Neural Mechanisms of Binaural Processing in the Auditory Brainstem.

Spatial hearing, and more specifically the ability to localize sounds in space, is one of the most studied and best understood aspects of hearing. Because there is no coding of acoustic space at the receptor organ, physiological sensitivity to spatial aspects of sounds first emerges in the central nervous system. Much progress has been made in the identification and characterization of the circuits in the auditory brainstem that create sensitivity to binaural and monaural cues toward acoustic space. We review the progress over the past third of a century, with a focus on the mammalian brainstem and on the anatomy and cellular physiology underlying the physiological tuning of monaural and binaural circuits to acoustic cues toward spatial hearing. In addition to examining the detailed mechanisms involved in the processing of the three main spatial cues, we also review the integration of these cues and their use toward behavior. © 2019 American Physiological Society. Compr Physiol 9:1503-1575, 2019.

What Can We Learn From Point-of-Care Blood Glucose Values Deleted and Repeated by Nurses?

BACKGROUND: Hospitals rely on point-of-care (POC) blood glucose (BG) values to guide important decisions related to insulin administration and glycemic control. Evaluation of POC BG in hospitalized patients is associated with measurement and operator errors. Based on a previous quality improvement (QI) project we introduced an option for operators to delete and repeat POC BG values suspected as erroneous. The current project evaluated our experience with deleted POC BG values over a 2-year period. METHOD: A retrospective QI project included all patients hospitalized at two regional academic medical centers in the Pacific Northwest during 2014 and 2015. Laboratory Medicine POC BG data were reviewed to evaluate all inpatient episodes of deleted and repeated POC BG. RESULTS: Inpatient operators choose to delete and repeat only 0.8% of all POC BG tests. Hypoglycemic and extreme hyperglycemic BG values are more likely to be deleted and repeated. Of initial values <40 mg/dL, 58% of deleted values (18% of all values) are errors. Of values >400 mg/dL, 40% of deleted values (5% of all values) are errors. Not all repeated POC BG values are first deleted. Optimal use of the option to delete and repeat POC BG values <40 mg/dL could decrease reported rates of severe hypoglycemia by as much as 40%. CONCLUSIONS: This project demonstrates that operators are frequently able to identify POC BG values that are measurement/operator errors. Eliminating these errors significantly reduces documented rates of severe hypoglycemia and hyperglycemia, and has the potential to improve patient safety.

Behavior and modeling of two-dimensional precedence effect in head-unrestrained cats.

The precedence effect (PE) is an auditory illusion that occurs when listeners localize nearly coincident and similar sounds from different spatial locations, such as a direct sound and its echo. It has mostly been studied in humans and animals with immobile heads in the horizontal plane; speaker pairs were often symmetrically located in the frontal hemifield. The present study examined the PE in head-unrestrained cats for a variety of paired-sound conditions along the horizontal, vertical, and diagonal axes. Cats were trained with operant conditioning to direct their gaze to the perceived sound location. Stereotypical PE-like behaviors were observed for speaker pairs placed in azimuth or diagonally in the frontal hemifield as the interstimulus delay was varied. For speaker pairs in the median sagittal plane, no clear PE-like behavior occurred. Interestingly, when speakers were placed diagonally in front of the cat, certain PE-like behavior emerged along the vertical dimension. However, PE-like behavior was not observed when both speakers were located in the left hemifield. A Hodgkin-Huxley model was used to simulate responses of neurons in the medial superior olive (MSO) to sound pairs in azimuth. The novel simulation incorporated a low-threshold potassium current and frequency mismatches to generate internal delays. The model exhibited distinct PE-like behavior, such as summing localization and localization dominance. The simulation indicated that certain encoding of the PE could have occurred before information reaches the inferior colliculus, and MSO neurons with binaural inputs having mismatched characteristic frequencies may play an important role.

Dynamic sound localization in cats.

Sound localization in cats and humans relies on head-centered acoustic cues. Studies have shown that humans are able to localize sounds during rapid head movements that are directed toward the target or other objects of interest. We studied whether cats are able to utilize similar dynamic acoustic cues to localize acoustic targets delivered during rapid eye-head gaze shifts. We trained cats with visual-auditory two-step tasks in which we presented a brief sound burst during saccadic eye-head gaze shifts toward a prior visual target. No consistent or significant differences in accuracy or precision were found between this dynamic task (2-step saccade) and the comparable static task (single saccade when the head is stable) in either horizontal or vertical direction. Cats appear to be able to process dynamic auditory cues and execute complex motor adjustments to accurately localize auditory targets during rapid eye-head gaze shifts.

Point-of-care blood glucose measurement errors overestimate hypoglycaemia rates in critically ill patients.

BACKGROUND: Hypoglycaemia is associated with morbidity and mortality in critically ill patients, and many hospitals have programmes to minimize hypoglycaemia rates. Recent studies have established the hypoglycaemic patient-day as a key metric and have published benchmark inpatient hypoglycaemia rates on the basis of point-of-care blood glucose data even though these values are prone to measurement errors. METHODS: A retrospective, cohort study including all patients admitted to Harborview Medical Center Intensive Care Units (ICUs) during 2010 and 2011 was conducted to evaluate a quality improvement programme to reduce inappropriate documentation of point-of-care blood glucose measurement errors. Laboratory Medicine point-of-care blood glucose data and patient charts were reviewed to evaluate all episodes of hypoglycaemia. RESULTS: A quality improvement intervention decreased measurement errors from 31% of hypoglycaemic (<70 mg/dL) patient-days in 2010 to 14% in 2011 (p < 0.001) and decreased the observed hypoglycaemia rate from 4.3% of ICU patient-days to 3.4% (p < 0.001). Hypoglycaemic events were frequently recurrent or prolonged (~40%), and these events are not identified by the hypoglycaemic patient-day metric, which also may be confounded by a large number of very low risk or minimally monitored patient-days. CONCLUSIONS: Documentation of point-of-care blood glucose measurement errors likely overestimates ICU hypoglycaemia rates and can be reduced by a quality improvement effort. The currently used hypoglycaemic patient-day metric does not evaluate recurrent or prolonged events that may be more likely to cause patient harm. The monitored patient-day as currently defined may not be the optimal denominator to determine inpatient hypoglycaemic risk.

Simultaneous comparison of two sound localization measures.

Almost all behavioral studies of sound localization have used either an approach-to-target or pointing/orienting task to assess absolute sound localization performance, yet there are very few direct comparisons of these measures. In an approach-to-target task, the subject is trained to walk to a sound source from a fixed location. In an orienting task, finger, head and/or eye movements are monitored while the subject's body is typically constrained. The fact that subjects may also initiate head and eye movements toward the target during the approach-to-target task allows us to measure the accuracy of the initial orienting response and compare it with subsequent target selection. To perform this comparison, we trained cats to localize a broadband noise presented randomly from one of four speakers located ± 30° and ± 60° in azimuth. The cat responded to each sound presentation by walking to and pressing a lever at the perceived location, and a food reward was delivered if the first attempt was correct. In tandem, we recorded initial head and eye orienting movements, via magnetic search coils, immediately following target onset and prior to the walking response. Reducing either stimulus duration or level resulted in a systematic decline in both measurements of localization performance. When the task was easy, localization performance was accurate for both measures. When the task was more difficult, the number of incorrect (i.e., wrong selection) and no-go (i.e., no selection) responses increased. Interestingly, for many of the incorrect trials, there was a dissociation between the orienting response and the target selected, and for many of the no-go trials, the gaze oriented towards the correct target even though the cat did not move to it. This suggests different neural systems governing walking to a target as compared to unconditioned gaze orienting.

Localization of click trains and speech by cats: the negative level effect.

Although localization of sound in elevation is believed to depend on spectral cues, it has been shown with human listeners that the temporal features of sound can also greatly affect localization performance. Of particular interest is a phenomenon known as the negative level effect, which describes the deterioration of localization ability in elevation with increasing sound level and is observed only with impulsive or short-duration sound. The present study uses the gaze positions of domestic cats as measures of perceived locations of sound targets varying in azimuth and elevation. The effects of sound level on localization in terms of accuracy, precision, and response latency were tested for sound with different temporal features, such as a click train, a single click, a continuous sound that had the same frequency spectrum of the click train, and speech segments. In agreement with previous human studies, negative level effects were only observed with click-like stimuli and only in elevation. In fact, localization of speech sounds in elevation benefited significantly when the sound level increased. Our findings indicate that the temporal continuity of a sound can affect the frequency analysis performed by the auditory system, and the variation in the frequency spectrum contained in speech sound does not interfere much with the spectral coding for its location in elevation.

Evaluation of point-of-care blood glucose measurements in patients with diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome admitted to a critical care unit.

BACKGROUND: Point-of-care (POC) blood glucose (BG) measurement is currently not recommended in the treatment of patients presenting with diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS). METHODS: We prospectively evaluated and compared capillary and venous POC BG values with laboratory venous glucose in patients with DKA or HHS admitted to one critical care unit over 8 months. RESULTS: Venous laboratory glucose was strongly correlated with venous (r = 0.98) and capillary (r = 0.96) POC glucose values, though POC glucose values were higher than venous laboratory values (venous POC 21 ± 3 mg/dl, capillary POC 30 ± 4 mg/dl; both p < .001). Increased plasma osmolality had no effect on glucose meter error, while acidemia (pH < 7.3) was associated with greater glucose meter error (p = .04) independent of glucose levels. Comparing hypothetical insulin infusion rates based on laboratory venous glucose to actual infusion rates based on POC glucose values showed that 33/61 insulin infusion rates would have been unchanged, while 28 out of 61 rates were on average 7% ± 2% higher. There were no instances of hypoglycemia in any of the patients. CONCLUSIONS: Overall, both venous and capillary POC BG values were safe for the purpose of titrating insulin infusions in patients with severe hyperglycemia. Acidemia, but not hyperosmolality, increased POC BG value errors.

Effects of forward masking on sound localization in cats: basic findings with broadband maskers.

Forward masking is traditionally measured with a detection task in which the addition of a preceding masking sound results in an increased signal-detection threshold. Little is known about the influence of forward masking on localization of free-field sound for human or animal subjects. Here we recorded gaze shifts of two head-unrestrained cats during localization using a search-coil technique. A broadband (BB) noise masker was presented straight ahead. A brief signal could come from 1 of the 17 speaker locations in the frontal hemifield. The signal was either a BB or a band-limited (BL) noise. For BB targets, the presence of the forward masker reduced localization accuracy at almost all target levels (20 to 80 dB SPL) along both horizontal and vertical dimensions. Temporal decay of masking was observed when a 15-ms interstimulus gap was added between the end of the masker and the beginning of the target. A large effect of forward masking was also observed for BL targets with low (0.2-2 kHz) and mid (2-7 kHz) frequencies, indicating that the interaural timing cue is susceptible to forward masking. Except at low sound levels, a small or little effect was observed for high-frequency (7-15 kHz) targets, indicating that the interaural level and the spectral cues in that frequency range remained relatively robust. Our findings suggest that different localization mechanisms can operate independently in a complex listening environment.

Gaze shifts to auditory and visual stimuli in cats.

While much is known about the metrics and kinematics of gaze shifts to visual targets in cats, little is known about gaze shifts to auditory targets. Here, cats were trained to localize auditory and visual targets via gaze shifts. Five properties of gaze shifts to sounds were observed. First, gaze shifts were accomplished primarily by large head movements. Unlike primates, the head movement in cats often preceded eye movement though the relative timing of eye in head and head latencies depended upon the target modality and gaze shift magnitude. Second, gaze shift latencies to auditory targets tended to be shorter than equivalent shifts to visual targets for some conditions. Third, the main sequences relating gaze amplitude to maximum gaze velocity for auditory and visual targets were comparable. However, head movements to auditory and visual targets were less consistent than gaze shifts and tended to undershoot the targets by 30 % for both modalities. Fourth, at the end of gaze movement, the proportion of the gaze shift accomplished by the eye-in-head movement was greater to visual than auditory targets. On the other hand, at the end of head movement, the proportion of the gaze shift accomplished by the head was greater to auditory than visual targets. Finally, gaze shifts to long-duration auditory targets were accurate and precise and were similar to accuracy of gaze shifts to long-duration visual targets. Because the metrics of gaze shifts to visual and auditory targets are nearly equivalent, as well as their accuracy, we conclude that both sensorimotor tasks use primarily the same neural substrates for the execution of movement.

Behavioral and modeling studies of sound localization in cats: effects of stimulus level and duration.

Sound localization accuracy in elevation can be affected by sound spectrum alteration. Correspondingly, any stimulus manipulation that causes a change in the peripheral representation of the spectrum may degrade localization ability in elevation. The present study examined the influence of sound duration and level on localization performance in cats with the head unrestrained. Two cats were trained using operant conditioning to indicate the apparent location of a sound via gaze shift, which was measured with a search-coil technique. Overall, neither sound level nor duration had a notable effect on localization accuracy in azimuth, except at near-threshold levels. In contrast, localization accuracy in elevation improved as sound duration increased, and sound level also had a large effect on localization in elevation. For short-duration noise, the performance peaked at intermediate levels and deteriorated at low and high levels; for long-duration noise, this "negative level effect" at high levels was not observed. Simulations based on an auditory nerve model were used to explain the above observations and to test several hypotheses. Our results indicated that neither the flatness of sound spectrum (before the sound reaches the inner ear) nor the peripheral adaptation influences spectral coding at the periphery for localization in elevation, whereas neural computation that relies on "multiple looks" of the spectral analysis is critical in explaining the effect of sound duration, but not level. The release of negative level effect observed for long-duration sound could not be explained at the periphery and, therefore, is likely a result of processing at higher centers.

The role of spectral composition of sounds on the localization of sound sources by cats.

Sound localization along the azimuthal dimension depends on interaural time and level disparities, whereas localization in elevation depends on broadband power spectra resulting from the filtering properties of the head and pinnae. We trained cats with their heads unrestrained, using operant conditioning to indicate the apparent locations of sounds via gaze shift. Targets consisted of broadband (BB), high-pass (HP), or low-pass (LP) noise, tones from 0.5 to 14 kHz, and 1/6 octave narrow-band (NB) noise with center frequencies ranging from 6 to 16 kHz. For each sound type, localization performance was summarized by the slope of the regression relating actual gaze shift to desired gaze shift. Overall localization accuracy for BB noise was comparable in azimuth and in elevation but was markedly better in azimuth than in elevation for sounds with limited spectra. Gaze shifts to targets in azimuth were most accurate to BB, less accurate for HP, LP, and NB sounds, and considerably less accurate for tones. In elevation, cats were most accurate in localizing BB, somewhat less accurate to HP, and less yet to LP noise (although still with slopes ∼0.60), but they localized NB noise much worse and were unable to localize tones. Deterioration of localization as bandwidth narrows is consistent with the hypothesis that spectral information is critical for sound localization in elevation. For NB noise or tones in elevation, unlike humans, most cats did not have unique responses at different frequencies, and some appeared to respond with a "default" location at all frequencies.

The impact of inpatient point-of-care blood glucose quality control testing.

Analyze the effectiveness of mandated point-of-care (POC) blood glucose (BG) meter quality control (QC) testing. All POC BG QC tests were analyzed to evaluate operator and strip/meter error rates and institutional cost. POC BG QC test failure (17/103,580 over 24 months) was low and no meters failed subsequent linearity testing. Examining individual QC measures shows that operator error occurs frequently and total error rate is related to QC familiarity (>50 QC tests/month, 2.4%; <50 QC tests/month, 3.8%, p < .001). Even among the most competent operators, strip/meter error (1.2 ± 0.3%) accounted for 50% of total error. Compared with manufacturer-recommended QC testing, Joint Commission mandated POC BG QC testing during 2008/2009 incurred excess costs of approximately US$127,000. POC BG meter failure within current guidelines is rare and does not justify the cost of daily QC testing. Frequent QC testing can identify operators needing retraining in POC testing. Strip/meter QC errors are common, are not prevented by current QC testing standards, and may contribute to clinical errors.

Axonal branching patterns as sources of delay in the mammalian auditory brainstem: a re-examination.

In models of temporal processing, time delays incurred by axonal propagation of action potentials play a prominent role. A pre-eminent model of temporal processing in audition is the binaural model of Jeffress (1948), which has dominated theories regarding our acute sensitivity to interaural time differences (ITDs). In Jeffress' model, a binaural cell is maximally active when the ITD is compensated by an internal delay, which brings the inputs from left and right ears in coincidence, and which would arise from axonal branching patterns of monaural input fibers. By arranging these patterns in systematic and opposite ways for the ipsilateral and contralateral inputs, a range of length differences, and thereby of internal delays, is created so that the ITD is transformed into a spatial activation pattern along the binaural nucleus. We reanalyze single, labeled, and physiologically characterized axons of spherical bushy cells of the cat anteroventral cochlear nucleus, which project to binaural coincidence detectors in the medial superior olive (MSO). The reconstructions largely confirm the observations of two previous reports, but several features are observed that are inconsistent with Jeffress' model. We found that ipsilateral projections can also form a caudally directed delay line pattern, which would counteract delays incurred by caudally directed contralateral projections. Comparisons of estimated axonal delays with binaural physiological data indicate that the suggestive anatomical patterns cannot account for the frequency-dependent distribution of best delays in the cat. Surprisingly, the tonotopic distribution of the afferent endings indicate that low characteristic frequencies are under-represented rather than over-represented in the MSO.

Short-latency, goal-directed movements of the pinnae to sounds that produce auditory spatial illusions.

The precedence effect (PE) is an auditory spatial illusion whereby two identical sounds presented from two separate locations with a delay between them are perceived as a fused single sound source whose position depends on the value of the delay. By training cats using operant conditioning to look at sound sources, we have previously shown that cats experience the PE similarly to humans. For delays less than +/-400 mus, cats exhibit summing localization, the perception of a "phantom" sound located between the sources. Consistent with localization dominance, for delays from 400 mus to approximately 10 ms, cats orient toward the leading source location only, with little influence of the lagging source. Finally, echo threshold was reached for delays >10 ms, where cats first began to orient to the lagging source. It has been hypothesized by some that the neural mechanisms that produce facets of the PE, such as localization dominance and echo threshold, must likely occur at cortical levels. To test this hypothesis, we measured both pinnae position, which were not under any behavioral constraint, and eye position in cats and found that the pinnae orientations to stimuli that produce each of the three phases of the PE illusion was similar to the gaze responses. Although both eye and pinnae movements behaved in a manner that reflected the PE, because the pinnae moved with strikingly short latencies ( approximately 30 ms), these data suggest a subcortical basis for the PE and that the cortex is not likely to be directly involved.

Influence of sound source location on the behavior and physiology of the precedence effect in cats.

Psychophysical experiments on the precedence effect (PE) in cats have shown that they localize pairs of auditory stimuli presented from different locations in space based on the spatial position of the stimuli and the interstimulus delay (ISD) between the stimuli in a manner similar to humans. Cats exhibit localization dominance for pairs of transient stimuli with |ISDs| from approximately 0.4 to 10 ms, summing localization for |ISDs| < 0.4 ms and breakdown of fusion for |ISDs| > 10 ms, which is the approximate echo threshold. The neural correlates to the PE have been described in both anesthetized and unanesthetized animals at many levels from auditory nerve to cortex. Single-unit recordings from the inferior colliculus (IC) and auditory cortex of cats demonstrate that neurons respond to both lead and lag sounds at ISDs above behavioral echo thresholds, but the response to the lag is reduced at shorter ISDs, consistent with localization dominance. Here the influence of the relative locations of the leading and lagging sources on the PE was measured behaviorally in a psychophysical task and physiologically in the IC of awake behaving cats. At all configurations of lead-lag stimulus locations, the cats behaviorally exhibited summing localization, localization dominance, and breakdown of fusion. Recordings from the IC of awake behaving cats show neural responses paralleling behavioral measurements. Both behavioral and physiological results suggest systematically shorter echo thresholds when stimuli are further apart in space.

The vestibulo-auricular reflex.

The mammalian orienting response to sounds consists of a gaze shift that can be a combination of head and eye movements. In animals with mobile pinnae, the ears also move. During head movements, vision is stabilized by compensatory rotations of the eyeball within the head because of the vestibulo-ocular reflex (VOR). While studying the gaze shifts made by cats to sounds, a previously uncharacterized compensatory movement was discovered. The pinnae exhibited short-latency, goal-directed movements that reached their target while the head was still moving. The pinnae maintained a fixed position in space by counter-rotating on the head with an equal but opposite velocity to the head movement. We call these compensatory ear movements the vestibulo-auricular reflex (VAR) because they shared many kinematic characteristics with the VOR. Control experiments ruled out efference copy of head position signals and acoustic tracking (audiokinetic) of the source as the cause of the response. The VAR may serve to stabilize the auditory world during head movements.

Can measures of sound localization acuity be related to the precision of absolute location estimates?

Studies of sound localization use relative or absolute psychoacoustic paradigms. Relative tasks assess acuity by determining the smallest angle separating two sources that subjects can discriminate, the minimum audible angle (MAA), whereas absolute tasks measure subjects' abilities to indicate sound location. It is unclear whether or how measures from the two tasks are related, though the belief that the MAA is specifically related to the precision of absolute localization is common. The present study aimed to investigate the basis of this relationship by comparing the precision of absolute location estimates with a measure of spatial acuity computed from the same data. Three cats were trained to indicate apparent sound source locations that varied in azimuth and elevation via orienting gaze shifts (combined eye and head movements). The precision of these absolute responses, as measured by their standard deviation, was compared with acuity thresholds derived from receiver operating characteristic (ROC) analyses of the cumulative distributions. Surprisingly, the acuity measures were occasionally very poor indicators of absolute localization precision. Incongruent results were attributed to errors in mean accuracy, which are disregarded in analyses of traditional relative tasks. Discussion focuses on the potential for internal biases to affect measures of localization acuity.

A matter of time: internal delays in binaural processing.

As an animal navigates its surroundings, the sounds reaching its two ears change in waveform similarity (interaural correlation) and in time of arrival (interaural time difference, ITD). Humans are exquisitely sensitive to these binaural cues, and it is generally agreed that this sensitivity involves coincidence detectors and internal delays that compensate for external acoustic delays (ITDs). Recent data show an unexpected relationship between the tuning of a neuron to frequency and to ITD, leading to several proposals for sources of internal delay and the neural coding of interaural temporal cues. We review the alternatives, and argue that an understanding of binaural mechanisms requires consideration of sensitivity not only to ITDs, but also to interaural correlation.

Interaural phase and level difference sensitivity in low-frequency neurons in the lateral superior olive.

The lateral superior olive (LSO) is believed to encode differences in sound level at the two ears, a cue for azimuthal sound location. Most high-frequency-sensitive LSO neurons are binaural, receiving inputs from both ears. An inhibitory input from the contralateral ear, via the medial nucleus of the trapezoid body (MNTB), and excitatory input from the ipsilateral ear enable level differences to be encoded. However, the classical descriptions of low-frequency-sensitive neurons report primarily monaural cells with no contralateral inhibition. Anatomical and physiological evidence, however, shows that low-frequency LSO neurons receive low-frequency inhibitory input from ipsilateral MNTB, which in turn receives excitatory input from the contralateral cochlear nucleus and low-frequency excitatory input from the ipsilateral cochlear nucleus. Therefore, these neurons would be expected to be binaural with contralateral inhibition. Here, we re-examined binaural interaction in low-frequency (less than approximately 3 kHz) LSO neurons and phase locking in the MNTB. Phase locking to low-frequency tones in MNTB and ipsilaterally driven LSO neurons with frequency sensitivities <1.2 kHz was enhanced relative to the auditory nerve. Moreover, most low-frequency LSO neurons exhibited contralateral inhibition: ipsilaterally driven responses were suppressed by raising the level of the contralateral stimulus; most neurons were sensitive to interaural time delays in pure tone and noise stimuli such that inhibition was nearly maximal when the stimuli were presented to the ears in-phase. The data demonstrate that low-frequency LSO neurons of cat are not monaural and can exhibit contralateral inhibition like their high-frequency counterparts.