Increase In Amplitude Of Response Research Articles

Simulation and experimental research on vibration response of microcracked compressor blades under variable working conditions

Compressor blades play a crucial role in aero-engines, experiencing complex alternating loads under variable working conditions (VWC). Resonance is inevitable under these conditions, leading to the development of blade crack faults. To understand and analyze this phenomenon, a finite element (FE) model of a microcracked blade was created using ANSYS. The model's accuracy was verified through a hammering experiment. Additionally, a resonance fatigue test was used to accurately obtain dynamic characteristics for prefabricated breathing cracks. The experiment demonstrated that cracked blades exhibit smaller responses in the time domain compared to intact blades, while showing super-harmonics in the frequency domain, thus validating the effectiveness of numerical simulation. The effects of VWC on the nonlinear vibration characteristics (VC) of the blade with a breathing microcrack were investigated. These VWC included variable speed, the amplitude of the exciting force (F0), depth of the microcrack (D), and length of the microcrack (L). The results revealed significant increases in the frequency domain response amplitude of the blade at super-harmonics with the increase of F0, D, and L at variable speeds. Furthermore, the breathing behavior of microcracked blades diminished with increasing rotating speed (N), D, and L. The observed decrease in frequency and the emergence of super-harmonic serves as indicators of the presence and severity of blade cracks. These findings are of great significance for the development of online monitoring technology for blade faults.

Parametric resonance for pipes conveying fluid in thermal environment

Parametric resonance is a kind of specific fluid-induced vibration for pipes conveying fluid. This paper focuses on revealing the qualitative characteristics of parametric resonances of the pipe with pulsating fluid speed in thermal environment, and compares the differences between the resonance characteristics in subcritical and supercritical regions. According to the generalized Hamilton's principle, the partial-differential-integral governing equation of a straight pipe is established. Under simply-supported boundary conditions, the non-trivial equilibrium configuration is obtained analytically. The governing equation of a supercritical pipe is derived by coordinate substitution on the basis of the new equilibrium configuration. The approximate analytical solution of parametric resonance for a pipe conveying fluid in a thermal environment is obtained by using the direct multi-scale method. The approximate analytical solution is verified to be reliable by using the Runge-Kutta method. The stability bounds of the parameters inducing parametric resonance are investigated via the introduced analytical method. The results show that the influence of temperature increment on sub-harmonic resonance is non-monotonic. In the subcritical region, when the temperature increment increases, the unstable region widens. This means that the system is more prone to parametric resonance, and the response amplitude decreases. In the supercritical region, when the temperature increment increases, the unstable bandwidth decreases, and the response amplitude increases. When viscous damping is increased or the average velocity is decreased, the sub-critical instability region decreases, and the supercritical instability region increases. With the increase in the pulsation velocity, the unstable bandwidth of subcritical and supercritical regions will increase, and parametric resonance is more likely to occur.

The role of electroneuromyography evaluation of the bulbocavernosal reflex in the diagnosis of pelvic nerve damage in patients with chronic pelvic pain syndrome

Introduction. One of the additional instrumental methods for diagnosing pudendal neuropathy is needle electroneuromyography (ENMG) of the bulbocavernosus reflex (BCR). The accumulated data on ENMG BCR in patients with primary chronic pelvic pain syndrome (CPPS) are insufficient due to the specificity of the procedure and its performance only in expert centres that specialise in the treatment of pelvic pain. Therefore, a study to investigate the features of ENMG BCR in patients with CPPS is of increased interest.Objective. To assess the representativeness and informativeness of the ENMG BCR technique in patients with CPPS and to identify factors influencing changes in the main parameters of the BCR M-response such as latency, amplitude, and duration.Materials & methods. Retrospective cohort study, which included 75 data from patients with (CPPS) who underwent needle-guided ENMG recording of BCR. Subjective complaints of patients were recorded using validated questionnaires: visual analogue scale (VAS) and chronic prostatitis and male pelvic pain syndrome symptom scale index (NIH-CPSI). Basic ENMG parameters such as the amplitude, latency, and duration of the M-responses were recorded.Results. We found statistically significant correlations between the duration and height of the M response of the patients (r = 0.31, p = 0.03) and their body weight (r = 0.34, p = 0.02). Anthropometric data did not correlate with amplitude and latency. Significant excess latency above 45 ms was observed, confirming nerve tissue destruction, in 11 (55%) women and 24 (44%) men. Although there were no statistically significant differences in any of the M-response parameters between men and women, there was a tendency for an increase in response amplitude in men and an increase in BCR latency time in women.Conclusion. The results of our study show that the duration of the M-response of BCR can correlate positively with the anthropometric data of the patient. At the same time, the mean latency and amplitude of the response are independent of anthropometric data, and the difference between them may be more determined by sex differences.

The influence of inter-bubble spacing on the resonance response of ultrasound contrast agent microbubbles

Ultrasound-driven microbubbles, typically between 1 and 8 µm in diameter, are resonant scatterers that are employed as diagnostic contrast agents and emerging as potentiators of targeted therapies. Microbubbles are administered in populations whereby their radial dynamics – key to their effectiveness - are greatly affected by intrinsic (e.g. bubble size) and extrinsic (e.g. boundaries) factors. In this work, we aim to understand how two neighbouring microbubbles influence each other. We developed a finite element model of a system of two individual phospholipid-encapsulated microbubbles vibrating in proximity to each other to study the effect of inter-bubble distance on microbubble radial resonance response. For the case of two equal-sized and identical bubbles, each bubble exhibits a decrease between 7 and 10% in the frequency of maximum response (fMR) and an increase in amplitude of maximum response (AMR) by 9–11% as compared to its isolated response in free-space, depending on the bubble size examined. For a system of two unequal-sized microbubbles, the large bubble shows no significant change, however the smaller microbubble shows an increase in fMR by 7–11% and a significant decrease in AMR by 38–52%. Furthermore, in very close proximity the small bubble shows a secondary off-resonance peak at the corresponding fMR of its larger companion microbubble. Our work suggests that frequency-dependent microbubble response is greatly affected by the presence of another bubble, which has implications in both imaging and therapy applications. Furthermore, our work suggests a mechanism by which nanobubbles show significant off-resonance vibrations in the clinical frequency range, a behaviour that has been observed experimentally but heretofore unexplained.

LES study on variation of flow pattern around a 4:1 rectangular cylinder and corresponding wind load during VIV

Vortex-induced vibration (VIV) is one of the typical flow-induced large amplitude vibrations. In this study, large eddy simulation (LES) is carried out to investigate the whole VIV process of a rectangular cylinder with aspect ratio 4. The flow fields and wind loads for rigid and elastic models are examined and compared to clarify the crucial flow characteristics during VIV. Results show that the time-averaged reattachment point of separated shear layer moves towards upstream direction with the increase of response amplitude. The mean negative pressure is consequently increased near leading edge of side face. For dynamic flow and wind load, in initial branch, the reattachment point of the separated shear layer, corresponding to the instant of largest side face wind load, gradually moves towards downstream with the increase of response amplitude. Meanwhile, the fluctuating lift coefficient and span-wise wind load correlation increase accordingly. In upper branch, the separated shear layer temporally separates from the side face, which leads to a sharp reduction of fluctuating lift coefficient and span-wise wind load correlation. The response amplitude, however, does not change apparently. In desynchronization, the response amplitude starts to decrease, as the vibration can no longer capture the shedding frequency of shape-induced vortex. The characteristics of the motion-induced wind loads corresponding to different wind speeds are also discussed in this study.

Ipsilateral auditory cortex responses to the intact ear after unilateral noise trauma in juvenile rats

BackgroundWhile ear stimulation produces a robust response in the contralateral auditory cortex (AC), it produces only a weak response in the ipsilateral AC, known as interhemispheric asymmetry. Unilateral deafness can lead to AC plastic changes, resulting in reduced interhemispheric asymmetry and auditory perceptual consequences. However, the unilateral hearing loss-associated plastic changes are far from fully understood. The purpose of this study was to investigate AC responses to the ipsilateral unimpaired ear after noise injury to the contralateral ear in juvenile rats. MethodsRats (50 days) were monaurally exposed to an intense noise (10.0-12.5 kHz, 126 dB SPL) for 2 hours. The unexposed ear-induced ipsilateral AC responses were recorded 2 days and 4 months after exposure and compared between groups. ResultsThe noise exposure resulted in complete hearing loss in the exposed ear, but normal function in the other. Two days after exposure, the ipsilateral AC response induced by the intact ear was significantly enhanced and the threshold decreased (the early-onset effect). Four months after noise exposure, in addition to the increased response amplitude, the “slow-increasing” firing pattern of the neurons in the ipsilateral AC turned into the contralateral-AC-response-like “sharp-increasing” pattern (the late-onset effect) with shortened response latency. DiscussionThe early-onset effect can result from release of inhibition due to decreased contralateral input, while the late-onset effect may imply the formation of direct connections in the ipsilateral auditory pathway. The enhanced AC response may help maintain loudness perception and monaural sound localization after unilateral deafness.

Imaging the influence of peripheral TRPV1-signaling on cerebral nociceptive processing applying fMRI-based graph theory in a resiniferatoxin rat model.

Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors—a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures.

Experimental investigation on vortex-induced vibration and solid-structure impact of a near-bottom horizontal flexible pipeline in oblique shear flow

Vortex-induced vibrations and solid-structure impacts of a horizontal flexible pipeline in the vicinity of a bottom wall boundary are experimentally investigated in a water flume. A neutrally-buoyant submerged pipe, with a length-to-diameter ratio of about 87 and fixed end supports, is subject to a shear flow with an oblique angle of 30°. The initial gap-to-diameter ratio between the wall and the pipe is equal to 0.2. A non-intrusive measurement with high-speed cameras is employed to simultaneously capture the space–time varying in-line and cross-flow vibrations in the normal flow reduced velocity range of 3–15 with a maximum Reynolds number of about 2780. Experimental results highlight new pipe equilibrium profiles and modal response branches being significantly broadened due to the wall proximity. Two solid-pipe impact features are discussed, including single-segment and two-segment alternating impacts depending on the dominant oscillation mode of the flexible pipe. Both the response amplitude and frequency increase with the reduced velocity, resulting in a more frequent impact with a greater impact force. A temporal evolution from a single point contact to a segment contact is observed for the two-segment alternating impact. Nevertheless, the lengths of the two contact segments are different as a result of the asymmetric response profile. In all cases, the pipe transversely impacts the bottom wall introducing a perturbation transmission along the pipe, which leads to the multi-mode, multi-frequency and asynchronous in-line and cross-flow oscillations with a 1:1 and 2:1 resonance. Due to a momentum energy consumption, the pipe experiences a slow post-impact bouncing phenomenon, contributing to a longer temporal period of the fluid–pipe interaction with a wall impact.

Task-related activity in human visual cortex.

The brain exhibits widespread endogenous responses in the absence of visual stimuli, even at the earliest stages of visual cortical processing. Such responses have been studied in monkeys using optical imaging with a limited field of view over visual cortex. Here, we used functional MRI (fMRI) in human participants to study the link between arousal and endogenous responses in visual cortex. The response that we observed was tightly entrained to task timing, was spatially extensive, and was independent of visual stimulation. We found that this response follows dynamics similar to that of pupil size and heart rate, suggesting that task-related activity is related to arousal. Finally, we found that higher reward increased response amplitude while decreasing its trial-to-trial variability (i.e., the noise). Computational simulations suggest that increased temporal precision underlies both of these observations. Our findings are consistent with optical imaging studies in monkeys and support the notion that arousal increases precision of neural activity.

Development of Neural Response to Novel Sounds in Fragile X Syndrome: Potential Biomarkers.

Auditory processing abnormalities in fragile X syndrome (FXS) may contribute to difficulties with language development, pattern identification, and contextual updating. Participants with FXS (N = 41) and controls (N = 27) underwent auditory event-related potentials during presentation of an oddball paradigm. Data was adequate for analysis for 33 participants with FXS and 27 controls (age 4-51 y, 13 females [FXS]; 4-54 y, 11 females [control]). Participants with FXS showed larger N1 and P2 amplitudes, abnormal lack of modulation of P1 and P2 amplitudes and P2 latency in response to oddball stimuli ) relative to controls: Females with FXS were more similar to controls. Participants with FXS showed a marginal speeding of the P2 latency, suggesting potentiation to oddball stimuli rather than habituation. Participants with FXS showed a heightened N1 habituation effect compared to controls. Gamma power was significantly higher for participants with FXS. Groups did not differ on mismatch negativity. Both controls and participants with FXS showed similar developmental trajectories in P1 and N1 amplitude, P2 latency, and gamma power, but not for P2 amplitude. One month retest analyses performed in 14 participants suggest strong test-retest reliability for most measures. Individuals with FXS show previously demonstrated increased response amplitude and high frequency neural activity. Despite an overall normal developmental trajectory for most measures, individuals with FXS show age-independent but gender-dependent decreases in complex processing of novel stimuli. Many markers show strong retest reliability even in children and thus are potential biomarkers for clinical trials in FXS.

Influence of age on the frequency characteristics of the soleus muscle response to Achilles tendon vibration during standing.

Proprioceptive sensory information from the ankle joint is critical for the control of upright posture and balance. We examined the influence of age (n=54 healthy adults, 20-82 years old) on lower limb muscle responses to proprioceptive perturbations evoked by Achilles tendon vibration during standing. The frequency bandwidth of the muscle response became narrower, and the gain (the muscle response relative to the stimulus) and scaling (increases in response amplitude with increases in stimulus amplitude) decreased with age. Mechanics of the muscle-tendon unit (mechanical admittance) did not differ with age during standing, and thus probably did not mediate the age-related changes observed in soleus muscle responses to vibration. These findings add to our understanding of how altered proprioceptive responses may contribute to impaired mobility and falls with ageing. Proprioceptive information from the ankle joint plays an important role in the control of upright posture and balance. Ageing influences many components of the sensorimotor system, which leads to poor mobility and falls. However, little is known about the influence of age on the characteristics of short latency muscle responses to proprioceptive stimuli during standing across frequencies that are encoded by muscle spindles. We examined the frequency characteristics of the soleus muscle response to noisy (10-115Hz) Achilles tendon vibration during standing in 54 healthy adults across a broad age range (20-82 years). The results showed the frequency bandwidth of the soleus response (vibration-electromyography coherence) became progressively narrower with ageing. Coherence was significantly lower in middle-aged relative to young adults between ∼7-11 and 28-62Hz, lower in older relative to middle-aged adults between ∼30-50Hz and lower in older relative to young adults between ∼7-64Hz. Muscle response gain was similar between age groups at low frequencies, although gain was lower in older relative to young adults between ∼28-54Hz. Across the age range, the response amplitude (peak-to-peak cross-covariance) and the scaling of the response with stimulus amplitude were both negatively correlated with age. Muscle-tendon mechanics (admittance) did not differ with age, suggesting this did not mediate differences in soleus responses. Our findings suggest there is a progressive change in the soleus response to proprioceptive stimuli with ageing during standing, which could contribute to poorer mobility and falls.

Retinal Response of Low Myopes during Orthokeratology Treatment.

The aim of this study was to evaluate the changes in retinal activity during orthokeratology (OK) treatment in 20 myopic eyes. Pattern electroretinography (PERG) and visual evoked potential (VEP) were assessed with the RETI-port/scan21 (Roland Consult, Wiesbaden, Germany). Measurements were taken at baseline (BL) and 1 night (1N), 15 nights (15N), 30 nights (30N), and 60 nights (60N) of OK lens wear. Repeated measures analysis of variance (ANOVA) and the Friedman test were used. Twenty eyes (23.20 ± 3.46 years, 70% female) with visual acuity ≤ 0.00 logMAR in post-treatment showed that despite a slight increase in retinal and cortical response amplitude, observed with both PERG and VEP, respectively, immediately after the initial treatment, these differences found were not statistically significant during the 60 days of OK treatment, despite a statistically significant increase in N95 response with PERG. This shows that retinal and cortical visual-related electrical activity is maintained or slightly increased during OK treatment.

Nonlinear superharmonic and subharmonic resonances of piezoelectric elliptic thin plates under thermoelastic coupling effect

This paper aims at investigating the nonlinear vibration characteristics of the piezoelectric elliptic thin plate under the combined action of external harmonic excitation and temperature field. Based on the Von-Karman plate theory of large deflection, the nonlinear governing equation is derived by using the Bubnov-Galerkin method. Then, the amplitude-frequency response equations are further obtained using the multi-scale method, and the stability conditions of the steady solution are determined according to the Routh-Hurwitz criterion. The effects of the temperature difference at the plate center, the effective damping coefficient, the external excitation amplitude, and the ratio of the semi-major axis to the semi-minor axis on superharmonic and subharmonic resonances behaviors of the piezoelectric elliptic thin plate are analyzed. It is found that the coexistence region of multiple solutions and the resonant amplitude decrease for superharmonic resonance, as the temperature difference at the plate center increases. For subharmonic resonance, with the increase in the temperature difference at the plate center, the response amplitude increases, while the distance between two branches of the amplitude-frequency response curve has no obvious change. The softened/hardened nonlinear characteristics of the system are determined by the ratio of the semi-major axis to the semi-minor axis of the piezoelectric elliptic thin plate.

Auditory adaptation time course in the Yangtze finless porpoises, Neophocaena asiaeorientalis asiaeorientalis

ABSTRACT Auditory adaptation manifests as temporary change in the hearing sensitivity under influence of sound stimuli, and little attention has been paid to hearing adaptation in cetaceans. In a Yangtze finless porpoise Neophocaena asiaeorientalis (Cetacea, Phocoenidae), effects of long-lasting sound stimuli (pip trains) on auditory evoked potentials (AEP) were investigated. The stimuli were rhythmic tone pips of either 90 or 128 kHz frequency. Stimulus levels varied from 80 to 120 dB re 1 μPa. During stimulation, the stimulus level was either kept constant the stimulus level changed up and down by 20 or 40 dB every 1000 ms. A stimulus level increase produced quick response amplitude increase with subsequent slower exponential decay; the exponent time constant was 59.2 ± 9.7 ms. A stimulus level decrease produced quick response amplitude suppression with subsequent exponent recovery; the exponent time constant was 153.9 ± 15.9 ms. The response variations were assessed as manifestations of adaptation processes. The finless porpoise is capable of quickly adjusting its sensitivity to the current auditory scene. This flexibility allows for quick sensitivity recovery after exposure to loud noises and is important for the effective use of auditory orientation. Abbreviations: RFR: rate-following response; AEP: auditory evoked potentials; A/D: analogue-to-digital (A/D); ERD: equivalent rectangular duration

Analysis of Nonlinear Dynamic Characteristics of a Mechanical-Electromagnetic Vibration System with Rubbing

In this study, a rotor-bearing-runner system (RBRS) considering multiple nonlinear factors is established, and the complex nonlinear dynamic behavior of the coupling system is studied. The effects of excitation current, radial stiffness, and friction coefficient on dynamic characteristics are analyzed by numerical simulation. The research results show that the dynamic properties of the coupling system caused by different nonlinear factors are interactional. With the changes of different parameters, the RBRS presents multiple motion states, including periodic-n, quasi-periodic, and chaotic motion. The increase of the excitation current Ij has a certain inhibitory effect on the response amplitude of the system and makes the motion state of the system more complex, the chaotic motion wider, and the jump discontinuity enhanced. With the increase of radial stiffness kr, the motion complexity of the coupling system increases, the chaotic region increases, the response amplitude increases, and the vibration intensity increases. With the increase of the friction coefficient μ, the chaotic region increases first and decreases, the different motions alternate frequently, and the response amplitude gradually increases. This study can not only help to understand the dynamic characteristics of RBRS, but also help the stable operation of the generator set.

Effects of Locomotion on Visual Responses in the Mouse Superior Colliculus.

Visual responses are extensively shaped by internal factors. This effect is drastic in the primary visual cortex (V1), where locomotion profoundly increases visually-evoked responses. Here we investigate whether a similar effect exists in another major visual structure, the superior colliculus (SC). By performing two-photon calcium imaging of head-fixed male and female mice running on a treadmill, we find that only a minority of neurons in the most superficial lamina of the SC display significant changes during locomotion. This modulation includes both increase and decrease in response amplitude and is similar between excitatory and inhibitory neurons. The overall change in the SC is small, whereas V1 responses almost double during locomotion. Additionally, SC neurons display lower response variability and less spontaneous activity than V1 neurons. Together, these experiments indicate that locomotion-dependent modulation is not a widespread phenomenon in the early visual system and that the SC and V1 use different strategies to encode visual information.SIGNIFICANCE STATEMENT Visual information captured by the retina is processed in parallel through two major pathways, one reaching the primary visual cortex through the thalamus, and the other projecting to the superior colliculus. The two pathways then merge in the higher areas of the visual cortex. Recent studies have shown that behavioral state such as locomotion is an essential component of vision and can strongly affect visual responses in the thalamocortical pathway. Here we demonstrate that neurons in the mouse superior colliculus and primary visual cortex display striking differences in their modulation by locomotion, as well as in response variability and spontaneous activity. Our results reveal an important "division of labor" in visual processing between these two evolutionarily distinct structures.

An objective signature of emotional expressions and context integration within a single glance: evidence from electroencephalographic frequency-tagging

The ability to quickly and accurately extract someone's emotional state from their face is crucial for social interaction. Over the last decades, the processing of emotional expressions has been studied mainly using isolated faces. However, at the behavioral level, contextual information often leads to radical changes in the categorization of facial expressions, yet the underlying mechanisms are not well understood (Aviezer et al., 2017, Current Opinion in Psychology, 17, 47–54; Barrett et al., 2011, Current Directions in Psychological Science, 20, 286 –290). Here we examined the impact of emotional visual scenes on the perception of emotional expressions within a single glance by means of fast periodic visual stimulation (FPVS). We recorded 128-channel EEG while participants viewed 60s sequences with a dual frequency-tagging paradigm (Boremanse et al, 2013, Journal of Vision (11):6, 1-18). We presented faces and scenes simultaneously, with each stimulus set flickering at specific frequency (f1=4.61 Hz and f2=5.99 Hz; frequencies were counterbalanced across stimuli). Each sequence displayed different faces with the same emotional expression (disgust, fear, or joy) within either positive or negative valence visual scenes. Periodic EEG responses at the image presentation frequencies (4.61 Hz and 5.99 Hz) captured general visual processing of the emotional faces and scenes, while intermodulation components (e.g. f2-f1: 5.99 – 4.61 Hz = 1.38 Hz) captured the integration between the emotional expressions and their context. At the group-level, emotional expressions elicited right-lateralized occipito-temporal electrophysiological responses that were stronger for negative valence expressions (especially disgust). Similarly, negative scenes elicited stronger neural responses than positive scenes over the medial occipital region. Finally, and critically, we observed intermodulation components that were prominent over right occipito-temporal sites and showed increased response amplitude for negative scenes, thereby providing an objective demonstration of the perceptual integration of emotional facial expressions with their emotional context.

Brain’s compensatory response to drug-induced cognitive impairment

ABSTRACTIntroduction: Topiramate (TPM), a frequently prescribed antiseizure medication, can cause severe cognitive side-effects. Though these side-effects have been studied behaviorally, the underlying neural mechanisms are unknown. In a double-blind, randomized, placebo-controlled, crossover study of TPM’s impact on cognition, nine healthy volunteers completed three study sessions: a no-drug baseline session and two sessions during which they received either TPM or placebo. Electroencephalogram was recorded during each session while subjects performed a working-memory task with three memory-loads.Results: Comparing TPM with baseline we found the following results. (a) TPM administration led to declines in behavioral performance. (b) Fronto-central event-related potentials (ERP) elicited by probe stimuli, representing the primary task network activity, showed strong memory-load modulations at baseline, but the magnitude of these load-dependent modulations was significantly reduced during TPM session, suggesting drug-induced impairments of the primary task network. (c) ERP responses over bilateral fronto-temporal electrodes, which were not load sensitive at baseline, showed significant memory-load modulations after TPM administration, suggesting the drug-related recruitment of additional neural resources. (d) At fronto-central scalp sites, there was significant increase in response amplitude for low memory-load during TPM session compared to baseline, and the amplitude increase was dependent on TPM plasma concentration, suggesting that the primary task network became less efficient under TPM impact. (e) At bilateral fronto-temporal electrodes, there were no ERP differences when comparing low memory-load trials, but TPM administration led to an increase in ERP responses to high load, the magnitude of which was positively correlated with task performance, suggesting that the recruited neural resources were beneficial for task performance. Placebo–TPM comparison yielded similar effects albeit with generally reduced significance and effect sizes.Conclusion: Our findings support the hypothesis that TPM impairs the primary task network by reducing its efficiency, which triggers compensatory recruitment of additional resources to maintain task performance.

Characterization of the effects of novel positive allosteric modulators on the functionality of the α7 nicotinic acetylcholine receptor (nAChR)

The α7 nicotinic acetylcholine receptor (nAChR) has been implicated in the development of various neurodegenerative disorders such as Alzheimer's, Parkinson's, Schizophrenia, and a series of inflammatory disorders. In recent years, there has been an increased interest in the pharmacological modulation of receptor function as a therapeutic target. However, these efforts have been limited due to poor temporal and tissue selectivity. Therefore, there is a growing need for the synthesis of new modulators that can address these problems. Positive allosteric modulators (PAMs) for the α7‐nAChR have grown in significance and are currently being developed by many pharmaceutical companies. The California Northstate University has provided us with three novel PAMs (PAM‐2, OCF‐3, CF‐3) in order to test their functionality on the α7‐nAChR. Previous tests on these compounds have shown indirect PAM activity through calcium influx tests using fluorescence microscopy. However, the direct effects of these drugs on the α7‐nAChR have not been tested. Taking advantage of the Xenopus oocyte expression system we are studying the direct effects of these drugs on the α7‐nAChR using Two‐Electrode Voltage Clamp (TEVC) electrophysiology. Our results show that pre‐application of 20 μM PAM‐2, OCF‐3, or CF‐3 on oocytes expressing the α7‐nAChR causes a significant increase in response amplitude compared to controls. Also, we observe a dose dependent increase in current amplitude for PAM‐2 and OCF‐3. These results are consistent with the idea of positive allosteric modulation. Reverse potentials were performed to verify the effects of PAM‐2 and OCF‐3 on calcium permeability of the α7‐nAChR. We have observed that for PAM‐2 the shift in Vrev (ΔVrev) is similar to that of our control. However, for OCF‐3 we observe a reduction in ΔVrev in a low vs high calcium solution. Further studies of these compounds will give us a better insight into their potential use as therapeutic targets of the α7‐nAChR.Support or Funding InformationThis project was funded by the MARC Program at the University of Puerto Rico, Rio Piedras NIGMS Grant #5T34GM007821‐38.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model

BackgroundDopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed.MethodsHere, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice.ResultsMale mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates.ConclusionsThese data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.