Modulation of Cortical Inhibition by Lovastatin in Neurofibromatosis Type 1: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial

Neurofibromatosis type 1 (NF1) is associated with GABAergic dysfunction which has been suggested as the underlying cause of cognitive impairments. Previous intervention trials investigated the statins’ effects using cognitive outcome measures. However, available outcome measures have led to inconclusive results and there is a need to identify other options. Here, we aimed at investigating alternative outcome measures in a feasibility trial targeting cortical inhibition mechanisms known to be altered in NF1. We explored the neurochemical and physiological changes elicited by lovastatin, with magnetic resonance spectroscopy and transcranial magnetic stimulation (TMS). Fifteen NF1 adults participated in this randomized, triple-blind, placebo-controlled crossover trial (Clinicaltrials.gov NCT03826940) composed by one baseline and two reassessment visits after lovastatin/placebo intake (60mg/day, 3-days). Motor cortex GABA+ and Glx concentrations were measured using HERMES and PRESS sequences, respectively. Cortical inhibition was investigated by paired-pulse, input-output curve and cortical silent period (CSP) TMS protocols. CSP ratios were significantly increased by lovastatin (relative: p=0.027; absolute: p=0.034) but not by placebo. CSP durations showed a negative correlation with LICI 50ms amplitude ratio. Lovastatin was able to modulate cortical inhibition in NF1, as assessed by TMS CSP ratios, highlighting the potential of this outcome measure to be considered in future large-scale studies.

Pulse-Width Modulation-based TMS mimics effects of conventional TMS on human primary motor cortex

Objective: We developed a novel transcranial magnetic stimulation (TMS) device to generate flexible stimuli and patterns. The system synthesizes digital equivalents of analog waveforms, relying on the filtering properties of the nervous system. Here, we test the hypothesis that the novel pulses can mimic the effect of conventional pulses on the cortex. Approach: A second-generation programmable TMS (pTMS2) stimulator with magnetic pulse shaping capabilities using pulse-width modulation (PWM) was tested. A computational and an in-human study on twelve healthy participants compared the neuronal effects of conventional and modulation-based stimuli. Main results: Both the computational modeling and the in-human stimulation showed that the PWM-based system can synthesize pulses to effectively stimulate the human brain, equivalent to conventional stimulators. The comparison includes motor threshold, MEP latency and input-output curve measurements. Significance: PWM stimuli can fundamentally imitate the effect of conventional magnetic stimuli while adding considerable flexibility to TMS systems, enabling the generation of highly configurable TMS protocols.

The Environmental Kuznets Curve: Recycling and the Role of Habit Formation

Our analysis focuses on a novel theoretical model which explains the relationship between pollution and output as well as recycling and output in the context of the Environmental Kuznets Curve (EKC) framework. Our model incorporates habit formation on recycling in a circular economy model and we find that the EKC is characterized by a downward sloping curve, while the recycling output curve by an increasing curve, results which are both in agreement with the general patterns of these curves supported by the literature.

N IMPROVED VARIABLE STEP SIZE MPPT METHOD FOR PHOTOVOLTAIC ARRAY UNDER PARTIAL SHADING CONDITIONS

Photovoltaic (PV) systems are prone to partial shading effects, which cause multi-peak power points on the output curve, named local maximum power point (LMPP). The traditional perturbation and observation (P&O) algorithm will search into it when tracking maximum power. This paper proposes an improved variable step size (IVSS) perturbation tracking method to reduce the impact of perturbation step size choice on dynamic PV performance. MATLAB/Simulink software is used to develop and simulate the improved maximum power point tracking (MPPT) system. The IVSS tracking algorithm uses a program to achieve step perturbation. Finally, simulation results of the traditional P&O algorithm are compared with those achieved using the MPPT, verifying the superiority of proposed method in terms of tracking time, steady-state accuracy and maximum output power.

SIMULATION OF COMMUTATION PROCESSES OF MULTI-LEVEL VOLTAGE INVERTER SWITCHES

An algorithm for controlling of commutator’s transistors of a single-phase multi-level voltage inverter is presented. The structure of the power circuit of the considered converter, in contrast to most existing circuits, does not depend on the levels number of the output curve due to the using of an universal source of levels, which are formed by output capacitors of two pulsed DC-converters. The commutator control algorithm ensures the formation of the required output curve of the inverter and excludes the occurrence of emergency situations during level commutating. Features of the converter and commutator operation in modes of active power transmission from pulse converters to the load and perception of the reactive power of the inverter load by them are considered. The commutator operation algorithm determines the sequence of control pulses, applied to the base of transistors, the sequence being synchronized with the process of the output voltage curve forming, as well as the direction of the inverter input current. At the same time, features of the level commutating are considered. They differ in the transition direction in value of level voltages: «up» from a lower value to a higher one and «down» from a higher value to a lower one. The sequence of supply and removal of pulses from control electrodes of switches and commutations caused by them, when the inverter input current is positive, are given. The similar commutating of levels is realized, when the inverter input current is negative. Wherein indexes of switches are rearranged in accordance with the direction replacement of their switching of the commutator circuit. A commutator model is realized using Micro-Cap 12 to demonstrate the operation of the algorithm. The transistor MJ15003 model is used as a commutator’s switch. In the model, output capacitors of pulse converters are represented by voltage sources, an autonomous inverter – by an active inductive load. The commutating from a higher voltage level to a lower one with a positive input current of the inverter is considered as an example. Simulation results confirm the performance of the algorithm.

Acquisition of novel ball-related skills associated with sports experience

Some individuals can quickly acquire novel motor skills, while others take longer. This study aimed to investigate the relationships between neurophysiological state, sports experience, and novel ball-related skill acquisition. We enrolled 28 healthy collegiate participants. The participants’ neurophysiological data (input–output curve of the corticospinal tract) were recorded through transcranial magnetic stimulation. Subsequently, the participants performed a novel motor task (unilateral two-ball juggling) on a different day, after which they reported their previous sports experience (types and years). We found that individuals with more years of experience in ball sports showed faster acquisition of novel ball-related skills. Further, this result was not limited to any single ball sport. Therefore, the acquisition of novel ball-related skills is associated with familiarity with a ball’s nature. Furthermore, gain of the corticospinal tract was negatively and positively correlated with the years of experience in primary ball and non-ball sports (implemented for the longest time in individuals), respectively. These results could be associated with the extent of proficiency in their primary sport. The chosen type of sports (e.g., ball or non-ball) could critically influence the future acquisition of novel motor skills. This study provides important insights regarding how to approach sports and physical activities.

A modular approach for modeling the cell cycle based on functional response curves

Modeling biochemical reactions by means of differential equations often results in systems with a large number of variables and parameters. As this might complicate the interpretation and generalization of the obtained results, it is often desirable to reduce the complexity of the model. One way to accomplish this is by replacing the detailed reaction mechanisms of certain modules in the model by a mathematical expression that qualitatively describes the dynamical behavior of these modules. Such an approach has been widely adopted for ultrasensitive responses, for which underlying reaction mechanisms are often replaced by a single Hill equation. Also time delays are usually accounted for by using an explicit delay in delay differential equations. In contrast, however, S-shaped response curves, which are often encountered in bistable systems, are not easily modeled in such an explicit way. Here, we extend the classical Hill function into a mathematical expression that can be used to describe both ultrasensitive and S-shaped responses. We show how three ubiquitous modules (ultrasensitive responses, S-shaped responses and time delays) can be combined in different configurations and explore the dynamics of these systems. As an example, we apply our strategy to set up a model of the cell cycle consisting of multiple bistable switches, which can account for events such as DNA damage and coupling to the circadian clock in a phenomenological way.Author summaryBistability plays an important role in many biochemical processes and typically emerges from complex interaction patterns such as positive and double negative feedback loops. Here, we propose to theoretically study the effect of bistability in a larger interaction network. We explicitly incorporate a functional expression describing an S-shaped input-output curve in the model equations, without the need for considering the underlying biochemical events. This expression can be converted into a functional module for an ultrasensitive response, and a time delay is easily included as well. Exploiting the fact that several of these modules can easily be combined in larger networks, we construct a cell cycle model consisting of multiple bistable switches and show how this approach can account for a number of known properties of the cell cycle.

V–, U–, L– or W–shaped economic recovery after Covid-19: Insights from an Agent Based Model

We discuss the impact of a Covid-19–like shock on a simple model economy, described by the previously developed Mark-0 Agent-Based Model. We consider a mixed supply and demand shock, and show that depending on the shock parameters (amplitude and duration), our model economy can display V-shaped, U-shaped or W-shaped recoveries, and even an L-shaped output curve with permanent output loss. This is due to the economy getting trapped in a self-sustained “bad” state. We then discuss two policies that attempt to moderate the impact of the shock: giving easy credit to firms, and the so-called helicopter money, i.e. injecting new money into the households savings. We find that both policies are effective if strong enough. We highlight the potential danger of terminating these policies too early, although inflation is substantially increased by lax access to credit. Finally, we consider the impact of a second lockdown. While we only discuss a limited number of scenarios, our model is flexible and versatile enough to accommodate a wide variety of situations, thus serving as a useful exploratory tool for a qualitative, scenario-based understanding of post-Covid recovery. The corresponding code is available on-line.

Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation

Various neuromodulation approaches have been employed to alter neuronal spiking activity and thus regulate brain functions and alleviate neurological disorders. Infrared neural stimulation (INS) could be a potential approach for neuromodulation because it requires no tissue contact and possesses a high spatial resolution. However, the risk of overheating and an unclear mechanism hamper its application. Here we show that midinfrared stimulation (MIRS) with a specific wavelength exerts nonthermal, long-distance, and reversible modulatory effects on ion channel activity, neuronal signaling, and sensorimotor behavior. Patch-clamp recording from mouse neocortical pyramidal cells revealed that MIRS readily provides gain control over spiking activities, inhibiting spiking responses to weak inputs but enhancing those to strong inputs. MIRS also shortens action potential (AP) waveforms by accelerating its repolarization, through an increase in voltage-gated K+ (but not Na+) currents. Molecular dynamics simulations further revealed that MIRS-induced resonance vibration of –C=O bonds at the K+ channel ion selectivity filter contributes to the K+ current increase. Importantly, these effects are readily reversible and independent of temperature increase. At the behavioral level in larval zebrafish, MIRS modulates startle responses by sharply increasing the slope of the sensorimotor input–output curve. Therefore, MIRS represents a promising neuromodulation approach suitable for clinical application.

Interleukin-1β Modulates Synaptic Transmission and Synaptic Plasticity During the Acute Phase of Sepsis in the Senescence-Accelerated Mouse Hippocampus

BackgroundAging and pre-existing cognitive impairment are considered to be independent risk factors for sepsis-associated encephalopathy. This study aimed to investigate the manner in which aging and pre-existing cognitive dysfunction modified neuroinflammation, synaptic plasticity, and basal synaptic transmission during the acute phase of sepsis using Senescence-Accelerated Mice Prone 8 (SAMP8) and Senescence-Accelerated Resistant Mice 1 (SAMR1).MethodsWe used 6-month-old SAMP8 and SAMR1. Sepsis was induced using cecal ligation and puncture (CLP). The animal’s hippocampi and blood were collected for subsequent investigations 24 h after surgery.ResultsLong-term potentiation (LTP) was impaired in the Shaffer-collateral (SC)-CA1 pathway of the hippocampus in SAMP8 without surgery compared to the age-matched SAMR1, which was reflective of cognitive dysfunction in SAMP8. CLP impaired the SC-CA1 LTP in SAMR1 compared to the sham-operated controls, but not in SAMP8. Moreover, CLP decreased the input-output curve and increased the paired-pulse ratio in SAMP8, suggesting the reduced probability of basal synaptic transmission due to sepsis. Immunohistochemical analysis revealed that CLP elevated IL-1β levels, especially in the hippocampi of SAMP8 with microglial activation. In vivo peripheral IL-1 receptor antagonist (IL-1ra) administration in the septic SAMP8 revealed that the neuroinflammation was not correlated with the peripheral elevation of IL-1β. Ex vivo IL-1ra administration to the hippocampus ameliorated LTP impairment in SAMR1 and the reduction in basal transmission in SAMP8 after sepsis.ConclusionsThe mechanism of the modulation of synaptic transmission and synaptic plasticity by the acute stage of sepsis differed between SAMR1 and SAMP8. These changes were related to centrally derived IL-1 receptor-mediated signaling and were accompanied by microglial activation, especially in SAMP8.