Top-down auditory attention modulates neural responses more strongly in neurotypical than ADHD young adults.

Human cognitive abilities naturally vary along a spectrum, even among those we call "neurotypical". Individuals differ in their ability to selectively attend to goal-relevant auditory stimuli. We sought to characterize this variability in a cohort of people with diverse attentional functioning. We recruited both neurotypical (N = 20) and ADHD (N = 25) young adults, all with normal hearing. Participants listened to one of three concurrent, spatially separated speech streams and reported the order of the syllables in that stream while we recorded electroencephalography (EEG). We tested both the ability to sustain attentional focus on a single "Target" stream and the ability to monitor the Target but flexibly either ignore or switch attention to an unpredictable "Interrupter" stream from another direction that sometimes appeared. Although differences in both stimulus structure and task demands affected behavioral performance, ADHD status did not. In both groups, the Interrupter evoked larger neural responses when it was to be attended compared to when it was irrelevant, including for the P3a "reorienting" response previously described as involuntary. This attentional modulation was weaker in ADHD listeners, even though their behavioral performance was the same. Across the entire cohort, individual performance correlated with the degree of top-down modulation of neural responses. These results demonstrate that listeners differ in their ability to modulate neural representations of sound based on task goals, while suggesting that adults with ADHD may have weaker volitional control of attentional processes than their neurotypical counterparts.

Learning to Feel Textures: Predicting Perceptual Similarities From Unconstrained Finger-Surface Interactions.

Whenever we touch a surface with our fingers, we perceive distinct tactile properties that are based on the underlying dynamics of the interaction. However, little is known about how the brain aggregates the sensory information from these dynamics to form abstract representations of textures. Earlier studies in surface perception all used general surface descriptors measured in controlled conditions instead of considering the unique dynamics of specific interactions, reducing the comprehensiveness and interpretability of the results. Here, we present an interpretable modeling method that predicts the perceptual similarity of surfaces by comparing probability distributions of features calculated from short time windows of specific physical signals (finger motion, contact force, fingernail acceleration) elicited during unconstrained finger-surface interactions. The results show that our method can predict the similarity judgments of individual participants with a maximum Spearman's correlation of 0.7. Furthermore, we found evidence that different participants weight interaction features differently when judging surface similarity. Our findings provide new perspectives on human texture perception during active touch, and our approach could benefit haptic surface assessment, robotic tactile perception, and haptic rendering.

Partial Repetition Costs are Reduced but not Eliminated with Practice.

Often, we depart from an intended course of events to react to sudden situational demands (an intervening event) before resuming the originally planned action. Executing an action to an intervening event can be delayed if the features of this action plan partly overlap with an action plan retained in working memory (WM) compared to when they completely overlap or do not overlap. This delay is referred to as a partial repetition cost (PRC). PRCs are typically attributed to code confusion between action plans in WM. We tested this by training the component action plans extensively to reduce their reliance on WM. If PRCs are caused by code confusion within WM, then PRCs should be reduced and possibly eliminated with extensive practice. To test this, participants performed a partial repetition (PR) task after 0, 4 and 8.5 sessions of stimulus-response (S-R) training. In the PR task, participants saw two visual events. They retained an action to the first event while executing a speeded action to a second (intervening) event; afterwards, they executed the retained action. The two action plans either partly overlapped or did not overlap. Results showed that extensive (S-R and PR task) practice reduced but did not eliminate PRCs. A reduction in PRCs (code confusion) with practice is compatible with memory models that assume action events become more specific and less reliant on WM with practice. These findings merit expansions of PR tasks to other domains and broader conceptions of action plans that incorporate the formal structure of memory models.

Partial repetition between action plans delays responses to ideomotor compatible stimuli.

Often one must depart from an intended course of events to react to sudden situational demands before resuming his or her original action retained in working memory. Retaining an action plan in working memory (WM) can delay or facilitate the execution of an intervening action when the action features of the two action plans partly overlap (partial repetition) compared to when they do not overlap. We investigated whether partial repetition costs (PRCs) or benefits (PRBs) occur when the intervening event is an ideomotor-compatible stimulus that is a biological representation of the response required by the participant. Participants viewed two visual events and retained an action plan to the first event (A) while executing a speeded response to the second, intervening event (B). In Experiment 1A, the two visual events were ideomotor compatible, non-ideomotor compatible (abstract), or one was ideomotor compatible, and the other abstract. Results showed PRCs for all event A-B stimulus combinations with reduced PRCs for intervening, ideomotor compatible events. In contrast to previous research, there was no evidence that ideomotor-compatible actions were automatic and bypassed the selection bottleneck. Experiment 1B confirmed PRCs for ideomotor compatible stimuli that more accurately mimicked the required response. Findings suggest that mechanisms for activating, selecting, and retaining action plans are similar between ideomotor compatible and abstract visual events. We conclude that PRCs occur in response to intervening events when action plans are generated offline and rely on WM, including those for ideomotor-compatible stimuli; but PRBs may be restricted to actions generated online. This conclusion is consistent with the perceptual-motor framework by Goodale and Milner (Trends in Neuroscience 15:22-25, 1992).

Mechanobiological Interactions between Dynamic Compressive Loading and Viscoelasticity on Chondrocytes in Hydrazone Covalent Adaptable Networks for Cartilage Tissue Engineering.

Mechanobiological cues influence chondrocyte biosynthesis and are often used in tissue engineering applications to improve the repair of articular cartilage in load-bearing joints. In this work, the biophysical effects of an applied dynamic compression on chondrocytes encapsulated in viscoelastic hydrazone covalent adaptable networks (CANs) is explored. Here, hydrazone CANs exhibit viscoelastic loss tangents ranging from (9.03 ± 0.01) 10-4 to (1.67 ± 0.09) 10-3 based on the molar percentages of alkyl-hydrazone and benzyl-hydrazone crosslinks. Notably, viscoelastic alkyl-hydrazone crosslinks improve articular cartilage specific gene expression showing higher SOX9 expression in free swelling hydrogels and dynamic compression reduces hypertrophic chondrocyte markers (COL10A1, MMP13) in hydrazone CANs. Interestingly, dynamic compression also improves matrix biosynthesis in elastic benzyl-hydrazone controls but reduces biosynthesis in viscoelastic alkyl-hydrazone CANs. Additionally, intermediate levels of viscoelastic adaptability demonstrate the highest levels of matrix biosynthesis in hydrazone CANs, demonstrating on average 70 ± 4 µg of sulfated glycosaminoglycans per day and 31 ± 3 µg of collagen per day over one month in dynamic compression bioreactors. Collectively, the results herein demonstrate the role of matrix adaptability and viscoelasticity on chondrocytes in hydrazone CANs during dynamic compression, which may prove useful for tissue engineering applications in load-bearing joints.

Viscoelasticity of hydrazone crosslinked poly(ethylene glycol) hydrogels directs chondrocyte morphology during mechanical deformation.

Chondrocyte deformation influences disease progression and tissue regeneration in load-bearing joints. In this work, we found that viscoelasticity of dynamic covalent crosslinks temporally modulates the biophysical transmission of physiologically relevant compressive strains to encapsulated chondrocytes. Chondrocytes in viscoelastic alky-hydrazone hydrogels demonstrated (91.4 ± 4.5%) recovery of native rounded morphologies during mechanical deformation, whereas primarily elastic benzyl-hydrazone hydrogels significantly limited morphological recovery (21.2 ± 1.4%).

Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors.

The oxidative stress response, gated by the protein-protein interaction of KEAP1 and NRF2, has garnered significant interest in the past decade. Misregulation in this pathway has been implicated in disease states such as multiple sclerosis, rheumatoid arthritis, and diabetic chronic wounds. Many of the known activators of NRF2 are electrophilic in nature and may operate through several biological pathways rather than solely through the activation of the oxidative stress response. Recently, our lab has reported a nonelectrophilic, monoacidic, naphthalene-based NRF2 activator which exhibited good potency in vitro. Herein, we report a detailed structure-activity relationship of naphthalene-based NRF2 activators, an X-ray crystal structure of our monoacidic KEAP1 inhibitor, and identification of an underexplored area of the NRF2 binding pocket of KEAP1.

Free-choice and forced-choice actions: Shared representations and conservation of cognitive effort.

We examined two questions regarding the interplay of planned and ongoing actions. First: Do endogenous (free-choice) and exogenous (forced-choice) triggers of action plans activate similar cognitive representations? And, second: Are free-choice decisions biased by future action goals retained in working memory? Participants planned and retained a forced-choice action to one visual event (A) while executing an immediate forced-choice or free-choice action (action B) to a second visual event (B); then the retained action (A) was executed. We found performance costs for action B if the two action plans partly overlapped versus did not overlap (partial repetition costs). This held true even when action B required a free-choice response indicating that forced-choice and free-choice actions are represented similarly. Partial repetition costs for free-choice actions were evident regardless of whether participants did or did not show free-choice response biases. Also, a subset of participants showed a bias to freely choose actions that did not overlap (vs. did overlap) with the action plan retained in memory, which led to improved performance in executing action B and recalling action A. Because cognitive effort is likely required to resolve feature code competition and confusion assumed to underlie partial repetition costs, this free-choice decision bias may serve to conserve cognitive effort and preserve the future action goal retained in working memory.

Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability.

Pharmacological activation of NRF2 (nuclear factor erythroid 2-related factor 2) arises from blocking the interaction of NRF2 with its negative regulator, KEAP1 (Kelch-like ECH-associated protein 1). We previously reported an isoquinoline-based NRF2 activator, but this compound showed negative logD7.4 and a -2 charge at physiological pH, which may have limited its membrane permeability. In this work, we report potent, metabolically stable analogs that result from replacing a carboxymethyl group at the 4-position with a fluoroalkyl group.

Learning to Predict Perceptual Distributions of Haptic Adjectives.

When humans touch an object with their fingertips, they can immediately describe its tactile properties using haptic adjectives, such as hardness and roughness; however, human perception is subjective and noisy, with significant variation across individuals and interactions. Recent research has worked to provide robots with similar haptic intelligence but was focused on identifying binary haptic adjectives, ignoring both attribute intensity and perceptual variability. Combining ordinal haptic adjective labels gathered from human subjects for a set of 60 objects with features automatically extracted from raw multi-modal tactile data collected by a robot repeatedly touching the same objects, we designed a machine-learning method that incorporates partial knowledge of the distribution of object labels into training; then, from a single interaction, it predicts a probability distribution over the set of ordinal labels. In addition to analyzing the collected labels (10 basic haptic adjectives) and demonstrating the quality of our method's predictions, we hold out specific features to determine the influence of individual sensor modalities on the predictive performance for each adjective. Our results demonstrate the feasibility of modeling both the intensity and the variation of haptic perception, two crucial yet previously neglected components of human haptic perception.

Hydrazone covalent adaptable networks modulate extracellular matrix deposition for cartilage tissue engineering.

Cartilage tissue engineering strategies often rely on hydrogels with fixed covalent crosslinks for chondrocyte encapsulation, yet the resulting material properties are largely elastic and can impede matrix deposition. To address this limitation, hydrazone crosslinked poly(ethylene glycol) hydrogels were formulated to achieve tunable viscoelastic properties and to study how chondrocyte proliferation and matrix deposition vary with the time-dependent material properties of covalent adaptable networks. Hydrazone equilibrium differences were leveraged to produce average stress relaxation times from hours (4.01 × 103 s) to months (2.78 × 106 s) by varying the percentage of alkyl-hydrazone (aHz) and benzyl-hydrazone (bHz) crosslinks. Swelling behavior and degradation associated with adaptability were characterized to quantify temporal network changes that can influence the behavior of encapsulated chondrocytes. After four weeks, mass swelling ratios varied from 36 ±â€¯3 to 17 ±â€¯0.4 and polymer retention ranged from 46 ±â€¯4% to 92 ±â€¯5%, with higher aHz content leading to loss of network connectivity with time. Hydrogels were formulated near the Flory-Stockmayer bHz percolation threshold (17% bHz) to investigate chondrocyte response to distinct levels of covalent architecture adaptability. Four weeks post-encapsulation, formulations with average relaxation times of 3 days (2.6 × 105s) revealed increased cellularity and an interconnected articular cartilage-specific matrix. Chondrocytes embedded in this adaptable formulation (22% bHz) deposited 190 ±â€¯30% more collagen and 140 ±â€¯20% more sulfated glycosaminoglycans compared to the 100% bHz control, which constrained matrix deposition to pericellular space. Collectively, these findings indicate that incorporating highly adaptable aHz crosslinks enhanced regenerative outcomes. However, connected networks containing more stable bHz bonds were required to achieve the highest quality neocartilaginous tissue. STATEMENT OF SIGNIFICANCE: Covalently crosslinked hydrogels provide robust mechanical support for cartilage tissue engineering applications in articulating joints. However, these materials traditionally demonstrate purely elastic responses to deformation despite the dynamic viscoelastic properties of native cartilage tissue. Here, we present hydrazone poly(ethylene glycol) hydrogels with tunable viscoelastic properties and study covalent adaptable networks for cartilage tissue engineering. Using hydrazone equilibrium and Flory-Stockmayer theory we identified average relaxation times leading to enhanced regenerative outcomes and showed that extracellular matrix deposition was biphasic as a function of the hydrazone covalent adaptability. We also showed that the incorporation of highly adaptable covalent crosslinks could improve cellularity of neotissue, but that a percolating network of more stable bonds was required to maintain scaffold integrity and form the highest quality neocartilaginous tissue.

Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.

Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhibition of the KEAP1/NRF2 interaction with small molecules leads to NRF2 activation. Previously, we and others described naphthalene-based NRF2 activators, but the 1,4-diaminonaphthalene scaffold may not represent a drug-like scaffold. Paying particular attention to aqueous solubility, metabolic stability, potency, and mutagenicity, we modified a previously known, naphthalene-based nonelectrophilic NRF2 activator to give a series of non-naphthalene and heterocyclic scaffolds. We found that, compared to previously reported naphthalene-based compounds, a 1,4-isoquinoline scaffold provides a better mutagenic profile without sacrificing potency, stability, or solubility.

Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators.

Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.

Dorsal stream activity and connectivity associated with action priming of ambiguous apparent motion.

Theories proposing a bidirectional influence between action and perception are well supported by behavioral findings. In contrast to the growing literature investigating the brain mechanisms by which perception influences action, there is a relative dearth of neural evidence documenting how action may influence perception. Here we show that action priming of apparent motion perception is associated with increased functional connectivity between dorsal cortical regions connecting vision with action. Participants manually rotated a joystick in a clockwise or counter-clockwise direction while viewing ambiguous apparent rotational motion. Actions influenced perception when the perceived direction of the ambiguous display was the same as manual rotation. For comparison, participants also rotated the joystick while viewing non-ambiguous apparent motion and in the absence of apparent motion. In a final control condition, participants viewed ambiguous apparent motion without manual rotation. Actions influence on perception was accompanied by a significant increase in alpha and beta band event related desynchronization (ERD) in contralateral primary motor cortex, superior parietal lobe and middle occipital gyrus. Increased ERD across these areas was accompanied by an increase in gamma band phase locking between primary motor, parietal, striate and extrastriate regions. Similar patterns were not observed when action was compatible with perception, but did not influence it. These data demonstrate that action influences perception by strengthening the interaction across a broad sensorimotor network for the putative purpose of integrating compatible action outcomes and sensory information into a single coherent percept.

The effect of supplemental dietary taurine on tinnitus and auditory discrimination in an animal model.

Loss of central inhibition has been hypothesized to underpin tinnitus and impact auditory acuity. Taurine, a partial agonist at inhibitory glycine and γ-amino butyric acid receptors, was added to the daily diet of rats to examine its effects on chronic tinnitus and normal auditory discrimination. Eight rats were unilaterally exposed once to a loud sound to induce tinnitus. The rats were trained and tested in an operant task shown to be sensitive to tinnitus. An equivalent unexposed control group was run in parallel. Months after exposure, 6 of the exposed rats showed significant evidence of chronic tinnitus. Two concentrations of taurine in drinking water were given over several weeks (attaining average daily doses of 67 mg/kg and 294 mg/kg). Water consumption was unaffected. Three main effects were obtained: (1) The high taurine dose significantly attenuated tinnitus, which returned to near pre-treatment levels following washout. (2) Auditory discrimination was significantly improved in unexposed control rats at both doses. (3) As indicated by lever pressing, taurine at both doses had a significant group-equivalent stimulant effect. These results are consistent with the hypothesis that taurine attenuates tinnitus and improves auditory discrimination by increasing inhibitory tone and decreasing noise in the auditory pathway.