or intensive care. Abused children's parents had a history of mental illness, unemployment, substance abuse, incarceration, and/or low annual income. CONCLUSIONS: Scalds via forced immersion remain the most common mechanism of PNABs. All health care professionals must remain vigilant, be able to recognize subtle signs of abuse, triage patients appropriately, report to police and/or social services, and ensure no further harm is made to the child or children. Repeated abuse with burns can lead to death. Prevention and education are the cornerstones for addressing this social phenomenon.

Biased competition in the absence of input bias revealed through corticostriatal computation.

Classical accounts of biased competition require an input bias to resolve the competition between neuronal ensembles driving downstream processing. However, flexible and reliable selection of behaviorally relevant ensembles can occur with unbiased stimulation: striatal D1 and D2 spiny projection neurons (SPNs) receive balanced cortical input, yet their activity determines the choice between GO and NO-GO pathways in the basal ganglia. We here present a corticostriatal model identifying three mechanisms that rely on physiological asymmetries to effect rate- and time-coded biased competition in the presence of balanced inputs. First, tonic input strength determines which one of the two SPN phenotypes exhibits a higher mean firing rate. Second, low-strength oscillatory inputs induce higher firing rate in D2 SPNs but higher coherence between D1 SPNs. Third, high-strength inputs oscillating at distinct frequencies can preferentially activate D1 or D2 SPN populations. Of these mechanisms, only the latter accommodates observed rhythmic activity supporting rule-based decision making in prefrontal cortex.

'Love makes me feel good inside and my heart is fixed': What adults with intellectual disabilities have to say about love and relationships.

BACKGROUND: Adults with intellectual disabilities have historically been hindered, rather than supported, in their desire to form loving relationships. This paper sought to explore with them what kinds of support they wanted in the 21st Century. METHOD: Semi-structured in-depth interviews were conducted with 40 adults with intellectual disabilities in the United Kingdom. RESULTS: Participants placed a high value on having a partner and being supported to maintain and develop a loving relationship. The factors which constrained them in achieving this included a lack of social opportunities, barriers created by social care services and limits on them exercising autonomy. Facilitating factors included access to specialist dating agencies, strong family and staff support and opportunities to learn about relationships. CONCLUSIONS: The importance of a loving relationship as a source of pleasure and meaning in the lives of adults with intellectual disabilities who are often disadvantaged in many other spheres of life is emphasised.

A biophysical model of striatal microcircuits suggests gamma and beta oscillations interleaved at delta/theta frequencies mediate periodicity in motor control.

Striatal oscillatory activity is associated with movement, reward, and decision-making, and observed in several interacting frequency bands. Local field potential recordings in rodent striatum show dopamine- and reward-dependent transitions between two states: a "spontaneous" state involving ß (∼15-30 Hz) and low γ (∼40-60 Hz), and a state involving θ (∼4-8 Hz) and high γ (∼60-100 Hz) in response to dopaminergic agonism and reward. The mechanisms underlying these rhythmic dynamics, their interactions, and their functional consequences are not well understood. In this paper, we propose a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms, as well as their modulation by dopamine. Building on previous modeling and experimental work suggesting that striatal projection neurons (SPNs) are capable of generating ß oscillations, we show that networks of striatal fast-spiking interneurons (FSIs) are capable of generating δ/θ (ie, 2 to 6 Hz) and γ rhythms. Under simulated low dopaminergic tone our model FSI network produces low γ band oscillations, while under high dopaminergic tone the FSI network produces high γ band activity nested within a δ/θ oscillation. SPN networks produce ß rhythms in both conditions, but under high dopaminergic tone, this ß oscillation is interrupted by δ/θ-periodic bursts of γ-frequency FSI inhibition. Thus, in the high dopamine state, packets of FSI γ and SPN ß alternate at a δ/θ timescale. In addition to a mechanistic explanation for previously observed rhythmic interactions and transitions, our model suggests a hypothesis as to how the relationship between dopamine and rhythmicity impacts motor function. We hypothesize that high dopamine-induced periodic FSI γ-rhythmic inhibition enables switching between ß-rhythmic SPN cell assemblies representing the currently active motor program, and thus that dopamine facilitates movement in part by allowing for rapid, periodic shifts in motor program execution.

Enhanced Recovery After Surgery Protocol With Ultrasound-Guided Regional Blocks in Outpatient Plastic Surgery Patients Leads to Decreased Opioid Prescriptions and Consumption.

BACKGROUND: Opioids are a mainstay of pain management. To limit the use of opioids, enhanced recovery after surgery (ERAS) protocols implement multimodal approaches to treat postoperative pain. OBJECTIVES: The aim of this paper was to be the first to assess the efficacy of an ERAS protocol for plastic surgery outpatients that includes ultrasound-guided, surgeon-led regional blocks. METHODS: A retrospective review of patients undergoing outpatient plastic surgery on an ERAS protocol was performed. These patients were compared to a well-matched group not on an ERAS protocol (pre-ERAS). Endpoints included the amounts of opioid, antinausea, and antispasmodic medication prescribed. ERAS patients were given a postoperative questionnaire to assess both pain levels (0-10) and opioid consumption. ERAS patients anticipated to have higher levels of pain received ultrasound-guided anesthetic blocks. RESULTS: There were 157 patients in the pre-ERAS group and 202 patients in the ERAS group. Patients in the pre-ERAS group were prescribed more opioid (332.3 vs 100.3 morphine milligram equivalents (MME)/patient; P < 0.001), antinausea (664 vs 16.3 mg of promethazine/patient; P < 0.001), and antispasmodic (401.3 vs 31.2 mg of cyclobenzaprine/patient; P < 0.001) medication. Patients on the ERAS protocol consumed an average total of 22.7 MME/patient postoperatively. Average pain scores in this group peaked at 5.32 on postoperative day 1 and then decreased significantly daily. CONCLUSIONS: Implementation of an ERAS protocol for plastic surgery outpatients with utilization of ultrasound-guided regional anesthetic blocks is feasible and efficacious. The ability to significantly decrease prescribed opioids in this unique patient population is noteworthy.

Risk of forced marriage amongst people with learning disabilities in the UK: Perspectives of South Asian carers.

BACKGROUND: People with intellectual disabilities are at increased risk of forced marriage compared to those without intellectual disabilities. In the UK, this risk is particularly, though not exclusively, associated with South Asian communities and is linked to the desire to secure long-term care. METHOD: Focus groups and semi-structured interviews were undertaken with South Asian parents and family carers (n = 22) of adults with intellectual disability and the resultant data thematically analysed. RESULTS: Although securing care for their intellectually disabled relative was identified as a key motivator for forced marriage, other important themes also emerged. These included cultural and religious beliefs about disability and marriage, and limited understanding of relevant laws. Factors militating against forced marriage were also identified, including fears of abuse and neglect. CONCLUSIONS: Implications for the provision of services and the need for improved access to information on forced marriage of people with intellectual disabilities are highlighted.

Social networks and people with intellectual disabilities: A systematic review.

BACKGROUND: Despite the importance of social networks for health and well-being, relatively little is known about the ways in which adults with intellectual disabilities in the U.K. experience their social networks. METHOD: A systematic review was completed to identify research focused on the social networks of adults with intellectual disabilities. Studies published from 1990 to 2019 were identified. Studies were thematically analysed. RESULTS: Quantitative, qualitative and mixed methods studies were analysed to identify key factors influencing social networks. Experiences of people with intellectual disabilities identified themes of identity, powerlessness, inclusion, family and support. These themes are discussed with reference to theories of stigma and normalisation. CONCLUSIONS: Stigma and normalisation can be used to better understand the needs, desires and dreams of people with intellectual disabilities for ordinary relationships, from which they are regularly excluded. Implications for policy and practice are discussed in relation to building and repairing often spoiled identities.

Oral Ondansetron to Reduce Vomiting in Children Receiving Intranasal Fentanyl and Inhaled Nitrous Oxide for Procedural Sedation and Analgesia: A Randomized Controlled Trial.

STUDY OBJECTIVE: Intranasal fentanyl and inhaled nitrous oxide are increasingly combined to provide procedural sedation and analgesia in the pediatric emergency setting. This regimen is attractive because of its nonparenteral administration, but is associated with a higher incidence of vomiting than nitrous oxide alone. We seek to assess whether prophylactic oral ondansetron use could reduce the incidence of vomiting associated with intranasal fentanyl and nitrous oxide for procedural sedation compared with placebo. METHODS: This was a double-blind, randomized controlled trial of oral ondansetron versus placebo conducted at a single tertiary care pediatric emergency department. Children aged 3 to 18 years with planned sedation with intranasal fentanyl and nitrous oxide were randomized to receive oral ondansetron or placebo 30 to 60 minutes before nitrous oxide administration. The primary outcome was early vomiting associated with procedural sedation, defined as occurring during or up to 1 hour after nitrous oxide administration. Secondary outcomes included vomiting 1 to 24 hours after procedural sedation, procedural sedation duration, adverse events, and quality of sedation across the 2 groups. RESULTS: We recruited 442 participants and 436 were included for analysis. There was no significant difference in the primary outcome, early vomiting associated with procedural sedation, between the groups: ondansetron 12% versus placebo 16%, with a difference in proportions of -4.6% (95% confidence interval -11% to 2.0%; P=.18). Most sedations were reported as optimal by treating clinicians (91%). Only 2 minor adverse events occurred, both in the placebo group. CONCLUSION: Oral ondansetron does not significantly reduce vomiting during or shortly after procedural sedation with combined intranasal fentanyl and inhaled nitrous oxide.

Portable Color-Flow Ultrasound Facilitates Precision Flap Planning and Perforator Selection in Reconstructive Plastic Surgery.

BACKGROUND: Precise flap planning and perforator selection are paramount for successful perforator flap surgery. Portable color-flow ultrasound (PCFU) is a convenient, low-cost, easily accessible imaging modality that is pivotal in the planning of perforator flaps where anatomic variability is the rule. METHODS: Perforator mapping was performed using an L12-4 linear-array ultrasound probe connected to an Android tablet. Images were obtained with the Lumify app (Philips Lumify, usa.philips.com). Perforator characteristics were recorded (arterial diameter, emergence points from fascia, subcutaneous course, and projection onto the skin surface) using still images and real-time videos. RESULTS: Thirty consecutive patients had 40 perforator or musculocutaneous flap reconstructions over a 2-year period. For the 15 flaps that had preoperative computed tomographic angiography (CTA) imaging, the preoperative sonographic measurements correlated with CTA and intraoperative findings. Portable color-flow ultrasound allowed perforator flap design and selection based on the largest available perforator, the most appropriate flap thickness, and comparison of multiple donor sites including left versus right. Two deep inferior epigastric perforator patients required take-back to the operating room for debridement of devitalized nonflap tissue. The superior gluteal artery perforator flap was abandoned intraoperatively due to proximal vascular anomalies. Overall flap success rate was 98% (39/40 flaps). CONCLUSIONS: Our experience with PCFU has rapidly improved, allowing individualized perforator flap selection and design based on each patient's unique perforator anatomy, reconstructive requirements, and donor site characteristics. In our practice, PCFU has supplemented CTA and in many cases has supplanted CTA as the primary imaging modality of choice in the planning of perforator flap reconstruction.

Preoperative Evaluation of the Superficial Fascial System Can Predict Wound Complications in Body Contouring Surgery.

BACKGROUND: The demand for body contouring surgery continues to rise. The inclusion of the superficial fascial system (SFS) during closure of such procedures has been shown to improve outcomes; however, currently reported wound complication rates remain high. The authors assess whether decreased quantities of SFS are associated with wound complications in these patients. METHODS: A retrospective study of patients undergoing body contouring surgery was performed. Preoperatively, ultrasound images were obtained of the SFS. Using Cellprofiler, the mean gray values (MGVs) of the SFS were calculated to quantify this structure. Chart review was performed to identify postoperative wound complications. RESULTS: Thirty-six patients were included: 30 abdominoplasties, 3 bilateral medial thigh lifts, and 3 bilateral brachioplasties. The overall wound complication rate was 22.5%. There were no significant differences in body mass index, age, smoking status, weight of resected specimen, or diabetes when comparing the complication and noncomplication groups. However, the MGV was significantly greater in the noncomplication group compared with the complication group (0.135 ± 0.008 vs 0.099 ± 0.005, respectively, P = 0.03). The average MGV for the entire cohort was 0.127. Patients with an MGV of greater than 0.127 had a wound complication rate of 0% compared with that of 39% for patients with an MGV of 0.127 or less (P = 0.005). CONCLUSIONS: Poor quantities of SFS identified by ultrasound were associated with increased wound complications in patients undergoing body contouring surgery. Furthermore, patients with better than average SFS seem to be protected from such complications.

Specialist hospital treatment and care as reported by children with intellectual disabilities and a cleft lip and/or palate, their parents and healthcare professionals.

BACKGROUND: Research into hospital treatment and care of children with intellectual disabilities is extremely limited, but available literature points to difficulties. Some children have a co-occurring condition alongside an intellectual disability which requires ongoing treatment, such as a cleft lip/palate. To date, their experiences remain untapped. METHOD: Semi-structured interviews with 23 participants; five children with intellectual disabilities (aged 11-16), their parents (n = 9) and nine healthcare professionals working in cleft care. Thematic analysis determined patterns across the data. RESULTS: Three key themes were found: struggles (stress and distress, and power imbalance), tensions (perceived levels of choice and control in decision making, lack of training around intellectual disability assumptions and jargon) and good practice (appropriate communication and information, and tailored treatment). CONCLUSION: Good practice was evident, but was ad hoc. Individualized treatment and communication based upon children's needs are required as is further investigation into general anaesthetic induction for children with intellectual disabilities.

Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits.

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.

"Put bluntly, they are targeted by the worst creeps society has to offer": Police and professionals' views and actions relating to domestic violence and women with intellectual disabilities.

BACKGROUND: Little is known about the attitudes and practices of key personnel towards the domestic violence experienced by women with intellectual disabilities. METHOD: An online survey was conducted of Police officers and health and social care professionals. A total of 717 Police and other professionals across a wide variety of UK sites responded. Research questions were focussed on direct experience, attitudes and responses. RESULTS: Approximately half of all respondents had direct experience of working with a woman with intellectual disabilities who had been through domestic violence. Professionals were more likely than the Police to see women with intellectual disabilities as being especially vulnerable. The majority of both professionals and Police believed women with intellectual disabilities were deliberately targeted by violent and abusive men. CONCLUSIONS: More training is needed for both the Police and health and social care professionals specifically in domestic violence as it affects women with intellectual disabilities.

Striatal cholinergic receptor activation causes a rapid, selective and state-dependent rise in cortico-striatal ß activity.

Cortico-basal ganglia-thalamic (CBT) ß oscillations (15-30 Hz) are elevated in Parkinson's disease and correlated with movement disability. To date, no experimental paradigm outside of loss of dopamine has been able to specifically elevate ß oscillations in the CBT loop. Here, we show that activation of striatal cholinergic receptors selectively increased ß oscillations in mouse striatum and motor cortex. In individuals showing simultaneous ß increases in both striatum and M1, ß partial directed coherence (PDC) increased from striatum to M1 (but not in the reverse direction). In individuals that did not show simultaneous ß increases, ß PDC increased from M1 to striatum (but not in the reverse direction), and M1 was characterized by persistent ß-high frequency oscillation phase-amplitude coupling. Finally, the direction of ß PDC distinguished between ß sub-bands. This suggests that (1) striatal cholinergic tone exerts state-dependent and frequency-selective control over CBT ß power and coordination; (2) ongoing rhythmic dynamics can determine whether elevated ß oscillations are expressed in striatum and M1; and (3) altered striatal cholinergic tone differentially modulates distinct ß sub-bands.

Thalamocortical control of propofol phase-amplitude coupling.

The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.