Tracheal sound parameters of respiratory cycle phases show differences between flow-limited and normal breathing during sleep.

The objective of the present work was to develop new computational parameters to examine the characteristics of respiratory cycle phases from the tracheal breathing sound signal during sleep. Tracheal sound data from 14 patients (10 males and 4 females) were examined. From each patient, a 10 min long section of normal and a 10 min section of flow-limited breathing during sleep were analysed. The computationally determined proportional durations of the respiratory phases were first investigated. Moreover, the phase durations and breathing sound amplitude levels were used to calculate the area under the breathing sound envelope signal during inspiration and expiration phases. An inspiratory sound index was then developed to provide the percentage of this type of area during the inspiratory phase with respect to the combined area of inspiratory and expiratory phases. The proportional duration of the inspiratory phase showed statistically significantly higher values during flow-limited breathing than during normal breathing and inspiratory pause displayed an opposite difference. The inspiratory sound index showed statistically significantly higher values during flow-limited breathing than during normal breathing. The presented novel computational parameters could contribute to the examination of sleep-disordered breathing or as a screening tool.

Intelligent methods for identifying respiratory cycle phases from tracheal sound signal during sleep.

We present two methods for identifying respiratory cycle phases from tracheal sound signal during sleep. The methods utilize the Hilbert transform in envelope extraction. They determine automatically a patient-specific amplitude threshold to be used in the detection. The core of one method is designed to be amplitude-independent whereas the other method uses solely the amplitude information. The methods provided average sensitivities of 98% and 99%, respectively, and positive prediction values of 100% on the total of 1434 respiratory cycles analysed from six different patients. The developed methods seem promising as such or as tools for analysing sleep disordered breathing.

New tracheal sound feature for apnoea analysis.

Sleep apnoea syndrome is common in the general population and is currently underdiagnosed. The aim of the present work was to develop a new tracheal sound feature for separation of apnoea events from non-apnoea time. Ten overnight recordings from apnoea patients containing 1,107 visually scored apnoea events totalling 7 h in duration and 72 h of non-apnoea time were included in the study. The feature was designed to describe the local spectral content of the sound signal. The median, maximum and mean smoothing of different time scales were compared in the feature extraction. The feature was designed to range from 0 to 1 irrespective of tracheal sound amplitudes. This constant range could offer application of the feature without patient-specific adjustments. The overall separation of feature values during apnoea events from non-apnoea time across all patients was good, reaching 80.8%. Due to the individual differences in tracheal sound signal amplitudes, developing amplitude-independent means for screening apnoea events is beneficial.

Detection of compressed tracheal sound patterns with large amplitude variation during sleep.

The objective of the present work was to develop automated methods for the compressed tracheal breathing sound analysis. Overnight tracheal breathing sound was recorded from ten apnoea patients. From each patient, three different types of tracheal sound deflection pattern, each of 10 min duration, were visually scored, viewing the compressed tracheal sound curve. Among them, high deflection patterns are of special interest due to the possible correlation with apnoea-hypopnoea sequences. Three methods were developed to detect patterns with high deflection, utilizing nonlinear filtering in local characterization of tracheal sounds. Method one comprises of local signal maximum, the second method of its local range, and the third of its relative range. The three methods provided 80% sensitivity with 57, 91 and 93% specificity, respectively. Method three provided an amplitude-independent approach. The nonlinear filtering based methods developed here offer effective means for analysing tracheal sounds of sleep-disordered breathing.

Interaction of age with shift-related sleep-wakefulness, sleepiness, performance, and social life.

It is not clear how the age-related changes in sleep are related to performance and subjective sleepiness at different time of the day. The aim of the present study was to study work shift related interactions of age with sleep-wakefulness, performance, and social life. A representative sample of aircraft maintenance workers in a continuous three-shift system was studied by a questionnaire (n = 275) and an on-site field (n = 49) study. In the field study, sleep length and quality and different ratings of social and other activities were studied with an actigraphy and a Pocket PC diary during 15 consecutive days. Subjective sleepiness (KSS) and vigilance performance (PVT) were registered at work. Although the shift type influenced the sleep, subjective sleepiness, performance, and social life, age was distinctly related only to shift-related changes in the amount of sleep, subjective sleepiness, and psychomotor vigilance. Night shifts were related with shorter sleep, decreased performance, and increased sleepiness. Although subjective sleepiness was greatest among the youngest (25-34 years) age group during the morning and the night shifts, the increase of performance lapses was higher among the middle-aged (35-49 years) and senior (50-58 years) groups during the night shifts compared to the youngest age group. According to the questionnaire, older shiftworkers also tended to perceive more frequently that subjective sleepiness decreases their work performance during the morning and night shifts. The results indicate of no direct link between age-related differences in subjective sleepiness and performance at night work. The shorter day sleep after the night shifts and higher deterioration of subjective and objective performance according to age urge on development of shift schedules aiming at lower fatigue levels during the night shifts.

Effect of a single-dose of olanzapine on sleep in healthy females and males.

The effect of a single dose of 10 mg olanzapine on healthy volunteers of both sexes was examined using polysomnography and power spectral analysis. The structure and continuity of sleep were unaffected by olanzapine in both sexes. The increase in both actual sleep time and slow wave sleep in females correlated with the increase in theta power, while delta power was not significantly elevated, suggesting that theta power may be a sensitive indicator of changes in sleep. The changes in sleep had the same tendency in men, but they were not significant. The difference between the sexes could not be explained by differences in body mass index. Olanzapine affects sleep probably through 5-HT(2C) receptors. The receptor gene is located on the X-chromosome, inducing an allelic difference between the females and males. This difference may contribute to the different effects of olanzapine on sleep. Olanzapine seems to preserve the normal structure of sleep and increase the amount of slow-wave sleep, which might be of additional benefit in treatment of schizophrenia. The effective clinical dose may be lower for females than males.

The relationship between audiogenic seizure (AGS) susceptibility and forebrain tone-responsiveness in genetically AGS-prone Wistar rats.

The present study characterized the intensity-response functions of extracellular field responsiveness of different cortical/subcortical structures of the forebrain following the free-field presentation of tone stimuli, within a population of genetically audiogenic seizure (AGS)-prone KM-Wistar rats. The neural response properties of each case were compared to its propensity to exhibit AGSs during the continuous tone stimulation (15 kHz, 90 s at max.). The amplitudes or slope components of the evoked responses and their peak latencies showed significant positive (amplitude and slope) and negative (peak latency) Bolzmann's sigmoid relationships with the onset-latency of AGS. These relationships, with areal differences in the slopes of saturation functions, applied for the three different data sets recorded simultaneously from the stratum radiatum dendritic layer of the hippocampal CA1 area, primary auditory cortex layers II-IV, and frontal cortex surface. In addition, the similar type of functions between the evoked response variables and AGS onset latency held when all the areas were considered together. These data suggest that the neural responsiveness to acoustic stimulation of the primary sensory, multimodal and association cortices of the forebrain may altogether contribute to the seizure initiation by that modality in the genetically AGS-prone rats. It has been previously shown that there exist abundant and dispersed auditory projections from these forebrain areas to the brain stem and spinal cord, structures that are generally considered to be the key predisposing factors in the generation of AGS. Hence, the types of correlation found reflect the subject-specific stage of forebrain responsiveness, being either related or unrelated to genetic AGS-specific changes, and possibly its triggering impact upon the lower brain AGS network. Accordingly, the mere comparison of forebrain response measures of these AGS-prone animals with those of the AGS-resistant ones could not reveal the result presented.

Lack of calbindin-D28k does not affect hearing level or survival of hair cells in acoustic trauma.

Calbindin is a cytosolic calcium-binding protein abundant in the hair cells of the inner ear and in distinct neurons of the auditory pathway. It is suggested to speed the return of potentially toxic calcium levels to normal. In this study, we show the basic hearing functions and the result of noise trauma from the calbindin null mutant mice generated by gene targeting. Auditory brainstem evoked response and distortion product otoacoustic emissions appear similar as in the control group. A moderate noise-induced trauma produced a similar loss of hair cells in calbindin null mutant mice than in wild-type controls. The result suggests that although calbindin is abundant in hair cells, it is not essential for the main hearing function and it does not provide physiological protection against a moderate noise-induced inner ear trauma in mice.

Rescue of hearing, auditory hair cells, and neurons by CEP-1347/KT7515, an inhibitor of c-Jun N-terminal kinase activation.

We have studied the mechanisms of auditory hair cell death after insults in vitro and in vivo. We show DNA fragmentation of hair cell nuclei after ototoxic drug and intense noise trauma. By using phospho-specific c-Jun-N-terminal kinase (JNK) and c-Jun antibodies in immunohistochemistry, we show that the JNK pathway, associated with stress, injury, and apoptosis, is activated in hair cells after trauma. CEP-1347, a derivative of the indolocarbazole K252a, is a small molecule that has been shown to attenuate neurodegeneration by blocking the activation of JNK (). Subcutaneously delivered CEP-1347 attenuated noise-induced hearing loss. The protective effect was demonstrated by functional tests, which showed less hearing threshold shift in CEP-1347-treated than in nontreated guinea pigs, and by morphometric methods showing less hair cell death in CEP-1347-treated cochleas. In organotypic cochlear cultures, CEP-1347 prevented neomycin-induced hair cell death. In addition to hair cells, CEP-1347 promoted survival of dissociated cochlear neurons. These results suggest that therapeutic intervention in the JNK signaling cascade, possibly by using CEP-1347, may offer opportunities to treat inner ear injuries.

Guinea pig auditory neurons are protected by glial cell line-derived growth factor from degeneration after noise trauma.

For patients with profound hearing loss, cochlear implants have become the treatment of choice. These devices provide auditory information through direct electrical stimulation of the auditory nerve. Prosthesis function depends on survival and electrical excitability of the cochlear neurons. Degeneration of the auditory nerve occurs after lesions of its peripheral target field (organ of Corti), specifically, including loss of inner hair cells (IHCs). There is now evidence that local treatment of the cochlea with neurotrophins may enhance survival of auditory neurons after aminoglycoside-induced deafness. Glial cell line-derived neurotrophic factor (GDNF) has recently been shown to be an important survival factor in other regions of the nervous system. By in situ hybridization, we now show that IHCs of the neonatal and mature rat cochlea synthesize GDNF and that GDNF-receptor alpha, but not c-Ret, is expressed in the rat spiral ganglion. We also show that GDNF is a potent survival-promoting factor for rat cochlear neurons in vitro. Finally, we examined GDNF efficacy to enhance cochlear-nerve survival after IHC lesions in vivo. We found that chronic intracochlear infusion of GDNF greatly enhances survival of guinea pig cochlear neurons after noise-induced IHC lesions. Our results demonstrate that GDNF is likely to be an endogeneous survival factor in the normal mammalian cochlea and it could have application as a pharmacological treatment to prevent secondary auditory nerve degeneration following organ of Corti damage.

Expression of neurotrophins and Trk receptors in the developing, adult, and regenerating avian cochlea.

We studied the expression of neurotrophins and their Trk receptors in the chicken cochlea. Based on in situ hybridization, brain-derived neurotrophic factor (BDNF) is the major neurotrophin there, in contrast to the mammalian cochlea, where neurotrophin-3 (NT-3) predominates. NT-3 mRNA labeling was weak and found only during a short time period in the early cochleas. During embryogenesis, BDNF mRNA was first seen in early differentiating hair cells. Afferent cochlear neurons expressed trkB mRNA from the early stages of gangliogenesis onward. In accordance, in vitro, BDNF promoted survival of dissociated neurons and stimulated neuritogenesis from ganglionic explants. High levels of BDNF mRNA in hair cells and trkB mRNA in cochlear neurons persisted in the mature cochlea. In addition, mRNA for the truncated TrkB receptor was expressed in nonneuronal cells, specifically in supporting cells, located adjacent to the site of BDNF synthesis and nerve endings. Following acoustic trauma, regenerated hair cells acquired BDNF mRNA expression at early stages of differentiation. Truncated trkB mRNA was lost from supporting cells that regenerated into hair cells. High levels of BDNF mRNA persisted in surviving hair cells and trkB mRNA in cochlear neurons after noise exposure. These results suggest that in the avian cochlea, peripheral target-derived BDNF contributes to the onset and maintenance of hearing function by supporting neuronal survival and regulating the (re)innervation process. Truncated TrkB receptors may regulate the BDNF concentration available to neurites, and they might have an important role during reinnervation.

The "toughening" phenomenon in rat's auditory organ.

In audiological "toughening" or "conditioning" phenomenon prior exposure to moderate noise reduces the extent of hearing deterioration caused by the subsequent exposure to traumatic test noise known to cause inner ear damage. "Toughening" has been demonstrated in many mammalian laboratory animals such as guinea pig and chinchilla but not in rat or mouse. Our aim was to study the occurrence of this phenomenon in the rat. Ninety-one white male Wistar rats were divided into four groups: unexposed control group (U, n = 10), "conditioning" only (C, n = 32), "conditioning" plus test noise (C + T, n = 36) and test noise only (T, n = 13). Groups C and C + T were "conditioned" for 10 hours with 4.0 kHz OBN between 55 and 95 dB sound pressure levels (SPLs). After 10 hours rest groups C + T and T were exposed to the same noise at 105 dB SPL for 13 hours. The hearing thresholds were determined by auditory brainstem response audiometry (ABR) either immediately after or 3 weeks after the exposures. After that the animals were sacrificed. The cochleas were removed and perilymphatically fixed and further processed for quantitative cytocochleograms. Both the temporary (TTS) and the permanent threshold shifts (PTS) were smaller in animals which had been "conditioned" prior exposure to traumatic noise. Yet only 95 dB SPL "conditioning" gave statistically significant difference (p < 0.05) in PTS. From our results we conclude that "conditioning" effect seems to be present also in the rat. However to confirm this, further experiments are needed. The mechanisms behind "conditioning" are still unknown and also to clarify them, further efforts are needed.

Effect of hyperbaric oxygen treatment on permanent threshold shift in acoustic trauma among rats.

Impulse noise from firearms is a common cause of acute acoustic trauma (AAT). Recently hyperbaric oxygen treatment has become available in many hospitals treating AAT. We exposed 39 Wistar rats to intense impulse noise of 60 shots from the assault rifle (162 dB SPL). After the exposure 15 animals were given hyperbaric oxygen treatment (HBO) by 10 treatment cycles of 90 minutes 100% oxygen in 0.25 MPa, one treatment cycle per day. Four weeks after the exposure the hearing thresholds were measured with auditory brainstem response audiometry at frequencies of 1.0, 2.0, 4.0, 6.0, 8.0 and 10.0 kHz. Characteristics for the resulting noise-induced hearing loss were large variations in its severity not only between animals, but also between the ears of a single animal. The largest permanent threshold shifts were found at 6.0, 8.0 and 10.0 kHz. Most of the HBO-treated animals showed less threshold shift than the non-treated animals. The difference between the HBO group and the control group was only slightly statistically significant (p = 0.067).