Nitric oxide increases gain in the ventral cochlear nucleus of guinea pigs with tinnitus

Previous work has led to the hypothesis that, during the production of noise‐induced tinnitus, higher levels of nitric oxide (NO), in the ventral cochlear nucleus (VCN), increase the gain applied to a reduced input from the cochlea. To test this hypothesis, we noise‐exposed 26 guinea pigs, identified evidence of tinnitus in 12 of them and then compared the effects of an iontophoretically applied NO donor or production inhibitor on VCN single unit activity. We confirmed that the mean driven firing rate for the tinnitus and control groups were the same while it had fallen in the non‐tinnitus group. By contrast, the mean spontaneous rate had increased for the tinnitus group relative to control while it remained the same for the non‐tinnitus group. A greater proportion of units responded to exogenously applied NO in the tinnitus (56%) and non‐tinnitus groups (71%) than a control population (24%). In the tinnitus group, endogenous NO facilitated the driven firing rate in 37% (7/19) of neurons and appeared to bring the mean driven rate back up to control levels by a mechanism involving N‐Methyl‐D‐aspartic acid (NMDA) receptors. By contrast, in the non‐tinnitus group, endogenous NO only facilitated the driven firing rate in 5% (1/22) of neurons and there was no facilitation of driven rate in the control group. The effects of endogenous NO on spontaneous activity were unclear. These results suggest that NO is involved in increasing the gain applied to driven activity but other factors are also involved in the increase in spontaneous activity

Nitric oxide regulates the firing rate of neuronal subtypes in the guinea pig ventral cochlear nucleus

The gaseous free radical, nitric oxide (NO) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase (nNOS) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a sub-population of each major neuronal type in the ventral cochlear nucleus (VCN). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L-NAME (L-NG-Nitroarginine methyl ester) and the NO donors SIN-1 (3-Morpholinosydnonimine hydrochloride) and SNOG (S-Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurons. Inhibition of endogenous NO production with L-NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L-NAME on NMDA (N-Methyl-D-aspartic acid)-evoked excitation, with 30% of units showing enhanced NMDA-evoked excitation during L-NAME application (reduced NO levels). Approximately 25% of neurons contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss

Gap-induced reductions of evoked potentials in the auditory cortex: a possible objective marker for the presence of tinnitus in animals

Animal models of tinnitus are essential for determining the underlying mechanisms and testing pharmacotherapies. However, there is doubt over the validity of current behavioural methods for detecting tinnitus. Here, we applied a stimulus paradigm widely used in a behavioural test (gap-induced inhibition of the acoustic startle reflex GPIAS) while recording from the auditory cortex, and showed neural response changes that mirror those found in the behavioural tests. We implanted guinea pigs (GPs) with electrocorticographic (ECoG) arrays and recorded baseline auditory cortical responses to a startling stimulus. When a gap was inserted in otherwise continuous background noise prior to the startling stimulus, there was a clear reduction in the subsequent evoked response (termed gap-induced reductions in evoked potentials; GIREP), suggestive of a neural analogue of the GPIAS test. We then unilaterally exposed guinea pigs to narrowband noise (left ear; 8-10 kHz; 1 hour) at one of two different sound levels - either 105 dB SPL or 120 dB SPL – and recorded the same responses seven-to-ten weeks following the noise exposure. Significant deficits in GIREP were observed for all areas of the auditory cortex (AC) in the 120 dB-exposed GPs, but not in the 105 dB-exposed GPs. These deficits could not simply be accounted for by changes in response amplitudes. Furthermore, in the contralateral (right) caudal AC we observed a significant increase in evoked potential amplitudes across narrowband background frequencies in both 105 dB and 120 dB-exposed GPs. Taken in the context of the large body of literature that has used the behavioural test as a demonstration of the presence of tinnitus, these results are suggestive of objective neural correlates of the presence of noise-induced tinnitus and hyperacusis

Effective health care for older people living and dying in care homes: A realist review

Background: Care home residents in England have variable access to health care services. There is currently no coherent policy or consensus about the best arrangements to meet these needs. The purpose of this review was to explore the evidence for how different service delivery models for care home residents support and/or improve wellbeing and health-related outcomes in older people living and dying in care homes. Methods: We conceptualised models of health care provision to care homes as complex interventions. We used a realist review approach to develop a preliminary understanding of what supported good health care provision to care homes. We completed a scoping of the literature and interviewed National Health Service and Local Authority commissioners, providers of services to care homes, representatives from the Regulator, care home managers, residents and their families. We used these data to develop theoretical propositions to be tested in the literature to explain why an intervention may be effective in some situations and not others. We searched electronic databases and related grey literature. Finally the findings were reviewed with an external advisory group. Results: Strategies that support and sustain relational working between care home staff and visiting health care professionals explained the observed differences in how health care interventions were accepted and embedded into care home practice. Actions that encouraged visiting health care professionals and care home staff jointly to identify, plan and implement care home appropriate protocols for care, when supported by ongoing facilitation from visiting clinicians, were important. Contextual factors such as financial incentives or sanctions, agreed protocols, clinical expertise and structured approaches to assessment and care planning could support relational working to occur, but of themselves appeared insufficient to achieve change. Conclusion: How relational working is structured between health and care home staff is key to whether health service interventions achieve health related outcomes for residents and their respective organisations. The belief that either paying clinicians to do more in care homes and/or investing in training of care home staff is sufficient for better outcomes was not supported.This research was funded by National Institute of Health Research Health Service Delivery and Research programme (HSDR 11/021/02)

Olivocochlear projections contribute to superior intensity coding in cochlear nucleus small cells

Understanding communication signals, especially in noisy environments, is crucial to social interactions. Yet, as we age, acoustic signals can be disrupted by cochlear damage and the subsequent auditory nerve fibre degeneration. The most vulnerable medium‐ and high‐threshold‐auditory nerve fibres innervate various cell types in the cochlear nucleus, among which the small cells are unique in receiving this input exclusively. Furthermore, small cells project to medial olivocochlear (MOC) neurons, which in turn send branched collaterals back into the small cell cap. Here, we use single‐unit recordings to characterise small cell firing characteristics and demonstrate superior intensity coding in this cell class. We show converse effects when activating/blocking the MOC system, demonstrating that small‐cell unique coding properties are facilitated by direct cholinergic input from the MOC system. Small cells also maintain tone‐level coding in the presence of background noise. Finally, small cells precisely code low‐frequency modulation more accurately than other ventral cochlear nucleus cell types, demonstrating accurate envelope coding that may be important for vocalisation processing. These results highlight the small cell olivocochlear circuit as a key player in signal processing in noisy environments, which may be selectively degraded in ageing or after noise insult.Key pointsCochlear nucleus small cells receive input from low/medium spontaneous rate auditory nerve fibres and medial olivocochlear neurons.Electrical stimulation of medial olivocochlear neurons in the ventral nucleus of the trapezoid body and blocking cholinergic input to small cells using atropine demonstrates an excitatory cholinergic input to small cells, which increases responses to suprathreshold sound.Unique inputs to small cells produce superior sound intensity coding.This coding of intensity is preserved in the presence of background noise, an effect exclusive to this cell type in the cochlear nucleus.These results suggest that small cells serve an essential function in the ascending auditory system, which may be relevant to disorders such as hidden hearing loss.Abstract figure legend The small cell – medial olivocochlear (MOC) circuit. Small cells project to and receive input from MOC neurons in the ventral nucleus of the trapezoid body (VNTB). VNTB excitatory input to small cells enhances their activity in response to suprathreshold sounds, thus counteracting the suppressive effect of MOC input on the cochlea (IHC, inner hair cell; OHC, outer hair cell).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171204/1/tjp14887.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171204/2/tjp14887_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171204/3/tjp14887-sup-0001-SuppMat.pd