Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Effects of Breastfeeding Promotion Intervention and Dietary Treatment in Postpartum Women with Overweight and Obesity: Results from a Randomized Controlled Trial on Weight and Cardiometabolic Risk Factors.

BACKGROUND: Childbearing increases the risk of weight gain and cardiometabolic disease. The reset hypothesis suggests that lactation has protective cardiometabolic effects on the mother. The hypothesis is based on observational studies, and the possible interacting role of weight loss needs to be elucidated. OBJECTIVES: This study aimed to examine the individual and interaction effects of a breastfeeding promotion intervention (BPI) and dietary intervention for weight loss postpartum (Diet) on body weight and cardiometabolic risk factors at 6 mo postpartum. METHODS: Pregnant women (n = 156) with a prepregnancy BMI of 25 to 35 kg/m2 were randomized to 4 groups in a 2 × 2 factorial design: BPI, Diet, both treatments, or no treatment. BPI consisted of individual counseling by a lactation consultant during pregnancy, at childbirth, and monthly thereafter or more frequently based on individual needs. Diet was initiated at 11 wk postpartum. Body weight, body composition, waist and hip circumferences, markers of lipid and glucose metabolism, and blood pressure were measured at 2 wk and 6 mo postpartum. We analyzed main and interaction effects using 2-way analysis of covariance adjusted for baseline values. RESULTS: Among the participants attending both visits (n = 108), 99% practiced any breastfeeding at baseline and 97% at follow-up. The BPI did not affect rates of exclusive or partial breastfeeding, age at introduction of complementary foods, or have main effects on body weight or cardiometabolic risk factors. There was a main effect of Diet reducing body weight, fat mass, fat-free mass, percentage fat mass, waist and hip circumferences, fasting glucose, and insulin (all P ≤ 0.03), with no interactions between the treatments. CONCLUSIONS: There were no effects of BPI on body weight or cardiometabolic risk factors at 6 mo postpartum. Diet caused weight loss and had favorable effects on risk factors for cardiovascular disease and type 2 diabetes. This study was registered at clinicaltrials.gov as NCT03580057.

The power of three: Atrial rate limit power-on-reset - A non-electromagnetic cause of pacemaker-induced extracardiac stimulation.

BACKGROUND: Power-on reset (PoR) is most commonly due to electromagnetic interference. Full PoR results in a switch to an inhibited mode (VVI) pacing and resets pacing outputs to maximal unipolar settings, leading to extracardiac stimulation. METHODS: We present a case of PoR occurrence in the absence of electromagnetic interference, resulting in pectoral stimulation triggered by violation of the atrial rate limit. CONCLUSIONS: It is useful for clinicians to recognizethe occurrence of PoR in the setting of atrial limit violation andthe appropriate management in such circumstances.

Neural Oscillations and Multisensory Processing.

Neural oscillations play a role in sensory processing by coordinating synchronized neuronal activity. Synchronization of gamma oscillations is engaged in local computation of feedforward signals and synchronization of alpha-beta oscillations is engaged in feedback processing over long-range areas. These spatially and spectrally segregated bi-directional signals may be integrated by a mechanism of cross-frequency coupling. Synchronization of neural oscillations has also been proposed as a mechanism for information integration across multiple sensory modalities. A transient stimulus or rhythmic stimulus from one modality may lead to phase alignment of ongoing neural oscillations in multiple sensory cortices, through a mechanism of cross-modal phase reset or cross-modal neural entrainment. Synchronized activities in multiple sensory cortices are more likely to boost stronger activities in downstream areas. Compared to synchronized oscillations, asynchronized oscillations may impede signal processing, and may contribute to sensory selection by setting the oscillations in the target-related cortex and the oscillations in the distractor-related cortex to opposite phases.

Early targeted heart rate exercise is safe and May hasten return-to-duty in service members with acute concussion, a preliminary study.

OBJECTIVE: To evaluate the feasibility of an exercise tolerance assessment and intervention added to the Progressive Return to Activity Clinical Recommendations (PRA-CR) in acutely concussed service members (SMs). METHODS: This non-randomized, pilot trial was performed at one center. SMs in the experimental group (ERG) performed the Buffalo Concussion March-in-place Test (BCMT) at every clinic visit and were prescribed at least 20 minutes/day of targeted exercise in addition to PRA-CR. Data for the control group (SCG) were extracted from the same clinic immediately prior to ERG. SMs in both groups were assessed by the same clinician to determine return-to-duty. RESULTS: BCMT identified concussion-related exercise intolerance in 100% (n = 14) at screening visit (mean 3.4 days after injury) and in 0% (n = 7) who had recovered. No adverse effects were associated with BCMT. The estimated recovery time for ERG who performed the exercise intervention (n = 12) was 17.0 (12.8, 21.2) days and for SCG (n = 15) was 23.7 (19.9, 27.5) days (p = 0.039). CONCLUSION: Assessment of exercise tolerance was feasible and could be incorporated into the PRA-CR. Future definitive, randomized controlled trials should be performed to assess the effectiveness of exercise reset program for SMs after concussion.

Modulating motor cortical oscillation with coordinated reset multifocal transcranial magnetic stimulation.

According to the theory of coordinated reset (CR) stimulation, multifocal bursts of stimuli delivered in a random order with a specific interval may reduce the resonance power of the oscillatory generator in the epicenter. We develop a noninvasive coordinated multifocal burst stimulation (COMBS) with three repetitive transcranial stimulation machines based on CR theory to modulate the target frequency in the primary motor cortex and to assess its effect on motor cortical excitability in separate experiments. Electroencephalography and electromyography were recorded in 16 healthy participants during a finger-tapping task, both before and after the intervention. The resting oscillatory power at the targeted frequency was not changed by COMBS. α-Band power was increased in both preparation and movement stages and the low ß-band power was increased in the movement stage of the finger tapping task. The extent of low ß-band event-related desynchronization was reduced by COMBS. There were no changes in reaction time, but there was a trend for a reduced error rate after COMBS. In another 14 healthy participants, there were no significant changes in cortical excitability before and after COMBS measured by rest motor threshold, short interval intracortical inhibition, short interval intracortical facilitation, and cortical silent period. The result indicates that COMBS may modify the cortical oscillatory power and its perturbation within specific movement stage.NEW & NOTEWORTHY This is the first study, to our knowledge, to apply coordinated reset (CR) neuromodulation to the motor cortex with three repetitive transcranial magnetic stimulation (rTMS) stimulators to assess its effect on cortical oscillation. The results revealed enhancement of α-band power specifically in preparation and movement stages and low ß-band power in the movement stage of a motor task. It postulated that CR stimulation may modify the motor cortical oscillation in the specific movement stages.

IPDT Model-Based Ziegler-Nichols Tuning Generalized to Controllers with Higher-Order Derivatives.

The paper extends the earlier work entitled "Making the PI and PID Controller Tuning Inspired by Ziegler and Nichols Precise and Reliable", to higher-order controllers and a broader range of experiments. The original series PI and PID controllers, based on automatic reset calculated by filtered controller outputs, are now augmented by higher-order output derivatives. This increases the number of degrees of freedom that can be used to modify the resulting dynamics, accelerates transient responses, and increases robustness to unmodeled dynamics and uncertainties. The fourth order noise attenuation filter used in the original work allows for the addition of an acceleration feedback signal, thus resulting in a series PIDA controller or even a jerk feedback that leads to a PIDAJ series controller. Such a design can further use the original process and filter approximation of the step responses through the integral-plus-dead-time (IPDT) model, while allowing experimentation with disturbance and setpoint step responses of the series PI, PID, PIDA and PIDAJ controllers, and thus, evaluating the role of output derivatives and noise attenuation from a broader perspective. All controllers considered are tuned using the Multiple Real Dominant Pole (MRDP) method, which is complemented by a factorization of the controller transfer functions to achieve the smallest possible time constant for automatic reset. The smallest time constant is chosen to improve the constrained transient response of the considered controller types. The obtained excellent performance and robustness allow the proposed controllers to be applied to a wider range of systems with dominant first-order dynamics. The proposed design is illustrated on a real-time speed control of a stable direct-current (DC) motor, which is approximated (together with a noise attenuation filter) by an IPDT model. The transient responses obtained are nearly time-optimal, with control signal limitations active for most setpoint step responses. Four controllers with different degrees of derivative with generalized automatic reset were used for comparison. It was found that controllers with higher-order derivatives may significantly improve the disturbance performance and virtually eliminate overshoots in the setpoint step responses in constrained velocity control.

Spintronic Integrate-Fire-Reset Neuron with Stochasticity for Neuromorphic Computing.

Spintronics has been recently extended to neuromorphic computing because of its energy efficiency and scalability. However, a biorealistic spintronic neuron with probabilistic "spiking" and a spontaneous reset functionality has not been demonstrated yet. Here, we propose a biorealistic spintronic neuron device based on the heavy metal (HM)/ferromagnet (FM)/antiferromagnet (AFM) spin-orbit torque (SOT) heterostructure. The spintronic neuron can autoreset itself after firing due to the exchange bias of the AFM. The firing process is inherently stochastic because of the competition between the SOT and AFM pinning effects. We also implement a restricted Boltzmann machine (RBM) and stochastic integration multilayer perceptron (SI-MLP) using our proposed neuron. Despite the bit-width limitation, the proposed spintronic model can achieve an accuracy of 97.38% in pattern recognition, which is even higher than the baseline accuracy (96.47%). Our results offer a spintronic device solution to emulate biologically realistic spiking neurons.

Visual cortex responds to sound onset and offset during passive listening.

Sounds enhance our ability to detect, localize, and respond to co-occurring visual targets. Research suggests that sounds improve visual processing by resetting the phase of ongoing oscillations in visual cortex. However, it remains unclear what information is relayed from the auditory system to visual areas and if sounds modulate visual activity even in the absence of visual stimuli (e.g., during passive listening). Using intracranial electroencephalography (iEEG) in humans, we examined the sensitivity of visual cortex to three forms of auditory information during a passive listening task: auditory onset responses, auditory offset responses, and rhythmic entrainment to sounds. Because some auditory neurons respond to both sound onsets and offsets, visual timing and duration processing may benefit from each. In addition, if auditory entrainment information is relayed to visual cortex, it could support the processing of complex stimulus dynamics that are aligned between auditory and visual stimuli. Results demonstrate that in visual cortex, amplitude-modulated sounds elicited transient onset and offset responses in multiple areas, but no entrainment to sound modulation frequencies. These findings suggest that activity in visual cortex (as measured with iEEG in response to auditory stimuli) may not be affected by temporally fine-grained auditory stimulus dynamics during passive listening (though it remains possible that this signal may be observable with simultaneous auditory-visual stimuli). Moreover, auditory responses were maximal in low-level visual cortex, potentially implicating a direct pathway for rapid interactions between auditory and visual cortices. This mechanism may facilitate perception by time-locking visual computations to environmental events marked by auditory discontinuities.NEW & NOTEWORTHY Using intracranial electroencephalography (iEEG) in humans during a passive listening task, we demonstrate that sounds modulate activity in visual cortex at both the onset and offset of sounds, which likely supports visual timing and duration processing. However, more complex auditory rate information did not affect visual activity. These findings are based on one of the largest multisensory iEEG studies to date and reveal the type of information transmitted between auditory and visual regions.

Safety and efficacy of a digital therapeutic for substance use disorder: Secondary analysis of data from a NIDA clinical trials network study.

Background: Traditional treatments for substance use disorders (SUDs) rely heavily on face-to-face interactions, which pose substantial limitations for patients. A clinical trial of a digital therapeutic (DT), delivering behavioral therapy demonstrated safety and efficacy in a population including patients with opioid use disorder (OUD) not treated with buprenorphine, which is not a guideline-recommended approach. This study re-analyzed the data excluding patients with OUD to more closely approximate real-world patient populations. Methods: Secondary analysis of patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (n = 399, patients with OUD excluded) from a previously-published randomized controlled trial. Patients received 12-weeks of outpatient treatment-as-usual (TAU; n = 193) or TAU with reduced counseling plus a DT (n = 206) providing computerized cognitive behavioral therapy and contingency management. Primary outcomes were abstinence in weeks 9-12 and retention in treatment. Results: The 399 patients in this analysis (206 in the DT group and 193 in the TAU group) reported substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (e.g., methamphetamines). Demographic and baseline characteristics including age, sex, race, education, and reported primary substance use disorder were balanced between treatment groups. Abstinence was significantly higher in the DT group compared to TAU (40.3 vs. 17.6%; p < 0.001) as was retention in therapy (76.2 vs. 63.2%, p = 0.004). Intergroup adverse event rates were not significantly different (p = 0.68). Conclusions: The results demonstrate that use of a DT safely increased abstinence (reduced substance use) and retention in treatment among patients with substance use disorders related to alcohol, cannabis, cocaine, or other stimulants (including methamphetamines).

Closed-Loop neuromodulation for clustering neuronal populations.

Pathological synchronization of neurons is associated with symptoms of movement disorders, such as Parkinson's disease and essential tremor. High-frequency deep brain stimulation (DBS) suppresses symptoms, presumably through the desynchronization of neurons. Coordinated reset (CR) delivers trains of high-frequency stimuli to different regions in the brain through multiple electrodes and may have more persistent therapeutic effects than conventional DBS. As an alternative to CR, we present a closed-loop control setup that desynchronizes neurons in brain slices by inducing clusters using a single electrode. Our setup uses calcium fluorescence imaging to extract carbachol-induced neuronal oscillations in real time. To determine the appropriate stimulation waveform for inducing clusters in a population of neurons, we calculate the phase of the neuronal populations and then estimate the phase response curve (PRC) of those populations to electrical stimulation. The phase and PRC are then fed into a control algorithm called the input of maximal instantaneous efficiency (IMIE). By using IMIE, the synchrony across the slice is decreased by dividing the population of neurons into subpopulations without suppressing the oscillations locally. The desynchronization effect is persistent 10 s after stimulation is stopped. The IMIE control algorithm may be used as a novel closed-loop DBS approach to suppress the symptoms of Parkinson's disease and essential tremor by inducing clusters with a single electrode.NEW & NOTEWORTHY Here, we present a closed-loop controller to desynchronize neurons in brain slices by inducing clusters using a single electrode using calcium imaging feedback. Phase of neurons are estimated in real time, and from the phase response curve stimulation is applied to achieve target phase differences. This method is an alternative to coordinated reset and is a novel therapy that could be used to disrupt synchronous neuronal oscillations thought to be the mechanism underlying Parkinson's disease.

Switching-Modulated Phase Change Memory Realized by Si-Containing Block Copolymers.

The phase change memory (PCM) is one of the key enabling memory technologies for next-generation non-volatile memory device applications due to its high writing speed, excellent endurance, long retention time, and good scalability. However, the high power consumption of PCM devices caused by the high switching current from a high resistive state to a low resistive state is a critical obstacle to be resolved before widespread commercialization can be realized. Here, a useful approach to reduce the writing current of PCM, which depends strongly on the contact area between the heater electrode and active layer, by employing self-assembly process of Si-containing block copolymers (BCPs) is presented. Self-assembled insulative BCP pattern geometries can locally block the current path of the contact between a high resistive film (TiN) and a phase-change material (Ge2 Sb2 Te5 ), resulting in a significant reduction of the writing current. Compared to a conventional PCM cell, the BCP-modified PCM shows excellent switching power reduction up to 1/20 given its use of self-assembled hybrid SiFex Oy /SiOx dot-in-hole nanostructures. This BCP-based bottom-up process can be extended to various applications of other non-volatile memory devices, such as resistive switching memory and magnetic storage devices.

Photoinduced-reset and multilevel storage transistor memories based on antimony-doped tin oxide nanoparticles floating gate.

Recently, antimony-doped tin oxide nanoparticles (ATO NPs) have been widely used in the fields of electronics, photonics, photovoltaics, sensing, and other fields because of their good conductivity, easy synthesis, excellent chemical stability, high mechanical strength, good dispersion and low cost. Herein, for the first time, a novel nonvolatile transistor memory device is fabricated using ATO NPs as charge trapping sites to enhance the memory performance. The resulting organic nano-floating gate memory (NFGM) device exhibits outstanding memory properties, including tremendous memory window (∼85 V), superhigh memory on/off ratio (∼109), long data retention (over 10 years) and eminent multilevel storage behavior, which are among the optimal performances in NFGM devices based on organic field effect transistors. Additionally, the device displays photoinduced-reset characteristic with low energy consumption erasing operation. This study provides novel avenues for the manufacture of simple and low-cost data storage devices with outstanding memory performance, multilevel storage behavior and suitability as platforms for integrated circuits.

Fast pathway ablation unmasks nodoventricular fibers in a 15-year-old patient with supraventricular tachycardia.

We described a 15-year-old boy who underwent the catheter ablation for the nodoventricular (NV) tachycardia that had difficulty in differentiation from atrioventricular nodal reentrant tachycardia with upper common pathway. The modification of the fast pathway revealed an anterograde conduction of the NV fiber. We successfully performed the catheter ablation targeting for the right ventricular insertion site of the NV fiber.

Transient Dynamics in the Random Growth and Reset Model.

A mean-field type model with random growth and reset terms is considered. The stationary distributions resulting from the corresponding master equation are relatively easy to obtain; however, for practical applications one also needs to know the convergence to stationarity. The present work contributes to this direction, studying the transient dynamics in the discrete version of the model by two different approaches. The first method is based on mathematical induction by the recursive integration of the coupled differential equations for the discrete states. The second method transforms the coupled ordinary differential equation system into a partial differential equation for the generating function. We derive analytical results for some important, practically interesting cases and discuss the obtained results for the transient dynamics.

Shock and Awe in the UNFSS.

The unholy alliance between the UN and the World Economic Forum in staging a Food Systems Summit is the culmination of deepening public partnerships with the corporate food sector on an international scale. This article examines how the WEF has exploited this relationship to position its private constituency to oversee global food market governance at the expense of multilateral principles, and against China's expanding state-centered model of international self-reliance.

The Great Reset. Restratification for lives, livelihoods, and the planet.

In reviewing the Great Reset, an initiative launched by the World Economic Forum (WEF) in response to the global coronavirus crisis, this perspective article considers the scenario of an epochal transition from capitalism to "restorism". To facilitate the observation of underlying trends and assumptions, a systems-theoretical framework is developed for the observation of both this Great Reset scenario and those scenarios that are by implication excluded by the WEF vision. It is thus shown that the "shared goals" advocated by the WEF would converge to a transition from a modern pluralist to a "new-normative" order stratified to the primacy of individual, institutional, and planetary health. In discussing sociological implications of this transition, a vision emerges of a new digitally enhanced medieval era where health plays the role once played by religion. In this restorist scenario of a neo-medieval world health society, the emergence of new social strata corresponding to different levels of purity, infection, or pollution would be a probable consequence. The paper concludes that idea of deliberately caused great resets and other control illusions nurtured by the WEF initiative are barely smarter than and spur what the UN Secretary-General refers to as "wild conspiracy theories".

Prospective evaluation of the utility of magnetic resonance imaging in patients with non-MRI-conditional pacemakers and defibrillators.

BACKGROUND: Magnetic resonance imaging (MRI) in patients with legacy cardiovascular implantable electronic devices (CIEDs) in situ is likely underutilized. We hypothesized the clinical benefit of MRI would outweigh the risks in legacy CIED patients. METHODS: This is a single-center retrospective study that evaluated and classified the utility of MRI using a prospectively maintained database. The outcomes were classified as aiding in diagnosis, treatment, or both for the patients attributable to the MRI. We then assessed the incidence of adverse effects (AE) when the MRI was performed. RESULTS: In 668, MRIs performed on 479 patients, only 13 (1.9%) MRIs did not aid in the diagnosis or treatment of the patient. Power-on reset events without clinical sequelae in three scans (0.45%) were the only AE. The probability of an adverse event happening without any benefit from the MRI scan was 1.1 × 10-4 . A maximum benefit in diagnosis using MRI was obtained in ruling out space-occupying lesions (121/185 scans, 65.4%). Scans performed in patients for elucidating answers to queries in treatment were most frequently done for disease staging at long term follow-up (167/470 scans, 35.5%). Conservative treatment (184/470 scans, 39%) followed by medication changes (153/470 scans, 28.7%) were the most common treatment decisions made. CONCLUSIONS: The utility of MRI in patients with non-MRI-conditional CIEDs far outweighs the risk of adverse events when imaging is done in the context of a multidisciplinary program that oversees patient safety.

Thiol-disulfide status regulates quality control of prion protein at the plasma membrane.

Rapid endoplasmic reticulum (ER) stress-induced export (RESET) is undoubtedly beneficial in that it eliminates misfolded prion protein (PrP) from a stressed ER. Considering that RESET induces rapid endocytosis of misfolded PrP for degradation, it is questionable whether RESET is beneficial when its product amount overwhelms the capacity of subsequent clearance pathways. We require a strategy to monitor the endocytic flux rate of misfolded PrPs. Here, we stabilized misfolded PrPs by inserting red fluorescent protein (RFP) and indirectly determined this rate by monitoring the lysosomal free RFP. We discovered a surveillance mechanism that limits endocytosis of misfolded PrPs through plasma membrane quality control (pmQC). pmQC was regulated by the thiol-disulfide status of misfolded PrPs and consequently accumulates nonpathogenic PrP variants at the plasma membrane. This variant alleviated prion proteotoxicity induced by persistent RESET. Thus, PrP endocytosis is regulated by pmQC to ensure the safety of endolysosomal pathway from persistent internalization of misfolded PrP.-Lee, D., Lee, S., Shin, Y., Song, Y., Kang, S.-W. Thiol-disulfide status regulates quality control of prion protein at the plasma membrane.

Repeated Reuse of Deoxyribozyme-Based Logic Gates.

Deoxyribozymes (DNAzymes) have demonstrated a significant capacity for biocomputing and hold promise for information processing within advanced biological devices if several key capabilities are developed. One required capability is reuse-having DNAzyme logic gates be cyclically, and controllably, activated and deactivated. We designed an oligonucleotide-based system for DNAzyme reuse that could (1) remove previously bound inputs by addition of complementary oligonucleotides via toe-hold mediated binding and (2) diminish output signal through the addition of quencher-labeled oligonucleotides complementary to the fluorophore-bound substrate. Our system demonstrated, for the first time, the ability for DNAzymes to have their activity toggled, with activity returning to 90-125% of original activity. This toggling could be performed multiple times with control being exerted over when the toggling occurs, with three clear cycles observed before the variability in activity became too great. Our data also demonstrated that fluorescent output of the DNAzyme activity could be actively removed and regenerated. This reuse system can increase the efficiency of DNAzyme-based logic circuits by reducing the number of redundant oligonucleotides and is critical for future development of reusable biodevices controlled by logical operations.