Contacts with primary and secondary healthcare before suicide by those under the care of mental health services: case-control, whole-population-based study using person-level linked routine data in Wales, UK during 2000-2015.

BACKGROUND: People under the care of mental health services are at increased risk of suicide. Existing studies are small in scale and lack comparisons. AIMS: To identify opportunities for suicide prevention and underpinning data enhancement in people with recent contact with mental health services. METHOD: This population-based study includes people who died by suicide in the year following a mental health services contact in Wales, 2001-2015 (cases), paired with similar patients who did not die by suicide (controls). We linked the National Confidential Inquiry into Suicide and Safety in Mental Health and the Suicide Information Database - Cymru with primary and secondary healthcare records. We present results of conditional logistic regression. RESULTS: We matched 1031 cases with 5155 controls. In the year before their death, 98.3% of cases were in contact with healthcare services, and 28.5% presented with self-harm. Cases had more emergency department contacts (odds ratio 2.4, 95% CI 2.1-2.7) and emergency hospital admissions (odds ratio 1.5, 95% CI 1.4-1.7), but fewer primary care contacts (odds ratio 0.7, 95% CI 0.6-0.9) and out-patient appointments (odds ratio 0.2, 95% CI 0.2-0.3) than controls. Odds ratios were larger in females than males for injury and poisoning (odds ratio: 3.3 (95% CI 2.5-4.5) v. 2.6 (95% CI 2.1-3.1)). CONCLUSIONS: We may be missing existing opportunities to intervene, particularly in emergency departments and hospital admissions with self-harm presentations and with unattributed self-harm, especially in females. Prevention efforts should focus on strengthening routine care contacts, responding to emergency contacts and better self-harm care. There are benefits to enhancing clinical audit systems with routinely collected data.

Understanding Suicide Clusters Through Exploring Self-Harm Behaviors.

Background: There is little information about characteristics and long-term outcomes of individuals who self-harm during a suicide cluster. Aims: To compare characteristics of individuals who self-harmed during a suicide cluster in South Wales (∼10 deaths between December 2007 and March 2008) with others who self-harmed prior to the cluster and to evaluate 10-year self-harm and mortality outcomes. Method: Using records from the hospital serving the catchment area of the suicide cluster, enhanced by national routinely collected linked data, we created the following two groups: individuals who self-harmed (a) during the suicide cluster and (b) 1 year before. We compared individuals' characteristics and performed logistic regression to compute odds ratios of 10-year self-harm and mortality outcomes. Results: Individuals who self-harmed during the cluster were less likely to be hospitalized or have a mental health history than those who self-harmed prior to the cluster. No significant group differences were found for 10-year self-harm outcomes, but all-cause mortality was higher for males. Limitations: Sample size was small, and data were lacking on psychological and social proximity to individuals who died during the suicide cluster. Conclusion: Our findings highlight the importance of long-term healthcare follow-up of those who self-harm during a suicide cluster, particularly males.

Trends in socioeconomic inequalities in incidence of severe mental illness - A population-based linkage study using primary and secondary care routinely collected data between 2000 and 2017.

OBJECTIVE: In 2008, the UK entered a period of economic recession followed by sustained austerity measures. We investigate changes in inequalities by area deprivation and urbanicity in incidence of severe mental illness (SMI, including schizophrenia-related disorders and bipolar disorder) between 2000 and 2017. METHODS: We analysed 4.4 million individuals from primary and secondary care routinely collected datasets (2000-2017) in Wales and estimated the incidence of SMI by deprivation and urbanicity measured by the Welsh Index of Multiple Deprivation (WIMD) and urban/rural indicator respectively. Using linear modelling and joinpoint regression approaches, we examined time trends of the incidence and incidence rate ratios (IRR) of SMI by the WIMD and urban/rural indicator adjusted for available confounders. RESULTS: We observed a turning point of time trends of incidence of SMI at 2008/2009 where slope changes of time trends were significantly increasing. IRRs by deprivation/urbanicity remained stable or significantly decreased over the study period except for those with bipolar disorder sourced from secondary care settings, with increasing trend of IRRs (increase in IRR by deprivation after 2010: 1.6 % per year, 95 % CI: 1.0 %-2.2 %; increase in IRR by urbanicity 1.0 % per year, 95 % CI: 0.6 %-1.3 %). CONCLUSIONS: There was an association between recession/austerity and an increase in the incidence of SMI over time. There were variations in the effects of deprivation/urbanicity on incidence of SMI associated with short- and long-term socioeconomic change. These findings may support targeted interventions and social protection systems to reduce incidence of SMI.

Self-harm, in-person bullying and cyberbullying in secondary school-aged children: A data linkage study in Wales.

INTRODUCTION: Although the evidence base on bullying victimization and self-harm in young people has been growing, most studies were cross-sectional, relied on self-reported non-validated measures of self-harm, and did not separate effects of in-person and cyberbullying. This study aimed to assess associations of self-harm following in-person bullying at school and cyberbullying victimization controlling for covariates. METHODS: School survey data from 11 to 16 years pupils collected in 2017 from 39 Welsh secondary schools were linked to routinely collected data. Inverse probability weighting was performed to circumvent selection bias. Survival analyses for recurrent events were conducted to evaluate relative risks (adjusted hazard ratios [AHR]) of self-harm among bullying groups within 2 years following survey completion. RESULTS: A total of 35.0% (weighted N = 6813) of pupils reported being bullied, with 18.1%, 6.4% and 10.5% being victims of in-person bullying at school only, cyberbullying only and both in-person bullying at school and cyberbullying respectively. Adjusting for covariates, effect sizes for self-harm were significant after being in-person bullied at school only (AHR = 2.2 [1.1-4.3]) and being both in-person bullied at school and cyberbullied (AHR = 2.2 [1.0-4.7]) but not being cyberbullied only (AHR = 1.2 [0.4-3.3]). Feeling lonely during recent summer holidays was also a robust predictor (AHR = 2.2 [1.2-4.0]). CONCLUSIONS: We reaffirm the role of in-person bullying victimization on self-harm. Pupils were twice as likely to self-harm following in-person bullying as their nonvictimised peers. Interventions for young people that minimize the potential impacts of bullying on self-harm should also include strategies to prevent loneliness.

Widening Excess Mortality During the COVID-19 Pandemic in Individuals Who Self-Harmed.

Background: Studies on COVID-19 pandemic-associated changes in mortality following self-harm remain scarce and inconclusive. Aims: To compare mortality risks in individuals who had self-harmed to those for individuals who had not, before and during the COVID-19 pandemic (Waves 1 and 2) in Wales, the United Kingdom, using population-based routinely collected data. Method: We linked whole population health data to all-cause mortality following an episode of self-harm between April 2016 and March 2021. Propensity score matching, Cox regression, and difference-in-differences were applied to compute changes in excess mortality (as ratios of hazard ratios, RHRs) before and during the pandemic for individuals who self-harmed. Results: The difference in mortality for individuals who self-harmed compared to those who did not widened during Wave 1 (RHR = 2.03, 95% CI: 1.04-4.03) and Wave 2 (RHR = 2.19, 95% CI: 1.12-4.29) from before the pandemic. Stratification by sex and age group produced no significant subgroup differences although risk for younger than 65 years group were higher. Limitations: Limitations include small sample size and incomplete data on cause-specific deaths during the pandemic. Conclusion: Our results underscore continuous monitoring of mortality of individuals who self-harm and effective interventions to address any increases in mortality.

Changes in daily mental health service use and mortality at the commencement and lifting of COVID-19 'lockdown' policy in 10 UK sites: a regression discontinuity in time design.

OBJECTIVES: To investigate changes in daily mental health (MH) service use and mortality in response to the introduction and the lifting of the COVID-19 'lockdown' policy in Spring 2020. DESIGN: A regression discontinuity in time (RDiT) analysis of daily service-level activity. SETTING AND PARTICIPANTS: Mental healthcare data were extracted from 10 UK providers. OUTCOME MEASURES: Daily (weekly for one site) deaths from all causes, referrals and discharges, inpatient care (admissions, discharges, caseloads) and community services (face-to-face (f2f)/non-f2f contacts, caseloads): Adult, older adult and child/adolescent mental health; early intervention in psychosis; home treatment teams and liaison/Accident and Emergency (A&E). Data were extracted from 1 Jan 2019 to 31 May 2020 for all sites, supplemented to 31 July 2020 for four sites. Changes around the commencement and lifting of COVID-19 'lockdown' policy (23 March and 10 May, respectively) were estimated using a RDiT design with a difference-in-difference approach generating incidence rate ratios (IRRs), meta-analysed across sites. RESULTS: Pooled estimates for the lockdown transition showed increased daily deaths (IRR 2.31, 95% CI 1.86 to 2.87), reduced referrals (IRR 0.62, 95% CI 0.55 to 0.70) and reduced inpatient admissions (IRR 0.75, 95% CI 0.67 to 0.83) and caseloads (IRR 0.85, 95% CI 0.79 to 0.91) compared with the pre lockdown period. All community services saw shifts from f2f to non-f2f contacts, but varied in caseload changes. Lift of lockdown was associated with reduced deaths (IRR 0.42, 95% CI 0.27 to 0.66), increased referrals (IRR 1.36, 95% CI 1.15 to 1.60) and increased inpatient admissions (IRR 1.21, 95% CI 1.04 to 1.42) and caseloads (IRR 1.06, 95% CI 1.00 to 1.12) compared with the lockdown period. Site-wide activity, inpatient care and community services did not return to pre lockdown levels after lift of lockdown, while number of deaths did. Between-site heterogeneity most often indicated variation in size rather than direction of effect. CONCLUSIONS: MH service delivery underwent sizeable changes during the first national lockdown, with as-yet unknown and unevaluated consequences.

Impact of schizophrenia genetic liability on the association between schizophrenia and physical illness: data-linkage study.

BACKGROUND: Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia. AIMS: To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability. METHOD: We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores. RESULTS: Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015-0.017), with carriers being 7.5-7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder. CONCLUSIONS: This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.

Area deprivation, urbanicity, severe mental illness and social drift - A population-based linkage study using routinely collected primary and secondary care data.

We investigated whether associations between area deprivation, urbanicity and elevated risk of severe mental illnesses (SMIs, including schizophrenia and bipolar disorder) is accounted for by social drift or social causation. We extracted primary and secondary care electronic health records from 2004 to 2015 from a population of 3.9 million. We identified prevalent and incident individuals with SMIs and their level of deprivation and urbanicity using the Welsh Index of Multiple Deprivation (WIMD) and urban/rural indicator. The presence of social drift was determined by whether odds ratios (ORs) from logistic regression is greater than the incidence rate ratios (IRRs) from Poisson regression. Additionally, we performed longitudinal analysis to measure the proportion of change in deprivation level and rural/urban residence 10 years after an incident diagnosis of SMI and compared it to the general population using standardised rate ratios (SRRs). Prevalence and incidence of SMIs were significantly associated with deprivation and urbanicity (all ORs and IRRs significantly >1). ORs and IRRs were similar across all conditions and cohorts (ranging from 1.1 to 1.4). Results from the longitudinal analysis showed individuals with SMIs are more likely to move compared to the general population. However, they did not preferentially move to more deprived or urban areas. There was little evidence of downward social drift over a 10-year period. These findings have implications for the allocation of resources, service configuration and access to services in deprived communities, as well as, for broader public health interventions addressing poverty, and social and environmental contexts.

Developing a standardised approach to the aggregation of inpatient episodes into person-based spells in all specialties and psychiatric specialties.

BACKGROUND: Electronic health record (EHR) data are available for research in all UK nations and cross-nation comparative studies are becoming more common. All UK inpatient EHRs are based around episodes, but episode-based analysis may not sufficiently capture the patient journey. There is no UK-wide method for aggregating episodes into standardised person-based spells. This study identifies two data quality issues affecting the creation of person-based spells, and tests four methods to create these spells, for implementation across all UK nations. METHODS: Welsh inpatient EHRs from 2013 to 2017 were analysed. Phase one described two data quality issues; transfers of care and episode sequencing. Phase two compared four methods for creating person spells. Measures were mean length of stay (LOS, expressed in days) and number of episodes per person spell for each method. RESULTS: 3.5% of total admissions were transfers-in and 3.1% of total discharges were transfers-out. 68.7% of total transfers-in and 48.7% of psychiatric transfers-in had an identifiable preceding transfer-out, and 78.2% of total transfers-out and 59.0% of psychiatric transfers-out had an identifiable subsequent transfer-in. 0.2% of total episodes and 4.0% of psychiatric episodes overlapped with at least one other episode of any specialty. Method one (no evidence of transfer required; overlapping episodes grouped together) resulted in the longest mean LOS (4.0 days for all specialties; 48.5 days for psychiatric specialties) and the fewest single episode person spells (82.4% of all specialties; 69.7% for psychiatric specialties). Method three (evidence of transfer required; overlapping episodes separated) resulted in the shortest mean LOS (3.7 days for all specialties; 45.8 days for psychiatric specialties) and the most single episode person spells; (86.9% for all specialties; 86.3% for psychiatric specialties). CONCLUSIONS: Transfers-in appear better recorded than transfers-out. Transfer coding is incomplete, particularly for psychiatric specialties. The proportion of episodes that overlap is small but psychiatric episodes are disproportionately affected. The most successful method for grouping episodes into person spells aggregated overlapping episodes and required no evidence of transfer from admission source/method or discharge destination codes. The least successful method treated overlapping episodes as distinct and required transfer coding. The impact of all four methods was greater for psychiatric specialties.

Gαi Proteins are Indispensable for Hearing.

BACKGROUND/AIMS: From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary ("hair") bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. METHODS: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gαi proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gαi isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. RESULTS: Here we report that lack of Gαi3 but not of the ubiquitously expressed Gαi2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gαi2 or Gαi3 had no impact. In contrast, double-deficiency for Gαi2 and Gαi3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gαi3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gαi3 is selectively involved in generation of neural gain during auditory processing. CONCLUSION: We propose a so far unrecognized complexity of isoform-specific and overlapping Gαi protein functions particular during final differentiation processes.

Author Correction: Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.

This corrects the article DOI: 10.1038/ncomms14907.

Premature mortality among people with severe mental illness - New evidence from linked primary care data.

Studies assessing premature mortality in people with severe mental illness (SMI) are usually based in one setting, hospital (secondary care inpatients and/or outpatients) or community (primary care). This may lead to ascertainment bias. This study aimed to estimate standardised mortality ratios (SMRs) for all-cause and cause-specific mortality in people with SMI drawn from linked primary and secondary care populations compared to the general population. SMRs were calculated using the indirect method for a United Kingdom population of almost four million between 2004 and 2013. The all-cause SMR was higher in the cohort identified from secondary care hospital admissions (SMR: 2.9; 95% CI: 2.8-3.0) than from primary care (SMR: 2.2; 95% CI: 2.1-2.3) when compared to the general population. The SMR for the combined cohort was 2.6 (95% CI: 2.5-2.6). Cause specific SMRs in the combined cohort were particularly elevated in those with SMI relative to the general population for ill-defined and unknown causes, suicide, substance abuse, Parkinson's disease, accidents, dementia, infections and respiratory disorders (particularly pneumonia), and Alzheimer's disease. Solely hospital admission based studies, which have dominated the literature hitherto, somewhat over-estimate premature mortality in those with SMI. People with SMI are more likely to die by ill-defined and unknown causes, suicide and other less common and often under-reported causes. Comprehensive characterisation of mortality is important to inform policy and practice and to discriminate settings to allow for proportionate interventions to address this health injustice.

Drug survival of second biological DMARD therapy in patients with rheumatoid arthritis: a retrospective non-interventional cohort analysis.

BACKGROUND: Since persistence to first biological disease modifying anti-rheumatic drugs (bDMARDs) is far from ideal in rheumatoid arthritis (RA) patients, many do receive a second and/or third bDMARD treatment. However, little is known about treatment persistence of the second-line bDMARD and it is specifically unknown whether the mode of action of such a treatment is associated with different persistence rates. We aimed to assess discontinuation-, re-initiation- or continuation-rates of a 2nd bDMARD therapy as well as switching-rates to a third biological DMARD (3rd bDMARD) therapy in RA patients. METHOD: Analysis was based on German claims data (2010-2013). Patients were included if they had received at least one prescription for an anti-TNF and at least one follow-up prescription of a 2nd bDMARD different from the first anti-TNF. Patient follow-up started on the date of the first prescription for the 2nd bDMARD and lasted for 12 months or until a patient's death. RESULTS: 2667 RA patients received at least one anti-TNF prescription. Of these, 451 patients received a second bDMARD (340 anti-TNF, mean age 52.6 years; 111 non-anti-TNF, mean age 55.9 years). During the follow-up, 28.8% vs. 11.7% of the 2nd anti-TNF vs. non-anti-TNF patients (p < 0.001) switched to a 3rd bDMARD; 14.1% vs. 19.8% (p = 0.179) discontinued without re-start; 3.8% vs.1.8% (p = 0.387) re-started and 53.5 vs. 66.7% (p < 0.050) continued therapy. Patients in the non-anti-TNF group demonstrated longer drug survival (295 days) than patients in the anti-TNF group (264 days; p = 0.016). Independent variables associated with earlier discontinuation (including re-start) or switch were prescription of an anti-TNF as 2nd bDMARD (HR = 1.512) and a higher comorbidity level (CCI, HR = 1.112), whereas previous painkiller medication (HR = 0.629) was associated with later discontinuation or switch. CONCLUSIONS: Only 56.8% of RA patients continued 2nd bDMARD treatment after 12 months; 60% if re-start was included. Non-anti-TNF patients had a higher probability of continuing 2nd bDMARD therapy.

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

Loss of auditory sensitivity from inner hair cell synaptopathy can be centrally compensated in the young but not old brain.

A dramatic shift in societal demographics will lead to rapid growth in the number of older people with hearing deficits. Poorer performance in suprathreshold speech understanding and temporal processing with age has been previously linked with progressing inner hair cell (IHC) synaptopathy that precedes age-dependent elevation of auditory thresholds. We compared central sound responsiveness after acoustic trauma in young, middle-aged, and older rats. We demonstrate that IHC synaptopathy progresses from middle age onward and hearing threshold becomes elevated from old age onward. Interestingly, middle-aged animals could centrally compensate for the loss of auditory fiber activity through an increase in late auditory brainstem responses (late auditory brainstem response wave) linked to shortening of central response latencies. In contrast, old animals failed to restore central responsiveness, which correlated with reduced temporal resolution in responding to amplitude changes. These findings may suggest that cochlear IHC synaptopathy with age does not necessarily induce temporal auditory coding deficits, as long as the capacity to generate neuronal gain maintains normal sound-induced central amplitudes.

BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury.

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO). We demonstrate that BDNF (Pax2) -KO but not BDNF (TrkC) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF (Pax2) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF (Pax2) -KO, but not of BDNF (TrkC) -KO mice. Also, BDNF (Pax2) -WT but not BDNF (Pax2) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.

Cochlear NMDA receptors as a therapeutic target of noise-induced tinnitus.

BACKGROUND: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. METHODS: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. RESULTS: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. CONCLUSION: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

Autonomous functions of murine thyroid hormone receptor TRα and TRß in cochlear hair cells.

Thyroid hormone acts on gene transcription by binding to its nuclear receptors TRα1 and TRß. Whereas global deletion of TRß causes deafness, global TRα-deficient mice have normal hearing thresholds. Since the individual roles of the two receptors in cochlear hair cells are still unclear, we generated mice with a hair cell-specific mutation of TRα1 or deletion of TRß using the Cre-loxP system. Hair cell-specific TRß mutant mice showed normal hearing thresholds but delayed BK channel expression in inner hair cells, slightly stronger outer hair cell function, and slightly reduced amplitudes of auditory brainstem responses. In contrast, hair cell-specific TRα mutant mice showed normal timing of BK channel expression, slightly reduced outer hair cell function, and slightly enhanced amplitudes of auditory brainstem responses. Our data demonstrate that TRß-related deafness originates outside of hair cells and that TRα and TRß play opposing, non-redundant roles in hair cells. A role for thyroid hormone receptors in controlling key regulators that shape signal transduction during development is discussed. Thyroid hormone may act through different thyroid hormone receptor activities to permanently alter the sensitivity of auditory neurotransmission.

The reduced cochlear output and the failure to adapt the central auditory response causes tinnitus in noise exposed rats.

Tinnitus is proposed to be caused by decreased central input from the cochlea, followed by increased spontaneous and evoked subcortical activity that is interpreted as compensation for increased responsiveness of central auditory circuits. We compared equally noise exposed rats separated into groups with and without tinnitus for differences in brain responsiveness relative to the degree of deafferentation in the periphery. We analyzed (1) the number of CtBP2/RIBEYE-positive particles in ribbon synapses of the inner hair cell (IHC) as a measure for deafferentation; (2) the fine structure of the amplitudes of auditory brainstem responses (ABR) reflecting differences in sound responses following decreased auditory nerve activity and (3) the expression of the activity-regulated gene Arc in the auditory cortex (AC) to identify long-lasting central activity following sensory deprivation. Following moderate trauma, 30% of animals exhibited tinnitus, similar to the tinnitus prevalence among hearing impaired humans. Although both tinnitus and no-tinnitus animals exhibited a reduced ABR wave I amplitude (generated by primary auditory nerve fibers), IHCs ribbon loss and high-frequency hearing impairment was more severe in tinnitus animals, associated with significantly reduced amplitudes of the more centrally generated wave IV and V and less intense staining of Arc mRNA and protein in the AC. The observed severe IHCs ribbon loss, the minimal restoration of ABR wave size, and reduced cortical Arc expression suggest that tinnitus is linked to a failure to adapt central circuits to reduced cochlear input.

Noise-induced inner hair cell ribbon loss disturbs central arc mobilization: a novel molecular paradigm for understanding tinnitus.

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.