Low-dimensional interference of mid-level sound statistics predicts human speech recognition in natural environmental noise.

Recognizing speech in noise, such as in a busy street or restaurant, is an essential listening task where the task difficulty varies across acoustic environments and noise levels. Yet, current cognitive models are unable to account for changing real-world hearing sensitivity. Here, using natural and perturbed background sounds we demonstrate that spectrum and modulations statistics of environmental backgrounds drastically impact human word recognition accuracy and they do so independently of the noise level. These sound statistics can facilitate or hinder recognition - at the same noise level accuracy can range from 0% to 100%, depending on the background. To explain this perceptual variability, we optimized a biologically grounded hierarchical model, consisting of frequency-tuned cochlear filters and subsequent mid-level modulation-tuned filters that account for central auditory tuning. Low-dimensional summary statistics from the mid-level model accurately predict single trial perceptual judgments, accounting for more than 90% of the perceptual variance across backgrounds and noise levels, and substantially outperforming a cochlear model. Furthermore, perceptual transfer functions in the mid-level auditory space identify multi-dimensional natural sound features that impact recognition. Thus speech recognition in natural backgrounds involves interference of multiple summary statistics that are well described by an interpretable, low-dimensional auditory model. Since this framework relates salient natural sound cues to single trial perceptual judgements, it may improve outcomes for auditory prosthetics and clinical measurements of real-world hearing sensitivity.

Can statin preventative treatment inform geroscience-guided therapeutics?

Potential senotherapeutic effect of statins may lead to prevention and reduction of frailty.

Generalized Dystonia Due to a Pathogenic THAP1 Variant Showing Sustained Response to Globus Pallidus Deep Brain Stimulation.

A 21-year-old woman of south Asian origin presented with cervical dystonia which had progressed over the previous three years. Her symptoms started as writer's cramp since the age of seven years. She did not respond to medications and needed botulinum toxin injection for generalised dystonia. Subsequent whole genome sequencing revealed a likely pathogenic c.98G>A p.(Cys33Tyr) heterozygous variant in the THAP1 gene. She underwent bilateral posteroventral globus pallidus interna (GPi) deep brain stimulation (Medtronic Activa PC) implantation at the age of thirty-one years. She responded well to the deep brain stimulation even after more than 8 years post-surgery though she needs botulinum toxin injection for her cervical dystonia.

Two stages of bandwidth scaling drives efficient neural coding of natural sounds.

Theories of efficient coding propose that the auditory system is optimized for the statistical structure of natural sounds, yet the transformations underlying optimal acoustic representations are not well understood. Using a database of natural sounds including human speech and a physiologically-inspired auditory model, we explore the consequences of peripheral (cochlear) and mid-level (auditory midbrain) filter tuning transformations on the representation of natural sound spectra and modulation statistics. Whereas Fourier-based sound decompositions have constant time-frequency resolution at all frequencies, cochlear and auditory midbrain filters bandwidths increase proportional to the filter center frequency. This form of bandwidth scaling produces a systematic decrease in spectral resolution and increase in temporal resolution with increasing frequency. Here we demonstrate that cochlear bandwidth scaling produces a frequency-dependent gain that counteracts the tendency of natural sound power to decrease with frequency, resulting in a whitened output representation. Similarly, bandwidth scaling in mid-level auditory filters further enhances the representation of natural sounds by producing a whitened modulation power spectrum (MPS) with higher modulation entropy than both the cochlear outputs and the conventional Fourier MPS. These findings suggest that the tuning characteristics of the peripheral and mid-level auditory system together produce a whitened output representation in three dimensions (frequency, temporal and spectral modulation) that reduces redundancies and allows for a more efficient use of neural resources. This hierarchical multi-stage tuning strategy is thus likely optimized to extract available information and may underlies perceptual sensitivity to natural sounds.

Effects of Testosterone on Mixed-Muscle Protein Synthesis and Proteome Dynamics During Energy Deficit.

CONTEXT: Effects of testosterone on integrated muscle protein metabolism and muscle mass during energy deficit are undetermined. OBJECTIVE: The objective was to determine the effects of testosterone on mixed-muscle protein synthesis (MPS), proteome-wide fractional synthesis rates (FSR), and skeletal muscle mass during energy deficit. DESIGN: This was a randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted at Pennington Biomedical Research Center. PARTICIPANTS: Fifty healthy men. INTERVENTION: The study consisted of 14 days of weight maintenance, followed by a 28-day 55% energy deficit with 200 mg testosterone enanthate (TEST, n = 24) or placebo (PLA, n = 26) weekly, and up to 42 days of ad libitum recovery feeding. MAIN OUTCOME MEASURES: Mixed-MPS and proteome-wide FSR before (Pre), during (Mid), and after (Post) the energy deficit were determined using heavy water (days 1-42) and muscle biopsies. Muscle mass was determined using the D3-creatine dilution method. RESULTS: Mixed-MPS was lower than Pre at Mid and Post (P < 0.0005), with no difference between TEST and PLA. The proportion of individual proteins with numerically higher FSR in TEST than PLA was significant by 2-tailed binomial test at Post (52/67; P < 0.05), but not Mid (32/67; P > 0.05). Muscle mass was unchanged during energy deficit but was greater in TEST than PLA during recovery (P < 0.05). CONCLUSIONS: The high proportion of individual proteins with greater FSR in TEST than PLA at Post suggests exogenous testosterone exerted a delayed but broad stimulatory effect on synthesis rates across the muscle proteome during energy deficit, resulting in muscle mass accretion during subsequent recovery.

Altered Pain Processing Associated with Administration of Dopamine Agonist and Antagonist in Healthy Volunteers.

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals' ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.

Daytime Sleep Behaviors and Cognitive Performance in Middle- to Older-Aged Adults Living with and without HIV Infection.

PURPOSE: We investigated whether daytime sleep behaviors (DSBs) such as frequent daytime sleepiness or napping are associated with worse cognitive performance, and whether HIV infection moderates this relationship. METHODS: Among 502,507 participants in the UK Biobank study, we identified 562 people living with HIV infection (PLWH; M age= 50.51±7.81; 25.09% female; 78.83% white) and extracted 562 uninfected controls who matched on age, sex, ethnic background, social-economic status, and comorbidities. DSB burden was assessed based on answers to two questions on DSBs. Participants who answered "sometimes" or "often/usually" to one of them were considered to have poor DSB burden, or otherwise were considered not having any. A composite cognition score was computed by averaging the available standardized individual test results from four neurocognitive tests: ie, a reaction time test for information processing speed, a pairs matching test for visual episodic memory, a fluid intelligence test for reasoning, and a prospective memory test. Mixed-effects models with adjustment for the variables used in extracting matched uninfected controls were performed to test the hypotheses. RESULTS: Having poor DSB burden was associated with a 0.15 - standard deviation (SD) decrease in cognitive performance (p = 0.006). People living with HIV infection (PLWH) also performed worse on the cognitive tasks than uninfected controls, with an effect size similar to that of having poor DSB burden (p = 0.003). HIV infection significantly modified the negative association between DSB burden and cognition (p for interaction: 0.008). Specifically, the association between DSB burden and cognition was not statistically significant in uninfected controls, whereas PLWH who reported having poor DSB burden had a 0.28 - SD decrease in cognitive performance compared to PLWH who did not. CONCLUSION: HIV infection significantly increased the adverse association between DSBs and cognitive performance. Further studies are needed to investigate the potential mechanisms that underlie this interaction effect and whether poor DSBs and worse cognitive performance are causally linked.

The seeds of invasion: enhanced germination in invasive European populations of black locust (Robinia pseudoacacia L.) compared to native American populations.

Local adaptation and the evolution of phenotypic plasticity may facilitate biological invasions. Both processes can enhance germination and seedling recruitment, which are crucial life-history traits for plants. The rate, timing and speed of germination have recently been documented as playing a major role during the invasion process. Black locust (Robinia pseudoacacia L.) is a North American tree, which has spread widely throughout Europe. A recent study demonstrated that a few populations are the source of European black locust. Thus, invasive populations can be compared to native ones in order to identify genetic-based phenotypic differentiation and the role of phenotypic plasticity can thereby be assessed. A quantitative genetics experiment was performed to evaluate 13 juvenile traits of both native and invasive black locust populations (3000 seeds, 20 populations) subjected to three different thermal treatments (18 °C, 22 °C and 31 °C). The results revealed European populations to have a higher germination rate than the native American populations (88% versus 60%), and even when genetic distance between populations was considered. Moreover, this trait showed lower plasticity to temperature in the invasive range than in the native one. Conversely, other studied traits showed high plasticity to temperature, but they responded in a similar way to temperature increase: the warmer the temperature, the higher the growth rate or germination traits values. The demonstrated genetic differentiation between native and invasive populations testifies to a shift between ranges for the maximum germination percentage. This pattern could be due to human-mediated introduction of black locust.

Distinct neural ensemble response statistics are associated with recognition and discrimination of natural sound textures.

The perception of sound textures, a class of natural sounds defined by statistical sound structure such as fire, wind, and rain, has been proposed to arise through the integration of time-averaged summary statistics. Where and how the auditory system might encode these summary statistics to create internal representations of these stationary sounds, however, is unknown. Here, using natural textures and synthetic variants with reduced statistics, we show that summary statistics modulate the correlations between frequency organized neuron ensembles in the awake rabbit inferior colliculus (IC). These neural ensemble correlation statistics capture high-order sound structure and allow for accurate neural decoding in a single trial recognition task with evidence accumulation times approaching 1 s. In contrast, the average activity across the neural ensemble (neural spectrum) provides a fast (tens of milliseconds) and salient signal that contributes primarily to texture discrimination. Intriguingly, perceptual studies in human listeners reveal analogous trends: the sound spectrum is integrated quickly and serves as a salient discrimination cue while high-order sound statistics are integrated slowly and contribute substantially more toward recognition. The findings suggest statistical sound cues such as the sound spectrum and correlation structure are represented by distinct response statistics in auditory midbrain ensembles, and that these neural response statistics may have dissociable roles and time scales for the recognition and discrimination of natural sounds.

Optimal Multichannel Artifact Prediction and Removal for Neural Stimulation and Brain Machine Interfaces.

Neural implants that deliver multi-site electrical stimulation to the nervous systems are no longer the last resort but routine treatment options for various neurological disorders. Multi-site electrical stimulation is also widely used to study nervous system function and neural circuit transformations. These technologies increasingly demand dynamic electrical stimulation and closed-loop feedback control for real-time assessment of neural function, which is technically challenging since stimulus-evoked artifacts overwhelm the small neural signals of interest. We report a novel and versatile artifact removal method that can be applied in a variety of settings, from single- to multi-site stimulation and recording and for current waveforms of arbitrary shape and size. The method capitalizes on linear electrical coupling between stimulating currents and recording artifacts, which allows us to estimate a multi-channel linear Wiener filter to predict and subsequently remove artifacts via subtraction. We confirm and verify the linearity assumption and demonstrate feasibility in a variety of recording modalities, including in vitro sciatic nerve stimulation, bilateral cochlear implant stimulation, and multi-channel stimulation and recording between the auditory midbrain and cortex. We demonstrate a vast enhancement in the recording quality with a typical artifact reduction of 25-40 dB. The method is efficient and can be scaled to arbitrary number of stimulus and recording sites, making it ideal for applications in large-scale arrays, closed-loop implants, and high-resolution multi-channel brain-machine interfaces.

Testosterone supplementation upregulates androgen receptor expression and translational capacity during severe energy deficit.

Testosterone supplementation during energy deficit promotes whole body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before, 1 h, and 6 h after exercise and a mixed meal (40 g protein, 1 h postexercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active nonobese men treated with 200 mg testosterone enanthate/wk (TEST) or placebo (PLA) during the ED. Participants (n = 10/group) exhibiting substantial increases in leg lean mass and total testosterone (TEST) were compared with those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 gene expression was lower in TEST vs. PLA during ED relative to WM (P < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA (P < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.

Spiking network optimized for word recognition in noise predicts auditory system hierarchy.

The auditory neural code is resilient to acoustic variability and capable of recognizing sounds amongst competing sound sources, yet, the transformations enabling noise robust abilities are largely unknown. We report that a hierarchical spiking neural network (HSNN) optimized to maximize word recognition accuracy in noise and multiple talkers predicts organizational hierarchy of the ascending auditory pathway. Comparisons with data from auditory nerve, midbrain, thalamus and cortex reveals that the optimal HSNN predicts several transformations of the ascending auditory pathway including a sequential loss of temporal resolution and synchronization ability, increasing sparseness, and selectivity. The optimal organizational scheme enhances performance by selectively filtering out noise and fast temporal cues such as voicing periodicity, that are not directly relevant to the word recognition task. An identical network arranged to enable high information transfer fails to predict auditory pathway organization and has substantially poorer performance. Furthermore, conventional single-layer linear and nonlinear receptive field networks that capture the overall feature extraction of the HSNN fail to achieve similar performance. The findings suggest that the auditory pathway hierarchy and its sequential nonlinear feature extraction computations enhance relevant cues while removing non-informative sources of noise, thus enhancing the representation of sounds in noise impoverished conditions.

Real world use of a neurophysiology service for the differential diagnosis of hyperkinetic movement disorders.

INTRODUCTION: Clinical neurophysiology constitutes a potentially useful aid in differentiating hyperkinetic movement disorders (HMD). Parameters including presence of a Bereitschaftspotential on back-averaged electroencephalography (EEG) have been demonstrated to help distinguish between these disorders. In 2008, a Movement Disorder neurophysiology service was established in Greater Manchester to aid in the diagnostic process. METHODS: We retrospectively reviewed records of patients with HMD who underwent EEG back-averaging through this service from January 2009 until January 2018. The aim was (i) to characterise the clinical features of our patient cohort and (ii) to determine how frequently neurophysiological testing altered the final diagnosis. RESULTS: A total of 39 patients (23 females, 16 males), with a mean age at onset of 42.6 years and mean disease duration of 2.0 years underwent neurophysiological examination. The clinical diagnosis was changed in 16 cases (41%) and refined in a further seven. Distractibility (P = 0.001), variability (P = 0.002), the presence of a Bereitschaftspotential (P < 0.0001), and electromyography burst duration > 300 ms (P = 0.012) were more frequent in those with an eventual diagnosis of functional movement disorder (n = 24) compared to other HMDs (n = 15). CONCLUSION: Neurophysiology is an invaluable adjunct in complex HMD, altering the diagnosis and treatment options for a significant proportion of patients. Our data also demonstrate, consistent with previous studies, that the majority of patients referred for jerky HMDs to a tertiary movement disorder service have a functional movement disorder.