Behavioural and neural correlates of tinnitus

Tinnitus, often defined as the perception of sound in the absence of an external stimulus, affects millions of people worldwide and, in extreme cases, can be severely debilitating. While certain changes within the auditory system have been linked to tinnitus, the exact underlying causes of the phenomenon have not, as yet, been elucidated. Animal models of tinnitus have considerably furthered understanding of the some of the changes associated with the condition, allowing researchers to examine changes following noise exposure, the most common trigger for tinnitus.This thesis documents the development of an animal model of tinnitus, using the guinea pig to examine neural changes following induction of tinnitus. In the first study, a novel adaptation of a behavioural test was developed, in order to be able to determine whether guinea pigs were experiencing tinnitus following the administration of sodium salicylate, a common inducer of tinnitus in humans. This test relies on a phenomenon known as prepulse inhibition, whereby a startle response can be reduced in amplitude by placing a gap in a low-level, continuous background noise immediately prior to the startling stimulus. The hypothesis for this test is that if the background sound is adjusted to be similar to an animal’s tinnitus (induced artificially following noise exposure or drug administration), the tinnitus percept will fill in the gap and the startle response will not be reduced. The results from this first study indicated that using the Preyer reflex (a flexion of the pinnae in response to a startling stimulus) as this startle measure was more robust in guinea pigs than the commonly-used whole-body startle. Furthermore, transient tinnitus was reliably identified following salicylate administration. Following the development and validation of this test, a study was conducted to determine whether guinea pigs experienced tinnitus following unilateral noise exposure. Neural changes commonly associated with the condition (increases in spontaneous firing rates and changes in auditory brainstem responses) were examined, to determine whether there were any differences between animals that did develop tinnitus following noise exposure and those that did not. Two different methods were applied to the behavioural data to determine which animals were experiencing tinnitus. Regardless of the behavioural criteria used, increased spontaneous firing rates were observed in the inferior colliculus of noise-exposed guinea pigs, in comparison to control animals, but there were no differences between tinnitus and no-tinnitus animals. Conversely, significant reductions in the latency of components of the auditory brainstem response were present only in the tinnitus animals. The final study examined whether the original hypothesis for the behavioural test (that tinnitus is filling in the gap) was valid, or whether there was an alternative explanation for the deficits in behavioural gap detection observed previously, such as changes in the temporal acuity of the auditory system preventing detection of the gap. Recordings were made in the inferior colliculus of noise-exposed animals, separated into tinnitus and no-tinnitus groups according to the behavioural test, as well as unexposed control animals, to determine whether there were changes in the responses of single-units in detecting gaps of varying duration embedded in background noise. While some minor changes were present in no-tinnitus animals, tinnitus animals showed no significant changes in neural gap detection thresholds, demonstrating that changes in temporal acuity cannot account for behavioural gap detection deficits observed following noise exposure. Interestingly, significant shifts in the response types of cells were observed which did appear to relate to tinnitus. The present data indicate that the Preyer reflex gap detection test is appropriate for examining tinnitus in guinea pigs. It also suggests that increases in spontaneous firing rates at the level of the inferior colliculus cannot solely account for tinnitus. Changes in auditory brainstem responses, as well as shifts in response types, do appear to relate to tinnitus and warrant further investigation

Behavioural and neural correlates of tinnitus

Tinnitus, often defined as the perception of sound in the absence of an external stimulus, affects millions of people worldwide and, in extreme cases, can be severely debilitating. While certain changes within the auditory system have been linked to tinnitus, the exact underlying causes of the phenomenon have not, as yet, been elucidated. Animal models of tinnitus have considerably furthered understanding of the some of the changes associated with the condition, allowing researchers to examine changes following noise exposure, the most common trigger for tinnitus.This thesis documents the development of an animal model of tinnitus, using the guinea pig to examine neural changes following induction of tinnitus. In the first study, a novel adaptation of a behavioural test was developed, in order to be able to determine whether guinea pigs were experiencing tinnitus following the administration of sodium salicylate, a common inducer of tinnitus in humans. This test relies on a phenomenon known as prepulse inhibition, whereby a startle response can be reduced in amplitude by placing a gap in a low-level, continuous background noise immediately prior to the startling stimulus. The hypothesis for this test is that if the background sound is adjusted to be similar to an animal’s tinnitus (induced artificially following noise exposure or drug administration), the tinnitus percept will fill in the gap and the startle response will not be reduced. The results from this first study indicated that using the Preyer reflex (a flexion of the pinnae in response to a startling stimulus) as this startle measure was more robust in guinea pigs than the commonly-used whole-body startle. Furthermore, transient tinnitus was reliably identified following salicylate administration. Following the development and validation of this test, a study was conducted to determine whether guinea pigs experienced tinnitus following unilateral noise exposure. Neural changes commonly associated with the condition (increases in spontaneous firing rates and changes in auditory brainstem responses) were examined, to determine whether there were any differences between animals that did develop tinnitus following noise exposure and those that did not. Two different methods were applied to the behavioural data to determine which animals were experiencing tinnitus. Regardless of the behavioural criteria used, increased spontaneous firing rates were observed in the inferior colliculus of noise-exposed guinea pigs, in comparison to control animals, but there were no differences between tinnitus and no-tinnitus animals. Conversely, significant reductions in the latency of components of the auditory brainstem response were present only in the tinnitus animals. The final study examined whether the original hypothesis for the behavioural test (that tinnitus is filling in the gap) was valid, or whether there was an alternative explanation for the deficits in behavioural gap detection observed previously, such as changes in the temporal acuity of the auditory system preventing detection of the gap. Recordings were made in the inferior colliculus of noise-exposed animals, separated into tinnitus and no-tinnitus groups according to the behavioural test, as well as unexposed control animals, to determine whether there were changes in the responses of single-units in detecting gaps of varying duration embedded in background noise. While some minor changes were present in no-tinnitus animals, tinnitus animals showed no significant changes in neural gap detection thresholds, demonstrating that changes in temporal acuity cannot account for behavioural gap detection deficits observed following noise exposure. Interestingly, significant shifts in the response types of cells were observed which did appear to relate to tinnitus. The present data indicate that the Preyer reflex gap detection test is appropriate for examining tinnitus in guinea pigs. It also suggests that increases in spontaneous firing rates at the level of the inferior colliculus cannot solely account for tinnitus. Changes in auditory brainstem responses, as well as shifts in response types, do appear to relate to tinnitus and warrant further investigation

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

Using Gap-Induced Inhibition of the Post-Auricular Muscle Response as an Objective Measure of Tinnitus in Humans

A widely used method for detecting tinnitus in rodents is the gap pre-pulse inhibition of the acoustic startle (GPIAS). One variant uses the Preyer reflex to assess the startle response and a component of this can be measured as a small muscle potential generated by the post-auricular muscle reflex (PAMR). The question was whether the GPIAS method could also be used to identify tinnitus in humans using the PAMR response. We recruited 19 participants with chronic tinnitus and 18 age-matched controls, but 12 tinnitus participants were unable to contribute data to the final result due to hyperacusis or lack of a PAMR. A majority of those tinnitus participants with a detectable PAMR showed some evidence of GPIAS (71%, 5/7). In the control group, most showed a PAMR response (67%, 12/18) and most of these demonstrated GPIAS (67%, 8/12). Our stimulus parameters were not completely optimal for showing a PAMR response so, with further refinement it may be possible to use the PAMR response and GPIAS as an objective method for demonstrating tinnitus in humans

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

Evaluating Microcounseling Training

An evaluation research design was developed as an attempt to provide a more satisfactory approach to microcounseling training program evaluation. Trainee performance was measured three times during a counseling practicum, with microcounseling training occurring between the second and third observations. Trainee performance was compared to a predetermined standard for counselor behavior. Results were analyzed for both the differences between observations, and the degree of similarity to the model. Counseling behavior of trainees after microcounseling training was significantly different from their behavior prior to the training. After training they were more like the standard. The trainees performed less like the standard after some counseling experience, but before receiving microcounseling training.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66901/2/10.1177_0193841X8300700206.pd

Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2′-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis

Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines.

To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness. We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds. We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion. We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access

Decreased PM10 exposure attenuates age-related lung function decline: genetic variants in p53, p21, and CCND1 modify this effect.

BACKGROUND: Decreasing exposure to airborne particulates was previously associated with reduced age-related decline in lung function. However, whether the benefit from improved air quality depends on genetic background is not known. Recent evidence points to the involvement of the genes p53 and p21 and of the cell cycle control gene cyclin D1 (CCND1) in the response of bronchial cells to air pollution. OBJECTIVE: We determined in 4,326 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) whether four single-nucleotide polymorphisms in three genes [CCND1 (rs9344 [P242P], rs667515), p53 (rs1042522 [R72P]), and p21 (rs1801270 [S31R])] modified the previously observed attenuation of the decline in the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF(25-75)) associated with improved air quality. METHODS: Subjects of the prospective population-based SAPALDIA cohort were assessed in 1991 and 2002 by spirometry, questionnaires, and biological sample collection for genotyping. We assigned spatially resolved concentrations of particulate matter with aerodynamic diameter < or = 10 microm (PM(10)) to each participant's residential history 12 months before the baseline and follow-up assessments. RESULTS: The effect of diminishing PM(10) exposure on FEF(25-75) decline appeared to be modified by p53 R72P, CCND1 P242P, and CCND1 rs667515. For example, a 10-microg/m(3) decline in average PM(10) exposure over an 11-year period attenuated the average annual decline in FEF(25-75) by 21.33 mL/year (95% confidence interval, 10.57-32.08) among participants homozygous for the CCND1 (P242P) GG genotype, by 13.72 mL/year (5.38-22.06) among GA genotypes, and by 6.00 mL/year (-4.54 to 16.54) among AA genotypes. CONCLUSIONS: Our results suggest that cell cycle control genes may modify the degree to which improved air quality may benefit respiratory function in adults