Motor, somatosensory, and executive cortical areas elicit monosynaptic and polysynaptic neuronal activity in the auditory midbrain.

We recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in auditory cortex (AC), but also in multiple 'non-auditory' regions of the cerebral cortex. Here, in anaesthetised rats, we used optogenetics and electrical stimulation, combined with recording in the inferior colliculus to determine the functional influence of these descending connections. Specifically, we determined the extent of monosynaptic excitation and the influence of these descending connections on spontaneous activity in the inferior colliculus. A retrograde virus encoding both green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICc) resulted in GFP expression in discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and primary motor cortex (M1) caused local activation of cortical neurones and increased the firing rate of neurones in ICc indicating a direct excitatory input from AC and M1 to ICc with a restricted distribution. In naïve animals, electrical stimulation at multiple different sites within M1, secondary motor, somatosensory, and prefrontal cortices increased firing rate in ICc. However, it was notable that stimulation at some adjacent sites failed to influence firing at the recording site in ICc. Responses in ICc comprised singular spikes of constant shape and size which occurred with a short, and fixed latency (∼ 5 ms) consistent with monosynaptic excitation of individual ICc units. Increasing the stimulus current decreased the latency of these spikes, suggesting more rapid depolarization of cortical neurones, and increased the number of (usually adjacent) channels on which a monosynaptic spike was seen, suggesting recruitment of increasing numbers of cortical neurons. Electrical stimulation of cortical regions also evoked longer latency, longer duration increases in firing activity, comprising multiple units with spikes occurring with significant temporal jitter, consistent with polysynaptic excitation. Increasing the stimulus current increased the number of spikes in these polysynaptic responses and increased the number of channels on which the responses were observed, although the magnitude of the responses always diminished away from the most activated channels. Together our findings indicate descending connections from motor, somatosensory and executive cortical regions directly activate small numbers of ICc neurones and that this in turn leads to extensive polysynaptic activation of local circuits within the ICc.

Differences Between Self-Reported and Objectively Measured Hearing Loss at Age 61-63 Years: The Newcastle Thousand Families Birth Cohort.

PURPOSE: Hearing loss is most prevalent among older adults, yet underestimated by patients, clinicians, and research communities. This study aimed to assess the accuracy of self-reported hearing difficulties among a group of adults aged 61-63 years, against audiometric measures. METHOD: The analysis used a sample (N = 346) of the Newcastle Thousand Families Study birth cohort. Data from audiological examinations and self-reported hearing difficulties were used to compare subjective and objective hearing. Hearing aid use was also assessed. RESULTS: Over 40% of the participants had some level of hearing loss (n = 155, 44.8%), and 31% (n = 133) of these reported having hearing problems during subjective assessment. Only 18 (10%) of those with objectively measured hearing loss reported using hearing aids. CONCLUSIONS: There was an inconsistency between measured and self-perceived hearing loss among adults aged 61-63 years in this cohort. The small number of hearing aid users in the cohort is a concern, in that people in this age group appear not to be getting the help they need. The data also add to the research evidence that people at this age underestimate their hearing loss.

Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: A central mechanism of tinnitus?

The anti-inflammatory drug salicylate induces tinnitus in animals and man. Salicylate reduces cochlear output but causes hyperactivity in higher auditory centres, including the inferior colliculus (the auditory midbrain). Using multi-electrode recording in anaesthetised guinea pigs (Cavia porcellus), we addressed the hypothesis that salicylate-induced hyperactivity in the inferior colliculus involves nitric oxide signalling secondary to increased ascending excitatory input. Systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing in the inferior colliculus (3-6 h post drug), with both onset and sustained responses to pure tones being massively increased. Reverse microdialysis of increasing concentrations of salicylate directly into the inferior colliculus (100 µM-10 mM, from 0 h) failed to mimic systemic salicylate. In contrast, it caused a small, transient, increase in sound-driven firing (1 h), followed by a larger sustained decrease in both spontaneous and sound-driven firing (2-5 h). When salicylate was given systemically, reverse microdialysis of the neuronal nitric oxide synthase inhibitor L-methyl arginine into the inferior colliculus (500 mM, 2-6 h) completely blocked the salicylate-induced increase in spontaneous and sound-driven neuronal firing. Our data indicate that systemic salicylate induces neuronal hyperactivity in the auditory midbrain via a mechanism outside the inferior colliculus, presumably upstream in the auditory pathway; and that the mechanism is ultimately dependent on nitric oxide signalling within the inferior colliculus. Given that nitric oxide is known to mediate NMDA receptor signalling in the inferior colliculus, we propose that salicylate activates an ascending glutamatergic input to the inferior colliculus and that this is an important mechanism underlying salicylate-induced tinnitus.

Electrical stimulation of the ventral tegmental area evokes sleep-like state transitions under urethane anaesthesia in the rat medial prefrontal cortex via dopamine D1 -like receptors.

The role of dopamine in regulating sleep-state transitions during, both natural sleep and under anaesthesia, is still unclear. Recording in vivo in the rat mPFC under urethane anaesthesia, we observed predominantly slow wave activity (SWA) of <1 Hz in the local field potential interrupted by occasional spontaneous transitions to a low-amplitude-fast (LAF) pattern of activity. During periods of SWA, transitions to LAF activity could be rapidly and consistently evoked by electrical stimulation of the ventral tegmental area (VTA). Spontaneous LAF activity, and that evoked by stimulation of the VTA, consisted of fast oscillations similar to those seen in the rapid eye movement (REM)-like sleep state. Spontaneous and VTA stimulation-evoked LAF activity occurred simultaneously along the dorsoventral extent of all mPFC subregions. Evoked LAF activity depended on VTA stimulation current and could be elicited using either regular (25-50 Hz) or burst stimulation patterns and was reproducible upon repeated stimulation. Simultaneous extracellular single-unit recordings showed that during SWA, presumed pyramidal cells fired phasically and almost exclusively on the Up state, while during both spontaneous and VTA-evoked LAF activity, they fired tonically. The transition to LAF activity evoked by VTA stimulation depended on dopamine D1 -like receptor activation as it was almost completely blocked by systemic administration of the D1 -like receptor antagonist SCH23390. Overall, our data demonstrate that activation of dopamine D1 -like receptors in the mPFC is important for regulating sleep-like state transitions.

Multiple Nonauditory Cortical Regions Innervate the Auditory Midbrain.

Our perceptual experience of sound depends on the integration of multiple sensory and cognitive domains, however the networks subserving this integration are unclear. Connections linking different cortical domains have been described, but we do not know the extent to which connections also exist between multiple cortical domains and subcortical structures. Retrograde tracing in adult male rats (Rattus norvegicus) revealed that the inferior colliculus, the auditory midbrain, receives dense descending projections not only, as previously established, from the auditory cortex, but also from the visual, somatosensory, motor, and prefrontal cortices. While all these descending connections are bilateral, those from sensory areas show a more pronounced ipsilateral dominance than those from motor and prefrontal cortices. Injections of anterograde tracers into the cortical areas identified by retrograde tracing confirmed those findings and revealed cortical fibers terminating in all three subdivisions of the inferior colliculus. Immunolabeling showed that cortical terminals target both GABAergic inhibitory, and putative glutamatergic excitatory neurons. These findings demonstrate that auditory perception and behavior are served by a network that includes extensive descending connections to the midbrain from sensory, behavioral, and executive cortices.SIGNIFICANCE STATEMENT Making sense of what we hear depends not only on the analysis of sound, but also on information from other senses together with the brain's predictions about the properties and significance of the sound. Previous work suggested that this interplay between the senses and the predictions from higher cognitive centers occurs within the cerebral cortex. By tracing neural connections in rat, we show that the inferior colliculus, the subcortical, midbrain center for hearing, receives extensive connections from areas of the cerebral cortex concerned with vision, touch, movement, and cognitive function, in addition to areas representing hearing. These findings demonstrate that wide-ranging cortical feedback operates at an earlier stage of the hearing pathway than previously recognized.

Modulated stimuli demonstrate asymmetric interactions between hearing and vision.

The nature of interactions between the senses is a topic of intense interest in neuroscience, but an unresolved question is how sensory information from hearing and vision are combined when the two senses interact. A problem for testing auditory-visual interactions is devising stimuli and tasks that are equivalent in both modalities. Here we report a novel paradigm in which we first equated the discriminability of the stimuli in each modality, then tested how a distractor in the other modality affected performance. Participants discriminated pairs of amplitude-modulated tones or size-modulated visual objects in the form of a cuboid shape, alone or when a similarly modulated distractor stimulus of the other modality occurred with one of the pair. Discrimination of sound modulation depth was affected by a modulated cuboid only when their modulation rates were the same. In contrast, discrimination of cuboid modulation depth was little affected by an equivalently modulated sound. Our results suggest that what observers perceive when auditory and visual signals interact is not simply determined by the discriminability of the individual sensory inputs, but also by factors that increase the perceptual binding of these inputs, such as temporal synchrony.

Puncta of Neuronal Nitric Oxide Synthase (nNOS) Mediate NMDA Receptor Signaling in the Auditory Midbrain.

Nitric oxide (NO) is a neurotransmitter synthesized in the brain by neuronal nitric oxide synthase (nNOS). Using immunohistochemistry and confocal imaging in the inferior colliculus (IC, auditory midbrain) of the guinea pig (Cavia porcellus, male and female), we show that nNOS occurs in two distinct cellular distributions. We confirm that, in the cortices of the IC, a subset of neurons show cytoplasmic labeling for nNOS, whereas in the central nucleus (ICc), such neurons are not present. However, we demonstrate that all neurons in the ICc do in fact express nNOS in the form of discrete puncta found at the cell membrane. Our multi-labeling studies reveal that nNOS puncta form multiprotein complexes with NMDA receptors, soluble guanylyl cyclase (sGC), and PSD95. These complexes are found apposed to glutamatergic terminals, which is indicative of synaptic function. Interestingly, these glutamatergic terminals express both vesicular glutamate transporters 1 and 2 denoting a specific source of brainstem inputs. With in vivo electrophysiological recordings of multiunit activity in the ICc, we found that local application of NMDA enhances sound-driven activity in a concentration-dependent and reversible fashion. This response is abolished by blockade of nNOS or sGC, indicating that the NMDA effect is mediated solely via the NO and cGMP signaling pathway. This discovery of a ubiquitous, but highly localized, expression of nNOS throughout the ICc and demonstration of the dramatic influence of the NMDA activated NO pathway on sound-driven neuronal activity imply a key role for NO signaling in auditory processing.SIGNIFICANCE STATEMENT We show that neuronal nitric oxide synthase (nNOS), the enzyme that synthesizes nitric oxide (NO), occurs as puncta in apparently all neurons in the central nucleus of the inferior colliculus (ICc) in the auditory midbrain. Punctate nNOS appears at glutamatergic synapses in a complex with glutamate NMDA receptors (NMDA-Rs), soluble guanylyl cyclase (sGC, the NO receptor), and PSD95 (a protein that anchors receptors and enzymes at the postsynaptic density). We show that NMDA-R modulation of sound-driven activity in the ICc is solely mediated by activation of nNOS and sGC. The presence of nNOS throughout this sensory nucleus argues for a major role of NO in hearing. Furthermore, this punctate form of nNOS expression may exist and have gone unnoticed in other brain regions.

Auditory motion-specific mechanisms in the primate brain.

This work examined the mechanisms underlying auditory motion processing in the auditory cortex of awake monkeys using functional magnetic resonance imaging (fMRI). We tested to what extent auditory motion analysis can be explained by the linear combination of static spatial mechanisms, spectrotemporal processes, and their interaction. We found that the posterior auditory cortex, including A1 and the surrounding caudal belt and parabelt, is involved in auditory motion analysis. Static spatial and spectrotemporal processes were able to fully explain motion-induced activation in most parts of the auditory cortex, including A1, but not in circumscribed regions of the posterior belt and parabelt cortex. We show that in these regions motion-specific processes contribute to the activation, providing the first demonstration that auditory motion is not simply deduced from changes in static spatial location. These results demonstrate that parallel mechanisms for motion and static spatial analysis coexist within the auditory dorsal stream.

Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat.

Cortical slow oscillations (0.1-1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC. In rodents the medial prefrontal cortex (mPFC) consists of several subregions: anterior cingulate cortex (ACC), prelimbic (PrL), infralimbic (IL), and dorsal peduncular cortices (DP). Although each region has a distinct anatomy and function, it is not known whether slow or fast network oscillations differ between subregions in vivo. We have simultaneously recorded slow and fast network oscillations in all four subregions of the rodent mPFC under urethane anesthesia. Slow oscillations were synchronous between the mPFC subregions, and across the hemispheres, with no consistent amplitude difference between subregions. Delta (2-4 Hz) activity showed only small differences between subregions. However, oscillations in the spindle (6-15 Hz)-, beta (20-30 Hz), gamma (30-80 Hz)-, and high-gamma (80-150 Hz)-frequency bands were consistently larger in the dorsal regions (ACC and PrL) compared with ventral regions (IL and DP). In dorsal regions the peak power of spindle, beta, and gamma activity occurred early after onset of the Up-state. In the ventral regions, especially the DP, the oscillatory power in the spindle-, beta-, and gamma-frequency ranges peaked later in the Up-state. These results suggest variations in fast network oscillations within the mPFC that may reflect the different functions and connectivity of these subregions.NEW & NOTEWORTHY We demonstrate, in the urethane-anesthetized rat, that within the medial prefrontal cortex (mPFC) there are clear subregional differences in the fast network oscillations associated with the slow oscillation Up-state. These differences, particularly between the dorsal and ventral subregions of the mPFC, may reflect the different functions and connectivity of these subregions.

Commissural Gain Control Enhances the Midbrain Representation of Sound Location.

Accurate localization of sound sources is essential for survival behavior in many species. The inferior colliculi (ICs) are the first point in the auditory pathway where cues used to locate sounds, ie, interaural time differences (ITDs), interaural level differences (ILDs), and pinna spectral cues, are all represented in the same location. These cues are first extracted separately on each side of the midline in brainstem nuclei that project to the ICs. Because of this segregation, each IC predominantly represents stimuli in the contralateral hemifield. We tested the hypothesis that commissural connections between the ICs mediate gain control that enhances sound localization acuity. We recorded IC neurons sensitive to either ITDs or ILDs in anesthetized guinea pig, before, during, and following recovery from deactivation of the contralateral IC by cryoloop cooling or microdialysis of procaine. During deactivation, responses were rescaled by divisive gain change and additive shifts, which reduced the dynamic range of ITD and ILD response functions and the ability of neurons to signal changes in sound location. These data suggest that each IC exerts multiplicative gain control and subtractive shifts over the other IC that enhances the neural representation of sound location. Furthermore, this gain control operates in a similar manner on both ITD- and ILD-sensitive neurons, suggesting a shared mechanism operates across localization cues. Our findings reveal a novel dependence of sound localization on commissural processing. SIGNIFICANCE STATEMENT: Sound localization, a fundamental process in hearing, is dependent on bilateral computations in the brainstem. How this information is transmitted from the brainstem to the auditory cortex, through several stages of processing, without loss of signal fidelity, is not clear. We show that the ability of neurons in the auditory midbrain to encode azimuthal sound location is dependent on gain control mediated by the commissure of the inferior colliculi. This finding demonstrates that commissural processing between homologous auditory nuclei, on either side of the midline, enhances the precision of sound localization.

Responding to Acute Care Needs of Patients With Cancer: Recent Trends Across Continents.

Remarkable progress has been made over the past decade in cancer medicine. Personalized medicine, driven by biomarker predictive factors, novel biotherapy, novel imaging, and molecular targeted therapeutics, has improved outcomes. Cancer is becoming a chronic disease rather than a fatal disease for many patients. However, despite this progress, there is much work to do if patients are to receive continuous high-quality care in the appropriate place, at the appropriate time, and with the right specialized expert oversight. Unfortunately, the rapid expansion of therapeutic options has also generated an ever-increasing burden of emergency care and encroaches into end-of-life palliative care. Emergency presentation is a common consequence of cancer and of cancer treatment complications. It represents an important proportion of new presentations of previously undiagnosed malignancy. In the U.K. alone, 20%-25% of new cancer diagnoses are made following an initial presentation to the hospital emergency department, with a greater proportion in patients older than 70 years. This late presentation accounts for poor survival outcomes and is often associated with poor patient experience and poorly coordinated care. The recent development of acute oncology services in the U.K. aims to improve patient safety, quality of care, and the coordination of care for all patients with cancer who require emergency access to care, irrespective of the place of care and admission route. Furthermore, prompt management coordinated by expert teams and access to protocol-driven pathways have the potential to improve patient experience and drive efficiency when services are fully established. The challenge to leaders of acute oncology services is to develop bespoke models of care, appropriate to local services, but with an opportunity for acute oncology teams to engage cancer care strategies and influence cancer care and delivery in the future. This will aid the integration of highly specialized cancer treatment with high-quality care close to home and help avoid hospital admission.

Amplitude-modulated stimuli reveal auditory-visual interactions in brain activity and brain connectivity.

The temporal congruence between auditory and visual signals coming from the same source can be a powerful means by which the brain integrates information from different senses. To investigate how the brain uses temporal information to integrate auditory and visual information from continuous yet unfamiliar stimuli, we used amplitude-modulated tones and size-modulated shapes with which we could manipulate the temporal congruence between the sensory signals. These signals were independently modulated at a slow or a fast rate. Participants were presented with auditory-only, visual-only, or auditory-visual (AV) trials in the fMRI scanner. On AV trials, the auditory and visual signal could have the same (AV congruent) or different modulation rates (AV incongruent). Using psychophysiological interaction analyses, we found that auditory regions showed increased functional connectivity predominantly with frontal regions for AV incongruent relative to AV congruent stimuli. We further found that superior temporal regions, shown previously to integrate auditory and visual signals, showed increased connectivity with frontal and parietal regions for the same contrast. Our findings provide evidence that both activity in a network of brain regions and their connectivity are important for AV integration, and help to bridge the gap between transient and familiar AV stimuli used in previous studies.

The topography of frequency and time representation in primate auditory cortices.

Natural sounds can be characterised by their spectral content and temporal modulation, but how the brain is organized to analyse these two critical sound dimensions remains uncertain. Using functional magnetic resonance imaging, we demonstrate a topographical representation of amplitude modulation rate in the auditory cortex of awake macaques. The representation of this temporal dimension is organized in approximately concentric bands of equal rates across the superior temporal plane in both hemispheres, progressing from high rates in the posterior core to low rates in the anterior core and lateral belt cortex. In A1 the resulting gradient of modulation rate runs approximately perpendicular to the axis of the tonotopic gradient, suggesting an orthogonal organisation of spectral and temporal sound dimensions. In auditory belt areas this relationship is more complex. The data suggest a continuous representation of modulation rate across several physiological areas, in contradistinction to a separate representation of frequency within each area.

The effect of childhood infection on hearing function at age 61 to 63 years in the newcastle thousand families study.

OBJECTIVES: It is known that childhood hearing function can become impaired after the occurrence of specific infections. However, evidence on the effect of common childhood infections on adult hearing function is limited. The objective of the study was to identify whether associations exist between the occurrence of common childhood infections in a UK birth cohort and hearing function across different frequencies at age 61 to 63 years. DESIGN: The Newcastle Thousand Families study is a birth cohort of all individuals born in May and June 1947 to mothers resident in Newcastle upon Tyne, United Kingdom. Of the original cohort members who had an audiometry test at age 61 to 63 years, 333 had data available on infections during their first year of life and 296 on infections up to their fifth year of life. These data were analyzed using linear regression in relation to adult hearing function across differing frequencies in isolation. RESULTS: After adjustment for sex, overcrowding in the first year, having had an ear operation, and having worked in a loud environment, significant negative associations were identified between adult hearing and tonsillitis at 250 Hz (p = 0.013), 1 kHz (p = 0.018), 6 kHz (p = 0.012), and 8 kHz (p = 0.033); otorrhea at 4 kHz (p = 0.005), 6 kHz (p = 0.003), and 8 kHz (p = 0.002); bronchitis (two or more episodes) at 2 kHz (p = 0.001), 3 kHz (p = 0.005), 4 kHz (p = 0.009), 6 kHz (p < 0.001), and 8 kHz (p < 0.001); and the total number of severe respiratory infections in the first year at 2 kHz (p = 0.037), 3 kHz (p = 0.049), 4 kHz (p = 0.030), 6 kHz (p < 0.001), and 8 kHz (p = 0.006). That is, individuals who had tonsillitis, bronchitis (twice or more), otorrhea, or a severe respiratory infection (twice or more) in their first year of life were more likely to have impaired adult hearing function than those who did not have any infections in early life. CONCLUSION: The occurrence of some, but not all, childhood infections appears to have an effect on adult hearing function across different frequencies. Reducing the incidence of infectious diseases in early life may reduce subsequent incidence of hearing impairment among adults. However, further research in modern cohorts is needed to clarify the links between infectious childhood diseases and adult hearing function.

Intercollicular commissural connections refine the representation of sound frequency and level in the auditory midbrain.

Connections unifying hemispheric sensory representations of vision and touch occur in cortex, but for hearing, commissural connections earlier in the pathway may be important. The brainstem auditory pathways course bilaterally to the inferior colliculi (ICs). Each IC represents one side of auditory space but they are interconnected by a commissure. By deactivating one IC in guinea pig with cooling or microdialysis of procaine, and recording neural activity to sound in the other, we found that commissural input influences fundamental aspects of auditory processing. The areas of nonV frequency response areas (FRAs) were modulated, but the areas of almost all V-shaped FRAs were not. The supra-threshold sensitivity of rate level functions decreased during deactivation and the ability to signal changes in sound level was decremented. This commissural enhancement suggests the ICs should be viewed as a single entity in which the representation of sound in each is governed by the other.

Childhood infections, but not early life growth, influence hearing in the Newcastle thousand families birth cohort at age 14 years.

BACKGROUND: While current research priorities include investigations of age-related hearing loss, there are concerns regarding effects on childhood hearing, for example through increased personal headphone use. By utilising historical data, it is possible to assess what factors may have increased hearing problems in children in the past, and this may be used to inform current public health policies to protect children against hearing loss and in turn reduce the long-term burden on individuals and services that may possible evolve. The aim of this study was to investigate which factors in early life significantly impacted on hearing level in childhood using existing data from the Newcastle Thousand Families Study, a 1947 birth cohort. METHODS: Data on early life factors, including growth, socio-economic status and illness, and hearing at age 14 years were collated for a representative subset of individuals from the cohort (n = 147). Factors were assessed using linear regression analysis to identify associations with hearing thresholds. RESULTS: Males were found to have lower hearing thresholds at 250 Hz, 500 Hz and 1 kHz. Main analyses showed no associations between hearing thresholds and early life growth or socio-economic indicators. An increasing number of ear infections from birth to age 13 years was associated with hearing thresholds at 250Hz (p = 0.04) and 500Hz (p = 0.03), which remained true for females (p = 0.050), but not males (p = 0.213) in sex-specific analysis. Scarlet fever and bronchitis were associated with hearing thresholds at 8 kHz. After adjustment for all significant predictors at each frequency, results remained unchanged. CONCLUSIONS: We found no associations between childhood hearing thresholds and early life growth and socio-economic status. Consistent with other studies, we found associations between childhood infections and hearing thresholds. Current public health strategies aimed at reducing childhood infections may also have a beneficial effect upon childhood hearing.

Classification of frequency response areas in the inferior colliculus reveals continua not discrete classes.

A differential response to sound frequency is a fundamental property of auditory neurons. Frequency analysis in the cochlea gives rise to V-shaped tuning functions in auditory nerve fibres, but by the level of the inferior colliculus (IC), the midbrain nucleus of the auditory pathway, neuronal receptive fields display diverse shapes that reflect the interplay of excitation and inhibition. The origin and nature of these frequency receptive field types is still open to question. One proposed hypothesis is that the frequency response class of any given neuron in the IC is predominantly inherited from one of three major afferent pathways projecting to the IC, giving rise to three distinct receptive field classes. Here, we applied subjective classification, principal component analysis, cluster analysis, and other objective statistical measures, to a large population (2826) of frequency response areas from single neurons recorded in the IC of the anaesthetised guinea pig. Subjectively, we recognised seven frequency response classes (V-shaped, non-monotonic Vs, narrow, closed, tilt down, tilt up and double-peaked), that were represented at all frequencies. We could identify similar classes using our objective classification tools. Importantly, however, many neurons exhibited properties intermediate between these classes, and none of the objective methods used here showed evidence of discrete response classes. Thus receptive field shapes in the IC form continua rather than discrete classes, a finding consistent with the integration of afferent inputs in the generation of frequency response areas. The frequency disposition of inhibition in the response areas of some neurons suggests that across-frequency inputs originating at or below the level of the IC are involved in their generation.

Deactivation of the inferior colliculus by cooling demonstrates intercollicular modulation of neuronal activity.

The auditory pathways coursing through the brainstem are organized bilaterally in mirror image about the midline and at several levels the two sides are interconnected. One of the most prominent points of interconnection is the commissure of the inferior colliculus (CoIC). Anatomical studies have revealed that these fibers make reciprocal connections which follow the tonotopic organization of the inferior colliculus (IC), and that the commissure contains both excitatory and, albeit fewer, inhibitory fibers. The role of these connections in sound processing is largely unknown. Here we describe a method to address this question in the anaesthetized guinea pig. We used a cryoloop placed on one IC to produce reversible deactivation while recording electrophysiological responses to sounds in both ICs. We recorded single units, multi-unit clusters and local field potentials (LFPs) before, during and after cooling. The degree and spread of cooling was measured with a thermocouple placed in the IC and other auditory structures. Cooling sufficient to eliminate firing was restricted to the IC contacted by the cryoloop. The temperature of other auditory brainstem structures, including the contralateral IC and the cochlea were minimally affected. Cooling below 20°C reduced or eliminated the firing of action potentials in frequency laminae at depths corresponding to characteristic frequencies up to ~8 kHz. Modulation of neural activity also occurred in the un-cooled IC with changes in single unit firing and LFPs. Components of LFPs signaling lemniscal afferent input to the IC showed little change in amplitude or latency with cooling, whereas the later components, which likely reflect inter- and intra-collicular processing, showed marked changes in form and amplitude. We conclude that the cryoloop is an effective method of selectively deactivating one IC in guinea pig, and demonstrate that auditory processing in the IC is strongly influenced by the other.

Orthogonal representation of sound dimensions in the primate midbrain.

Natural sounds are characterized by their spectral content and the modulation of energy over time. Using functional magnetic resonance imaging in awake macaques, we observed topographical representations of these spectral and temporal dimensions in a single structure, the inferior colliculus, the principal auditory nucleus in the midbrain. These representations are organized as a map with two approximately perpendicular axes: one representing increasing temporal rate and the other increasing spectral frequency.

Regularly firing neurons in the inferior colliculus have a weak interaural intensity difference sensitivity.

The spike discharge regularity may be important in the processing of information in the auditory pathway. It has already been shown that many cells in the central nucleus of the inferior colliculus fire regularly in response to monaural stimulation by the best frequency tones. The aim of this study was to find how the regularity of units was affected by adding ipsilateral tone, and how interaural intensity difference sensitivity is related to regularity. Single unit recordings were performed from 66 units in the inferior colliculus of the anaesthetized guinea pig in response to the best frequency tone. Regularity of firing was measured by calculating the coefficient of variation as a function of time of a unit's response. There was a positive correlation between coefficient of variation and interaural intensity difference sensitivity, indicating that highly regular units had very weak and irregular units had strong interaural intensity difference sensitivity responses. Three effects of binaural interaction on the sustained regularity were observed: constant coefficient of variation despite change in rate (66% of the units), negative (20%) and positive (13%) rate-CV relationships. A negative rate-coefficient of variation relationship was the dominant pattern of binaural interaction on the onset regularity.