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Hearing in noisy environments: noise invariance and contrast gain control.

Contrast gain control has recently been identified as a fundamental property of the auditory system. Electrophysiological recordings in ferrets have shown that neurons continuously adjust their gain (their sensitivity to change in sound level) in response to the contrast of sounds that are heard. At the level of the auditory cortex, these gain changes partly compensate for changes in sound contrast. This means that sounds which are structurally similar, but have different contrasts, have similar neuronal representations in the auditory cortex. As a result, the cortical representation is relatively invariant to stimulus contrast and robust to the presence of noise in the stimulus. In the inferior colliculus (an important subcortical auditory structure), gain changes are less reliably compensatory, suggesting that contrast- and noise-invariant representations are constructed gradually as one ascends the auditory pathway. In addition to noise invariance, contrast gain control provides a variety of computational advantages over static neuronal representations; it makes efficient use of neuronal dynamic range, may contribute to redundancy-reducing, sparse codes for sound and allows for simpler decoding of population responses. The circuits underlying auditory contrast gain control are still under investigation. As in the visual system, these circuits may be modulated by factors other than stimulus contrast, forming a potential neural substrate for mediating the effects of attention as well as interactions between the senses.

Multisensory training improves auditory spatial processing following bilateral cochlear implantation.

Cochlear implants (CIs) partially restore hearing to the deaf by directly stimulating the inner ear. In individuals fitted with CIs, lack of auditory experience due to loss of hearing before language acquisition can adversely impact outcomes. For example, adults with early-onset hearing loss generally do not integrate inputs from both ears effectively when fitted with bilateral CIs (BiCIs). Here, we used an animal model to investigate the effects of long-term deafness on auditory localization with BiCIs and approaches for promoting the use of binaural spatial cues. Ferrets were deafened either at the age of hearing onset or as adults. All animals were implanted in adulthood, either unilaterally or bilaterally, and were subsequently assessed for their ability to localize sound in the horizontal plane. The unilaterally implanted animals were unable to perform this task, regardless of the duration of deafness. Among animals with BiCIs, early-onset hearing loss was associated with poor auditory localization performance, compared with late-onset hearing loss. However, performance in the early-deafened group with BiCIs improved significantly after multisensory training with interleaved auditory and visual stimuli. We demonstrate a possible neural substrate for this by showing a training-induced improvement in the responsiveness of auditory cortical neurons and in their sensitivity to interaural level differences, the principal localization cue available to BiCI users. Importantly, our behavioral and physiological evidence demonstrates a facilitative role for vision in restoring auditory spatial processing following potential cross-modal reorganization. These findings support investigation of a similar training paradigm in human CI users.

Linking GABA and glutamate levels to cognitive skill acquisition during development.

Developmental adjustments in the balance of excitation and inhibition are thought to constrain the plasticity of sensory areas of the cortex. It is unknown however, how changes in excitatory or inhibitory neurochemical expression (glutamate, γ-aminobutyric acid (GABA)) contribute to skill acquisition during development. Here we used single-voxel proton magnetic resonance spectroscopy (1H-MRS) to reveal how differences in cortical glutamate vs. GABA ratios relate to face proficiency and working memory abilities in children and adults. We show that higher glutamate levels in the inferior frontal gyrus correlated positively with face processing proficiency in the children, but not the adults, an effect which was independent of age-dependent differences in underlying cortical gray matter. Moreover, we found that glutamate/GABA levels and gray matter volume are dissociated at the different maturational stages. These findings suggest that increased excitation during development is linked to neuroplasticity and the acquisition of new cognitive skills. They also offer a new, neurochemical approach to investigating the relationship between cognitive performance and brain development across the lifespan.

Incorporating Midbrain Adaptation to Mean Sound Level Improves Models of Auditory Cortical Processing.

UNLABELLED: Adaptation to stimulus statistics, such as the mean level and contrast of recently heard sounds, has been demonstrated at various levels of the auditory pathway. It allows the nervous system to operate over the wide range of intensities and contrasts found in the natural world. Yet current standard models of the response properties of auditory neurons do not incorporate such adaptation. Here we present a model of neural responses in the ferret auditory cortex (the IC Adaptation model), which takes into account adaptation to mean sound level at a lower level of processing: the inferior colliculus (IC). The model performs high-pass filtering with frequency-dependent time constants on the sound spectrogram, followed by half-wave rectification, and passes the output to a standard linear-nonlinear (LN) model. We find that the IC Adaptation model consistently predicts cortical responses better than the standard LN model for a range of synthetic and natural stimuli. The IC Adaptation model introduces no extra free parameters, so it improves predictions without sacrificing parsimony. Furthermore, the time constants of adaptation in the IC appear to be matched to the statistics of natural sounds, suggesting that neurons in the auditory midbrain predict the mean level of future sounds and adapt their responses appropriately. SIGNIFICANCE STATEMENT: An ability to accurately predict how sensory neurons respond to novel stimuli is critical if we are to fully characterize their response properties. Attempts to model these responses have had a distinguished history, but it has proven difficult to improve their predictive power significantly beyond that of simple, mostly linear receptive field models. Here we show that auditory cortex receptive field models benefit from a nonlinear preprocessing stage that replicates known adaptation properties of the auditory midbrain. This improves their predictive power across a wide range of stimuli but keeps model complexity low as it introduces no new free parameters. Incorporating the adaptive coding properties of neurons will likely improve receptive field models in other sensory modalities too.

Measuring the Performance of Neural Models.

Good metrics of the performance of a statistical or computational model are essential for model comparison and selection. Here, we address the design of performance metrics for models that aim to predict neural responses to sensory inputs. This is particularly difficult because the responses of sensory neurons are inherently variable, even in response to repeated presentations of identical stimuli. In this situation, standard metrics (such as the correlation coefficient) fail because they do not distinguish between explainable variance (the part of the neural response that is systematically dependent on the stimulus) and response variability (the part of the neural response that is not systematically dependent on the stimulus, and cannot be explained by modeling the stimulus-response relationship). As a result, models which perfectly describe the systematic stimulus-response relationship may appear to perform poorly. Two metrics have previously been proposed which account for this inherent variability: Signal Power Explained (SPE, Sahani and Linden, 2003), and the normalized correlation coefficient (CC norm , Hsu et al., 2004). Here, we analyze these metrics, and show that they are intimately related. However, SPE has no lower bound, and we show that, even for good models, SPE can yield negative values that are difficult to interpret. CC norm is better behaved in that it is effectively bounded between -1 and 1, and values below zero are very rare in practice and easy to interpret. However, it was hitherto not possible to calculate CC norm directly; instead, it was estimated using imprecise and laborious resampling techniques. Here, we identify a new approach that can calculate CC norm quickly and accurately. As a result, we argue that it is now a better choice of metric than SPE to accurately evaluate the performance of neural models.

Mistuning detection performance of ferrets in a go/no-go task.

The harmonic structure of sounds is an important grouping cue in auditory scene analysis. The ability of ferrets to detect mistuned harmonics was measured using a go/no-go task paradigm. Psychometric functions plotting sensitivity as a function of degree of mistuning were used to evaluate behavioral performance using signal detection theory. The mean (± standard error of the mean) threshold for mistuning detection was 0.8 ± 0.1 Hz, with sensitivity indices and reaction times depending on the degree of mistuning. These data provide a basis for investigation of the neural basis for the perception of complex sounds in ferrets, an increasingly used animal model in auditory research.

Translational neurocardiology: preclinical models and cardioneural integrative aspects.

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.

Procedural Success of Left Ventricular Lead Placement for Cardiac Resynchronization Therapy: A Meta-Analysis.

OBJECTIVES: The goal of this study was to assess the contemporary and historical success rates of transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy (CRT), their change over time, and the reasons for failure. BACKGROUND: In selected patients, CRT improves morbidity and mortality, but the placement of the LV lead can be technically challenging. METHODS: A literature search was used to identify all studies reporting success rates of LV lead placement for CRT via the coronary sinus (CS) route. A total of 164 studies were identified, and a meta-analysis was performed. RESULTS: The studies included 29,503 patients: 74% (95% confidence interval [CI]: 72% to 76%) were male; their mean age was 66 years (95% CI: 65 to 67); their mean New York Heart Association functional class was 2.8 (95% CI: 2.7 to 2.9); the mean LV ejection fraction was 26% (95% CI: 25% to 28%); and the mean QRS duration was 155 ms (95% CI: 150 to 160). The overall rate of failure of implantation of an LV lead was 3.6% (95% CI: 3.1 to 4.3). The rate of failure in studies commencing before 2005 was 5.4% (95% CI: 4.4% to 6.5%), and from 2005 onward it was 2.4% (95% CI: 1.9% to 3.1%; p < 0.001). Causes of failure (reported for 39% of failures) also changed over time. Failure to cannulate and navigate the CS decreased from 53% to 30% (p = 0.01), and the absence of any suitable, acceptable vein increased from 39% to 64% (p = 0.007). The proportion of leads in a lateral or posterolateral final position (reported for 26% of leads) increased from 66% to 82% (p = 0.004). CONCLUSIONS: The reported rate of failure to place an LV lead via the CS has decreased steadily over time. A greater proportion of failures in recent studies are due to coronary venous anatomy that is unsuitable for this technique.

Integration of visual and auditory information in bimodal neurones in the guinea-pig superior colliculus.

We have investigated the responses of neurones in the guinea-pig superior colliculus to combinations of visual and auditory stimuli. When these stimuli were presented separately, some of these neurones responded only to one modality, others to both and a few neurones reliably to neither. To bimodal stimulation, many of these neurones exhibited some form of cross-modality interaction, the degree and nature of which depended on the relative timing and location of the two stimuli. Facilitatory and inhibitory interactions were observed and, occasionally, both effects were found in the same neurone at different inter-stimulus intervals. Neurones whose responses to visual stimuli were enhanced by an auditory stimulus were found in the superficial layers. Although visual-enhanced and visual-depressed auditory neurones were found throughout the deep layers, the majority of them were recorded in the stratum griseum profundum. Neurones that responded to both visual and auditory stimuli presented separately and gave enhanced or depressed responses to bimodal stimulation were found throughout the deep layers, but were concentrated in the stratum griseum intermediale and extended into the stratum opticum.

Cells responsive to free-field auditory stimuli in guinea-pig superior colliculus: distribution and response properties.

We have investigated the responses of superior colliculus neurones in the anaesthetized guinea-pig to free-field auditory stimulation. The auditory cells were located throughout the deeper laminae and also in the lower part of the stratum opticum. Auditory cells were not found in the rostral pole of the superior colliculus. The auditory responses consisted of a few spikes at stimulus onset with a latency from stimulus arrival at the ear of 7-27 ms. Frequency response areas were measured for forty-five neurones; many of these areas were broad or multipeaked although some were well defined and 'V' shaped. White noise was a more effective stimulus than tones. The majority of cells in our sample responded best to sounds from a restricted horizontal location. Two major response types were found: (1) neurones responding to the same localized area of space despite changes in sound level and (2) neurones responding only to a localized area of space near threshold, but to an extensive area for louder sounds. As the site of the recording electrode was moved from the rostral to the caudal part of the superior colliculus, the location of the auditory receptive fields shifted from the anterior to the posterior field of the animal, thus indicating the presence of a map of auditory space. The visual projection to the guinea-pig superior colliculus was determined and found to be similar to that in other vertebrates. Comparison of visual and auditory space maps in the guinea-pig superior colliculus reveals that receptive fields are coincident over a wide range, but severe discrepancies were evident between the visual and auditory receptive field positions represented at single locations in rostral and caudal colliculus.

A monaural space map in the guinea-pig superior colliculus.

Under anechoic conditions, a horizontal array of loudspeakers was used to investigate the representation of auditory space in the guinea-pig superior colliculus. We have previously demonstrated that in animals with both ears intact, there is a topographical representation of the azimuthal dimension of auditory space in the deep layers of this nucleus. In the present study, we have investigated the contribution of monaural and binaural cues to the generation of the auditory space map. Occlusion of one ear or unilateral cochlear destruction resulted in omnidirectional responses in all cells to white-noise stimuli more than 20 dB suprathreshold. The sensitivity of cells to the location of sound at or near threshold was, however, unchanged and we demonstrate the presence of a threshold, monaural auditory space map. This monaural space map was destroyed by removal of the contralateral pinna and concha which resulted in all cells responding best, at threshold, to sounds opposite the external auditory meatus. Measurements of cochlear microphonic (CM) potentials, although variable, revealed that the pinna and concha may result in location-specific changes in the spectral pattern at the tympanic membrane.

The synaptic distribution of the retinal input in the superficial layers of the guinea-pig superior colliculus.

An evoked potential consisting of four postsynaptic components was recorded in the guinea-pig superior colliculus following electrical stimulation of the contralateral optic nerve. This potential was generated in response to the activation of four populations of optic nerve fibres with different conduction velocities. Current source-density analysis revealed that the two slower conducting fibre populations synapse in the upper third of the stratum griseum superficiale on dendrites whose cell bodies appear to be found in the lower part of this layer and in the stratum opticum. The two faster conducting populations synapse deeper, near the border of the stratum griseum superficiale and stratum opticum, on neurons with cell bodies that may lie towards the upper part of the stratum griseum superficiale. The locations of these postsynaptic sites correspond to the layers in which the optic nerve terminates as revealed by neuroanatomical tracing techniques. Furthermore, neurons of the shape and orientation predicted by the current source-density analysis were found in the superficial layers by using the Golgi-Cox technique.

Development of Multisensory Spatial Integration

© Oxford University Press 2004. All rights reserved. This chapter examines the development of multimodal perception and processing in humans and other species, and the major role that sensory experience plays during early life in linking modality-specific inputs to form a coherent multisensory representation of the environment. At a neurophysiological level, the developmental mechanisms involved in the synthesis of multisensory spatial information in the superior colliculus (SC), a midbrain structure involved in the control of target-directed orienting movements, have received the most attention.

The representation of auditory space in the mammalian superior colliculus.

Network Receptive Field Modeling Reveals Extensive Integration and Multi-feature Selectivity in Auditory Cortical Neurons.

Cortical sensory neurons are commonly characterized using the receptive field, the linear dependence of their response on the stimulus. In primary auditory cortex neurons can be characterized by their spectrotemporal receptive fields, the spectral and temporal features of a sound that linearly drive a neuron. However, receptive fields do not capture the fact that the response of a cortical neuron results from the complex nonlinear network in which it is embedded. By fitting a nonlinear feedforward network model (a network receptive field) to cortical responses to natural sounds, we reveal that primary auditory cortical neurons are sensitive over a substantially larger spectrotemporal domain than is seen in their standard spectrotemporal receptive fields. Furthermore, the network receptive field, a parsimonious network consisting of 1-7 sub-receptive fields that interact nonlinearly, consistently better predicts neural responses to auditory stimuli than the standard receptive fields. The network receptive field reveals separate excitatory and inhibitory sub-fields with different nonlinear properties, and interaction of the sub-fields gives rise to important operations such as gain control and conjunctive feature detection. The conjunctive effects, where neurons respond only if several specific features are present together, enable increased selectivity for particular complex spectrotemporal structures, and may constitute an important stage in sound recognition. In conclusion, we demonstrate that fitting auditory cortical neural responses with feedforward network models expands on simple linear receptive field models in a manner that yields substantially improved predictive power and reveals key nonlinear aspects of cortical processing, while remaining easy to interpret in a physiological context.

Behavioural benefits of multisensory processing in ferrets.

Enhanced detection and discrimination, along with faster reaction times, are the most typical behavioural manifestations of the brain's capacity to integrate multisensory signals arising from the same object. In this study, we examined whether multisensory behavioural gains are observable across different components of the localization response that are potentially under the command of distinct brain regions. We measured the ability of ferrets to localize unisensory (auditory or visual) and spatiotemporally coincident auditory-visual stimuli of different durations that were presented from one of seven locations spanning the frontal hemifield. During the localization task, we recorded the head movements made following stimulus presentation, as a metric for assessing the initial orienting response of the ferrets, as well as the subsequent choice of which target location to approach to receive a reward. Head-orienting responses to auditory-visual stimuli were more accurate and faster than those made to visual but not auditory targets, suggesting that these movements were guided principally by sound alone. In contrast, approach-to-target localization responses were more accurate and faster to spatially congruent auditory-visual stimuli throughout the frontal hemifield than to either visual or auditory stimuli alone. Race model inequality analysis of head-orienting reaction times and approach-to-target response times indicates that different processes, probability summation and neural integration, respectively, are likely to be responsible for the effects of multisensory stimulation on these two measures of localization behaviour.

Cost-Effectiveness Analysis of Quadripolar Versus Bipolar Left Ventricular Leads for Cardiac Resynchronization Defibrillator Therapy in a Large, Multicenter UK Registry.

OBJECTIVES: The objective of this study was to evaluate the cost-effectiveness of quadripolar versus bipolar cardiac resynchronization defibrillator therapy systems. BACKGROUND: Quadripolar left ventricular (LV) leads for cardiac resynchronization therapy reduce phrenic nerve stimulation (PNS) and are associated with reduced mortality compared with bipolar leads. METHODS: A total of 606 patients received implants at 3 UK centers (319 Q, 287 B), between 2009 and 2014; mean follow-up was 879 days. Rehospitalization episodes were costed at National Health Service national tariff rates, and EQ-5D utility values were applied to heart failure admissions, acute coronary syndrome events, and mortality data, which were used to estimate quality-adjusted life-year differences over 5 years. RESULTS: Groups were matched with regard to age and sex. Patients with quadripolar implants had a lower rate of hospitalization than those with bipolar implants (42.6% vs. 55.4%; p = 0.002). This was primarily driven by fewer hospital readmissions for heart failure (51 [16%] vs. 75 [26.1%], respectively, for quadripolar vs. bipolar implants; p = 0.003) and generator replacements (9 [2.8%] vs. 19 [6.6%], respectively; p = 0.03). Hospitalization for suspected acute coronary syndrome, arrhythmia, device explantation, and lead revisions were similar. This lower health-care utilization cost translated into a cumulative 5-year cost saving for patients with quadripolar systems where the acquisition cost was <£932 (US $1,398) compared with bipolar systems. Probabilistic sensitivity analysis results mirrored the deterministic calculations. For the average additional price of £1,200 (US $1,800) over a bipolar system, the incremental cost-effective ratio was £3,692 per quality-adjusted life-year gained (US $5,538), far below the usual willingness-to-pay threshold of £20,000 (US $30,000). CONCLUSIONS: In a UK health-care 5-year time horizon, the additional purchase price of quadripolar cardiac resynchronization defibrillator therapy systems is largely offset by lower subsequent event costs up to 5 years after implantation, which makes this technology highly cost-effective compared with bipolar systems.

Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis.

Aims: Endocardial left ventricular (LV) pacing for Cardiac Resynchronization Therapy has been proposed as an alternative to conventional LV lead placement via the coronary sinus. In order to assess the relative benefits and risks of this technique, we have performed a meta-analysis of published reports. Methods and results: A systemic search was performed using online databases to identify studies of lead-based endocardial pacing. A random-effects meta-analysis was performed, to assess the rate of complications and clinical response (defined as ≥1 decrease in NYHA class). We selected 23 studies, including 384 patients. The trans-atrial septal technique was used in 20 studies, 1 used the trans-ventricular apical technique, and 2 used the trans-ventricular septal technique. Mean age was 66 years, male 66%, EF 26%, NYHA class 3.0. Procedural success rates were over 95% in all studies. Clinical response was reported by 16 studies for 262 patients, giving a response estimate of 82% (95% CI 71-89%). There was significant heterogeneity, and response in the only large study was 59%. Thromboembolic (TE) complications were reported by all studies, over 22 ±32 months follow up. The rate of stroke was 2.5 events per 100 patient years (95% CI 1.5-4.3), and TIA 2.6 (1.1-6.1). The mortality rate was 4.5 (1.5-13.6) per 100 patient years. Conclusion: LV endocardial pacing appears to be a viable technique when conventional lead placement is not possible. Response rates were heterogeneous but comparable with conventional CRT. There is likely to be a small increase over expected rates of stroke, although included patients were high risk.

Physiology of shock and volume resuscitation

© 2016 Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This review therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to management. Fluid resuscitation saves lives but considerable debate remains regarding the ideal fluid type and strategy to use. Blood transfusion is also a critical therapy in the shocked, bleeding patient with a lower threshold for transfusion being appropriate in the elderly patient with less physiological reserve. Reversal of anticoagulant medications and the administration of coagulation products should support both fluid and red cell therapy to counteract the multifactorial coagulopathy that can accompany severe trauma, haemorrhage and shock. The aim is to stabilize the patient such that any interventional strategies (both percutaneous and surgical) can be considered for uncontrolled bleeding.

A dynamic network model of temporal receptive fields in primary auditory cortex.

Auditory neurons encode stimulus history, which is often modelled using a span of time-delays in a spectro-temporal receptive field (STRF). We propose an alternative model for the encoding of stimulus history, which we apply to extracellular recordings of neurons in the primary auditory cortex of anaesthetized ferrets. For a linear-non-linear STRF model (LN model) to achieve a high level of performance in predicting single unit neural responses to natural sounds in the primary auditory cortex, we found that it is necessary to include time delays going back at least 200 ms in the past. This is an unrealistic time span for biological delay lines. We therefore asked how much of this dependence on stimulus history can instead be explained by dynamical aspects of neurons. We constructed a neural-network model whose output is the weighted sum of units whose responses are determined by a dynamic firing-rate equation. The dynamic aspect performs low-pass filtering on each unit's response, providing an exponentially decaying memory whose time constant is individual to each unit. We find that this dynamic network (DNet) model, when fitted to the neural data using STRFs of only 25 ms duration, can achieve prediction performance on a held-out dataset comparable to the best performing LN model with STRFs of 200 ms duration. These findings suggest that integration due to the membrane time constants or other exponentially-decaying memory processes may underlie linear temporal receptive fields of neurons beyond 25 ms.