Mechanical Patterning in Animal Morphogenesis.

Morphogenesis is one of the most remarkable examples of biological pattern formation. Despite substantial progress in the field, we still do not understand the organizational principles responsible for the robust convergence of the morphogenesis process across scales to form viable organisms under variable conditions. Achieving large-scale coordination requires feedback between mechanical and biochemical processes, spanning all levels of organization and relating the emerging patterns with the mechanisms driving their formation. In this review, we highlight the role of mechanics in the patterning process, emphasizing the active and synergistic manner in which mechanical processes participate in developmental patterning rather than merely following a program set by biochemical signals. We discuss the value of applying a coarse-grained approach that considers the large-scale dynamics and feedback and complements the reductionist approach focused on molecular detail. A central challenge in this approach is identifying relevant coarse-grained variables and developing effective theories that can serve as a basis for an integrated framework toward understanding this remarkable pattern-formation process.

Real-Time Genetic Compensation Defines the Dynamic Demands of Feedback Control.

Biological signaling networks use feedback control to dynamically adjust their operation in real time. Traditional static genetic methods such as gene knockouts or rescue experiments can often identify the existence of feedback interactions but are unable to determine what feedback dynamics are required. Here, we implement a new strategy, closed-loop optogenetic compensation (CLOC), to address this problem. Using a custom-built hardware and software infrastructure, CLOC monitors, in real time, the output of a pathway deleted for a feedback regulator. A minimal model uses these measurements to calculate and deliver-on the fly-an optogenetically enabled transcriptional input designed to compensate for the effects of the feedback deletion. Application of CLOC to the yeast pheromone response pathway revealed surprisingly distinct dynamic requirements for three well-studied feedback regulators. CLOC, a marriage of control theory and traditional genetics, presents a broadly applicable methodology for defining the dynamic function of biological feedback regulators.

Topological wetting states of microdroplets on closed-loop structured surfaces: Breakdown of the Gibbs equation at the microscale.

Microdroplets are a class of soft matter that has been extensively employed for chemical, biochemical, and industrial applications. However, fabricating microdroplets with largely controllable contact-area shape and apparent contact angle, a key prerequisite for their applications, is still a challenge. Here, by engineering a type of surface with homocentric closed-loop microwalls/microchannels, we can achieve facile size, shape, and contact-angle tunability of microdroplets on the textured surfaces by design. More importantly, this class of surface topologies (with universal genus value = 1) allows us to reveal that the conventional Gibbs equation (widely used for assessing the edge effect on the apparent contact angle of macrodroplets) seems no longer applicable for water microdroplets or nanodroplets (evidenced by independent molecular dynamics simulations). Notably, for the flat surface with the intrinsic contact angle ~0°, we find that the critical contact angle on the microtextured counterparts (at edge angle 90°) can be as large as >130°, rather than 90° according to the Gibbs equation. Experiments show that the breakdown of the Gibbs equation occurs for microdroplets of different types of liquids including alcohol and hydrocarbon oils. Overall, the microtextured surface design and topological wetting states not only offer opportunities for diverse applications of microdroplets such as controllable chemical reactions and low-cost circuit fabrications but also provide testbeds for advancing the fundamental surface science of wetting beyond the Gibbs equation.

Spatial Organization of Single mRNPs at Different Stages of the Gene Expression Pathway.

mRNAs form ribonucleoprotein complexes (mRNPs) by association with proteins that are crucial for mRNA metabolism. While the mRNP proteome has been well characterized, little is known about mRNP organization. Using a single-molecule approach, we show that mRNA conformation changes depending on its cellular localization and translational state. Compared to nuclear mRNPs and lncRNPs, association with ribosomes decompacts individual mRNAs, while pharmacologically dissociating ribosomes or sequestering them into stress granules leads to increased compaction. Moreover, translating mRNAs rarely show co-localized 5' and 3' ends, indicating either that mRNAs are not translated in a closed-loop configuration, or that mRNA circularization is transient, suggesting that a stable closed-loop conformation is not a universal state for all translating mRNAs.

Closed-loop fluid-fluid immiscibility in binary lipid-sterol membranes.

We present two binary lipid-sterol membrane systems that exhibit fluid-fluid coexistence. Partial phase diagrams of binary mixtures of dimyristoylphosphatidylcholine with 25-hydroxyxholesterol and 27-hydroxycholesterol, determined from small-angle X-ray scattering and fluorescence microscopy studies, show closed-loop fluid-fluid immiscibility gaps, with the appearance of a single fluid phase both at higher and lower temperatures. Computer simulations suggest that this unusual phase behavior results from the ability of these oxysterol molecules to take different orientations in the membrane depending on the temperature.

Closed-loop network of skin-interfaced wireless devices for quantifying vocal fatigue and providing user feedback.

Vocal fatigue is a measurable form of performance fatigue resulting from overuse of the voice and is characterized by negative vocal adaptation. Vocal dose refers to cumulative exposure of the vocal fold tissue to vibration. Professionals with high vocal demands, such as singers and teachers, are especially prone to vocal fatigue. Failure to adjust habits can lead to compensatory lapses in vocal technique and an increased risk of vocal fold injury. Quantifying and recording vocal dose to inform individuals about potential overuse is an important step toward mitigating vocal fatigue. Previous work establishes vocal dosimetry methods, that is, processes to quantify vocal fold vibration dose but with bulky, wired devices that are not amenable to continuous use during natural daily activities; these previously reported systems also provide limited mechanisms for real-time user feedback. This study introduces a soft, wireless, skin-conformal technology that gently mounts on the upper chest to capture vibratory responses associated with vocalization in a manner that is immune to ambient noises. Pairing with a separate, wirelessly linked device supports haptic feedback to the user based on quantitative thresholds in vocal usage. A machine learning-based approach enables precise vocal dosimetry from the recorded data, to support personalized, real-time quantitation and feedback. These systems have strong potential to guide healthy behaviors in vocal use.

Closed-loop recyclable membranes enabled by covalent adaptable networks for water purification.

In the state-of-the-art membrane industry, membranes have linear life cycles and are commonly disposed of by landfill or incineration, sacrificing their sustainability. To date, little or no thought is given in the design phase to the end-of-life management of membranes. For the first time, we have innovated high-performance sustainable membranes, which can be closed-loop recycled after long-term usage for water purification. By synergizing membrane technology and dynamic covalent chemistry, covalent adaptable networks (CANs) with thermally reversible Diels-Alder (DA) adducts were synthesized and employed to fabricate integrally skinned asymmetric membranes via the nonsolvent-induced phase separation technique. Due to the stable and reversible features of CAN, the closed-loop recyclable membranes exhibit excellent mechanical properties and thermal and chemical stabilities as well as separation performance, which are comparable to or even higher than the state-of-the-art nonrecyclable membranes. Moreover, the used membranes can be closed-loop recycled with consistent properties and separation performance by depolymerization to remove contaminants, followed by refabrication into new membranes through the dissociation and reformation of DA adducts. This study may fill in the gaps in closed-loop recycling of membranes and inspire the advancement of sustainable membranes for a green membrane industry.

Closed-loop stimulation in periods with less epileptiform activity drives improved epilepsy outcomes.

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states-that is, stimulation during periods with a lower or higher risk of generating epileptiform activity-in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states and out of rhythmic high-risk states predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super-responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction.

On-demand low-frequency stimulation for seizure control: efficacy and behavioural implications.

Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults, is often refractory to medication and associated with hippocampal sclerosis. Deep brain stimulation represents an alternative treatment option for drug-resistant patients who are ineligible for resective brain surgery. In clinical practice, closed-loop stimulation at high frequencies is applied to interrupt ongoing seizures, yet has (i) a high incidence of false detections; (ii) the drawback of delayed seizure-suppressive intervention; and (iii) limited success in sclerotic tissue. As an alternative, low-frequency stimulation (LFS) has been explored recently in patients with focal epilepsies. In preclinical epilepsy models, hippocampal LFS successfully prevented seizures when applied continuously. Since it would be advantageous to reduce the stimulation load, we developed a protocol for on-demand LFS. Given the importance of the hippocampus for navigation and memory, we investigated potential consequences of LFS on hippocampal function. To this end, we used the intrahippocampal kainate mouse model, which recapitulates the key features of MTLE, including spontaneous seizure activity and hippocampal sclerosis. Specifically, our online detection algorithm monitored epileptiform activity in hippocampal local field potential recordings and identified short epileptiform bursts preceding focal seizure clusters, triggering hippocampal LFS to stabilize the network state. To probe behavioural performance, we tested the acute influence of LFS on anxiety-like behaviour in the light-dark box test, spatial and non-spatial memory in the object location memory and novel object recognition test, as well as spatial navigation and long-term memory in the Barnes maze. On-demand LFS was almost as effective as continuous LFS in preventing focal seizure clusters but with a significantly lower stimulation load. When we compared the behavioural performance of chronically epileptic mice to healthy controls, we found that both groups were equally mobile, but epileptic mice displayed an increased anxiety level, altered spatial learning strategy and impaired memory performance. Most importantly, with the application of hippocampal LFS before behavioural training and test sessions, we could rule out deleterious effects on cognition and even show an alleviation of deficits in long-term memory recall in chronically epileptic mice. Taken together, our findings may provide a promising alternative to current therapies, overcoming some of their major limitations, and inspire further investigation of LFS for seizure control in focal epilepsy syndromes.

State-dependent effects of responsive neurostimulation depend on seizure localization.

Brain-responsive neurostimulation is firmly ensconced among treatment options for drug-resistant focal epilepsy, but over a quarter of patients treated with the RNS System do not experience meaningful seizure reduction. Initial titration of RNS therapy is typically similar for all patients, raising the possibility that treatment response might be enhanced by consideration of patient-specific variables. Indeed, small, single-center studies have yielded preliminary evidence that RNS System effectiveness depends on the brain state during which stimulation is applied. The generalizability of these findings remains unclear, however, and it is unknown whether state-dependent effects of responsive neurostimulation are also stratified by location of the seizure onset zone where stimulation is delivered. We aimed to determine whether state-dependent effects of the RNS System are evident in the large, diverse, multi-center cohort of RNS System clinical trial participants and to test whether these effects differ between mesiotemporal and neocortical epilepsies. Eighty-one of 256 patients who were treated with the RNS System across 31 centers during clinical trials met criteria for inclusion in this retrospective study. Risk states were defined in relation to phases of daily and multi-day cycles of interictal epileptiform activity that are thought to determine seizure likelihood. We found that the probabilities of risk state transitions depended on the stimulation parameter being changed, the starting seizure risk state, and the stimulated brain region. Changes in two commonly adjusted stimulation parameters, charge density and stimulation frequency, produced opposite effects on risk state transitions depending on seizure localization. Greater variance in acute risk state transitions was explained by state-dependent responsive neurostimulation for bipolar stimulation for neocortical epilepsies and for monopolar stimulation for mesiotemporal epilepsies. Variability in effectiveness of RNS System therapy across individuals may relate, at least partly, to the fact that current treatment paradigms do not account fully for fluctuations in brain states or locations of simulation sites. State-dependence of electrical brain stimulation may inform development of next-generation closed-loop devices that can detect changes in brain state and deliver adaptive, localization-specific patterns of stimulation to maximize therapeutic effects.

Shaping overnight consolidation via slow-oscillation closed-loop targeted memory reactivation.

Sleep constitutes a privileged state for new memories to reactivate and consolidate. Previous work has demonstrated that consolidation can be bolstered experimentally either via delivery of reminder cues (targeted memory reactivation [TMR]) or via noninvasive brain stimulation geared toward enhancing endogenous sleep rhythms. Here, we combined both approaches, controlling the timing of TMR cues with respect to ongoing slow-oscillation (SO) phases. Prior to sleep, participants learned associations between unique words and a set of repeating images (e.g., car) while hearing a prototypical image sound (e.g., engine starting). Memory performance on an immediate test vs. a test the next morning quantified overnight memory consolidation. Importantly, two image sounds were designated as TMR cues, with one cue delivered at SO UP states and the other delivered at SO DOWN states. A novel sound was used as a TMR control condition. Behavioral results revealed a significant reduction of overnight forgetting for words associated with UP-state TMR compared with words associated with DOWN-state TMR. Electrophysiological results showed that UP-state cueing led to enhancement of the ongoing UP state and was followed by greater spindle power than DOWN-state cueing. Moreover, UP-state (and not DOWN-state) cueing led to reinstatement of target image representations. Together, these results unveil the behavioral and mechanistic effects of delivering reminder cues at specific phases of endogenous sleep rhythms and mark an important step for the endeavor to experimentally modulate memories during sleep.

The role of automated insulin delivery technology in diabetes.

The role of automated insulin delivery systems in diabetes is expanding. Hybrid closed-loop systems are being used in routine clinical practice for treating people with type 1 diabetes. Encouragingly, real-world data reflects the performance and usability observed in clinical trials. We review the commercially available hybrid closed-loop systems, their distinctive features and the associated real-world data. We also consider emerging indications for closed-loop systems, including the treatment of type 2 diabetes where variability of day-to-day insulin requirements is high, and other challenging applications for this technology. We discuss issues around access and implementation of closed-loop technology, and consider the limitations of present closed-loop systems, as well as innovative approaches that are being evaluated to improve their performance.

Glycaemic patterns during breastfeeding with postpartum use of closed-loop insulin delivery in women with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to describe the relationship between breastfeeding episodes and maternal glucose levels, and to assess whether this differs with closed-loop vs open-loop (sensor-augmented pump) insulin therapy. METHODS: Infant-feeding diaries were collected at 6 weeks, 12 weeks and 24 weeks postpartum in a trial of postpartum closed-loop use in 18 women with type 1 diabetes. Continuous glucose monitoring (CGM) data were used to identify maternal glucose patterns within the 3 h of breastfeeding episodes. Generalised mixed models adjusted for breastfeeding episodes in the same woman, repeat breastfeeding episodes, carbohydrate intake, infant age at time of feeding and early pregnancy HbA1c. This was a secondary analysis of data collected during a randomised trial (ClinicalTrials.gov registration no. NCT04420728). RESULTS: CGM glucose remained above 3.9 mmol/l in the 3 h post-breastfeeding for 93% (397/427) of breastfeeding episodes. There was an overall decrease in glucose at nighttime within 3 h of breastfeeding (1.1 mmol l-1 h-1 decrease on average; p=0.009). A decrease in nighttime glucose was observed with open-loop therapy (1.2 ± 0.5 mmol/l) but was blunted with closed-loop therapy (0.4 ± 0.3 mmol/l; p<0.01, open-loop vs closed-loop). CONCLUSIONS/INTERPRETATION: There is a small decrease in glucose after nighttime breastfeeding that usually does not result in maternal hypoglycaemia; this appears to be blunted with the use of closed-loop therapy.

Technology advances in diabetes pregnancy: right technology, right person, right time.

This review outlines some of the extraordinary recent advances in diabetes technology, which are transforming the management of type 1 diabetes before, during and after pregnancy. It highlights recent improvements associated with use of continuous glucose monitoring (CGM) but acknowledges that neither CGM nor insulin pump therapy are adequate for achieving the pregnancy glucose targets. Furthermore, even hybrid closed-loop (HCL) systems that are clinically effective outside of pregnancy may not confer additional benefits throughout pregnancy. To date, there is only one HCL system, the CamAPS FX, with a strong evidence base for use during pregnancy, suggesting that the pregnancy benefits are HCL system specific. This is in stark contrast to HCL system use outside of pregnancy, where benefits are HCL category specific. The CamAPS FX HCL system has a rapidly adaptive algorithm and lower glucose targets with benefits across all maternal glucose categories, meaning that it is applicable for all women with type 1 diabetes, before and during pregnancy. For women of reproductive years living with type 2 diabetes, the relative merits of using non-insulin pharmacotherapies vs diabetes technology (dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors) are unknown. Despite the urgent unmet need and potential benefits, studies of pharmacotherapy and technology use are extremely limited in pregnant women with type 2 diabetes.

Comparison between a tubeless, on-body automated insulin delivery system and a tubeless, on-body sensor-augmented pump in type 1 diabetes: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: This study compares the efficacy and safety of a tubeless, on-body automated insulin delivery (AID) system with that of a tubeless, on-body sensor-augmented pump (SAP). METHODS: This multicentre, parallel-group, RCT was conducted at 13 tertiary medical centres in South Korea. Adults aged 19-69 years with type 1 diabetes who had HbA1c levels of <85.8 mmol/mol (<10.0%) were eligible. The participants were assigned at a 1:1 ratio to receive a tubeless, on-body AID system (intervention group) or a tubeless, on-body SAP (control group) for 12 weeks. Stratified block randomisation was conducted by an independent statistician. Blinding was not possible due to the nature of the intervention. The primary outcome was the percentage of time in range (TIR), blood glucose between 3.9 and 10.0 mmol/l, as measured by continuous glucose monitoring. ANCOVAs were conducted with baseline values and study centres as covariates. RESULTS: A total of 104 participants underwent randomisation, with 53 in the intervention group and 51 in the control group. The mean (±SD) age of the participants was 40±11 years. The mean (±SD) TIR increased from 62.1±17.1% at baseline to 71.5±10.7% over the 12 week trial period in the intervention group and from 64.7±17.0% to 66.9±15.0% in the control group (difference between the adjusted means: 6.5% [95% CI 3.6%, 9.4%], p<0.001). Time below range, time above range, CV and mean glucose levels were also significantly better in the intervention group compared with the control group. HbA1c decreased from 50.9±9.9 mmol/mol (6.8±0.9%) at baseline to 45.9±7.4 mmol/mol (6.4±0.7%) after 12 weeks in the intervention group and from 48.7±9.1 mmol/mol (6.6±0.8%) to 45.7±7.5 mmol/mol (6.3±0.7%) in the control group (difference between the adjusted means: -0.7 mmol/mol [95% CI -2.0, 0.8 mmol/mol] (-0.1% [95% CI -0.2%, 0.1%]), p=0.366). No diabetic ketoacidosis or severe hypoglycaemia events occurred in either group. CONCLUSIONS/INTERPRETATION: The use of a tubeless, on-body AID system was safe and associated with superior glycaemic profiles, including TIR, time below range, time above range and CV, than the use of a tubeless, on-body SAP. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0008398 FUNDING: The study was funded by a grant from the Korea Medical Device Development Fund supported by the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare; and the Ministry of Food and Drug Safety (grant number: RS-2020-KD000056).

Applying technologies to simplify strategies for exercise in type 1 diabetes.

Challenges and fears related to managing glucose levels around planned and spontaneous exercise affect outcomes and quality of life in people living with type 1 diabetes. Advances in technology, including continuous glucose monitoring, open-loop insulin pump therapy and hybrid closed-loop (HCL) systems for exercise management in type 1 diabetes, address some of these challenges. In this review, three research or clinical experts, each living with type 1 diabetes, leverage published literature and clinical and personal experiences to translate research findings into simplified, patient-centred strategies. With an understanding of limitations in insulin pharmacokinetics, variable intra-individual responses to aerobic and anaerobic exercise, and the features of the technologies, six steps are proposed to guide clinicians in efficiently communicating simplified actions more effectively to individuals with type 1 diabetes. Fundamentally, the six steps centre on two aspects. First, regardless of insulin therapy type, and especially needed for spontaneous exercise, we provide an estimate of glucose disposal into active muscle meant to be consumed as extra carbohydrates for exercise ('ExCarbs'; a common example is 0.5 g/kg body mass per hour for adults and 1.0 g/kg body mass per hour for youth). Second, for planned exercise using open-loop pump therapy or HCL systems, we additionally recommend pre-emptive basal insulin reduction or using HCL exercise modes initiated 90 min (1-2 h) before the start of exercise until the end of exercise. Modifications for aerobic- and anaerobic-type exercise are discussed. The burden of pre-emptive basal insulin reductions and consumption of ExCarbs are the limitations of HCL systems, which may be overcome by future innovations but are unquestionably required for currently available systems.

Ageing well with diabetes: the role of technology.

Over the past two decades there has been a substantial rise in the adoption of diabetes therapeutic technology among children, adolescents and younger adults with type 1 diabetes, and its use is now also advocated for older individuals. Older people with diabetes are more prone to experience hypoglycaemia because of numerous predisposing factors and are at higher risk of hypoglycaemic events requiring third-party assistance as well as other adverse sequelae. Hypoglycaemia may also have long-term consequences, including cognitive impairment, frailty and disability. Diabetes in older people is often characterised by marked glucose variability related to age-associated changes such as variable appetite and levels of physical activity, comorbidities and polypharmacotherapy. Preventing hypoglycaemia and mitigating glucose excursions may have considerable positive impacts on physical and cognitive function and general well-being and may even prevent or improve frailty. Technology for older people includes continuous glucose monitoring systems, insulin pumps, automated insulin delivery systems and smart insulin pens. Clinical trials and real-world studies have shown that older people with diabetes benefit from technology in terms of glucose management, reductions in hypoglycaemic events, emergency department attendance and hospital admissions, and improvement in quality of life. However, ageing may bring physical impairments and other challenges that hinder the use of technology. Healthcare professionals should identify older adults with diabetes who may benefit from therapeutic technology and then adopt an individualised approach to education and follow-up for individuals and their caregivers. Future research should explore the impact of diabetes technology on outcomes relevant to older people with diabetes.

The use of technology in type 2 diabetes and prediabetes: a narrative review.

The increasing incidence of type 2 diabetes, which represents 90% of diabetes cases globally, is a major public health concern. Improved glucose management reduces the risk of vascular complications and mortality; however, only a small proportion of the type 2 diabetes population have blood glucose levels within the recommended treatment targets. In recent years, diabetes technologies have revolutionised the care of people with type 1 diabetes, and it is becoming increasingly evident that people with type 2 diabetes can also benefit from these advances. In this review, we describe the current knowledge regarding the role of technologies for people living with type 2 diabetes and the evidence supporting their use in clinical practice. We conclude that continuous glucose monitoring systems deliver glycaemic benefits for individuals with type 2 diabetes, whether treated with insulin or non-insulin therapy; further data are required to evaluate the role of these systems in those with prediabetes (defined as impaired glucose tolerance and/or impaired fasting glucose and/or HbA1c levels between 39 mmol/mol [5.7%] and 47 mmol/mol [6.4%]). The use of insulin pumps seems to be safe and effective in people with type 2 diabetes, especially in those with an HbA1c significantly above target. Initial results from studies exploring the impact of closed-loop systems in type 2 diabetes are promising. We discuss directions for future research to fully understand the potential benefits of integrating evidence-based technology into care for people living with type 2 diabetes and prediabetes.

Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation.

Millions of people suffer from dopamine-related disorders spanning disturbances in movement, cognition and emotion. These changes are often attributed to changes in striatal dopamine function. Thus, understanding how dopamine signalling in the striatum and basal ganglia shapes human behaviour is fundamental to advancing the treatment of affected patients. Dopaminergic neurons innervate large-scale brain networks, and accordingly, many different roles for dopamine signals have been proposed, such as invigoration of movement and tracking of reward contingencies. The canonical circuit architecture of cortico-striatal loops sparks the question, of whether dopamine signals in the basal ganglia serve an overarching computational principle. Such a holistic understanding of dopamine functioning could provide new insights into symptom generation in psychiatry to neurology. Here, we review the perspective that dopamine could bidirectionally control neural population dynamics, increasing or decreasing their strength and likelihood to reoccur in the future, a process previously termed neural reinforcement. We outline how the basal ganglia pathways could drive strengthening and weakening of circuit dynamics and discuss the implication of this hypothesis on the understanding of motor signs of Parkinson's disease (PD), the most frequent dopaminergic disorder. We propose that loss of dopamine in PD may lead to a pathological brain state where repetition of neural activity leads to weakening and instability, possibly explanatory for the fact that movement in PD deteriorates with repetition. Finally, we speculate on how therapeutic interventions such as deep brain stimulation may be able to reinstate reinforcement signals and thereby improve treatment strategies for PD in the future.

The neurophysiology of closed-loop auditory stimulation in sleep: A magnetoencephalography study.

Closed-loop auditory stimulation (CLAS) is a brain modulation technique in which sounds are timed to enhance or disrupt endogenous neurophysiological events. CLAS of slow oscillation up-states in sleep is becoming a popular tool to study and enhance sleep's functions, as it increases slow oscillations, evokes sleep spindles and enhances memory consolidation of certain tasks. However, few studies have examined the specific neurophysiological mechanisms involved in CLAS, in part because of practical limitations to available tools. To evaluate evidence for possible models of how sound stimulation during brain up-states alters brain activity, we simultaneously recorded electro- and magnetoencephalography in human participants who received auditory stimulation across sleep stages. We conducted a series of analyses that test different models of pathways through which CLAS of slow oscillations may affect widespread neural activity that have been suggested in literature, using spatial information, timing and phase relationships in the source-localized magnetoencephalography data. The results suggest that auditory information reaches ventral frontal lobe areas via non-lemniscal pathways. From there, a slow oscillation is created and propagated. We demonstrate that while the state of excitability of tissue in auditory cortex and frontal ventral regions shows some synchrony with the electroencephalography (EEG)-recorded up-states that are commonly used for CLAS, it is the state of ventral frontal regions that is most critical for slow oscillation generation. Our findings advance models of how CLAS leads to enhancement of slow oscillations, sleep spindles and associated cognitive benefits and offer insight into how the effectiveness of brain stimulation techniques can be improved.