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  • 1.
    Bagger-Sjoback, Dan
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Stromback, Karin
    Academic Hospital, Sweden.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden.
    Plue, Jan
    Stockholm University, Sweden.
    Larsson, Christina
    Karolinska University Hospital, Sweden.
    Hultcrantz, Malou
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Papatziamos, Georgios
    Karolinska University Hospital, Sweden.
    Smeds, Henrik
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Danckwardt-Lilliestrom, Niklas
    Academic Hospital, Sweden.
    Hellstrom, Sten
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Johansson, Ann
    Karolinska University Hospital, Sweden.
    Tideholm, Bo
    Karolinska University Hospital, Sweden.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden.
    A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, s. e0115657-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies. Methods We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo. Findings One year after surgery, high-frequency hearing had improved 2.7 +/- 3.8 dB in the placebo group (67 patients analysed) and 2.4 +/- 3.7 dB in the treated group (72 patients; means +/- 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting. Conclusions N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy.

  • 2.
    Bagger-Sjoback, Dan
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stromback, Karin
    Uppsala University, Sweden.
    Hultcrantz, Malou
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Papatziamos, Georgios
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Smeds, Henrik
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Danckwardt-Lilliestrom, Niklas
    Uppsala University, Sweden.
    Tideholm, Bo
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Johansson, Ann
    Karolinska University Hospital, Sweden.
    Hellstrom, Sten
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 13341Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Otosclerosis is a common disorder that leads to conductive hearing loss. Most patients with otosclerosis also have tinnitus, and surgical treatment is known to improve hearing as well as tinnitus. Some patients however experience worsening of tinnitus after the operation, but there are no known factors that allow surgeons to predict who will be at risk. In this prospective observational study on 133 patients undergoing stapedotomy, we show that postoperative air conduction thresholds at very high stimulus frequencies predict improvement of tinnitus, as assessed with proportional odds logistic regression models. Young patients were significantly more likely to experience reduction of tinnitus and patients whose tinnitus became better were also more satisfied with the outcome of the operation. These findings have practical importance for patients and their surgeons. Young patients can be advised that surgery is likely to be beneficial for their tinnitus, but a less positive message should be conveyed to older patients.

  • 3. Brownell, William E
    et al.
    Jacob, Stefan
    Hakizimana, Pierre
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Membrane cholesterol modulates cochlear electromechanics2011Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 461, nr 6, s. 677-686Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Changing the concentration of cholesterol in the plasma membrane of isolated outer hair cells modulates electromotility and prestin-associated charge movement, suggesting that a similar manipulation would alter cochlear mechanics. We examined cochlear function before and after depletion of membrane cholesterol with methyl-β-cyclodextrin (MβCD) in an excised guinea pig temporal bone preparation. The mechanical response of the cochlear partition to acoustic and/or electrical stimulation was monitored using laser interferometry and time-resolved confocal microscopy. The electromechanical response in untreated preparations was asymmetric with greater displacements in response to positive currents. Exposure to MβCD increased the magnitude and asymmetry of the response, without changing the frequency tuning of sound-evoked mechanical responses or cochlear microphonic potentials. Sodium salicylate reversibly blocked the enhanced electromechanical response in cholesterol depleted preparations. The increase of sound-evoked vibrations during positive current injection was enhanced following MβCD in some preparations. Imaging was used to assess cellular integrity which remained unchanged after several hours of exposure to MβCD in several preparations. The enhanced electromechanical response reflects an increase in outer hair cell electromotility and may reveal features of cholesterol distribution and trafficking in outer hair cells.

  • 4. Chen, Fangyi
    et al.
    Zha, Dingjun
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Choudhury, Niloy
    Jacques, Steven L
    Wang, Ruikang K
    Shi, Xiaorui
    Nuttall, Alfred L
    A differentially amplified motion in the ear for near-threshold sound detection2011Ingår i: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 14, nr 6, s. 770-774Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ear is a remarkably sensitive pressure fluctuation detector. In guinea pigs, behavioral measurements indicate a minimum detectable sound pressure of ∼20 μPa at 16 kHz. Such faint sounds produce 0.1-nm basilar membrane displacements, a distance smaller than conformational transitions in ion channels. It seems that noise within the auditory system would swamp such tiny motions, making weak sounds imperceptible. Here we propose a new mechanism contributing to a resolution of this problem and validate it through direct measurement. We hypothesized that vibration at the apical side of hair cells is enhanced compared with that at the commonly measured basilar membrane side. Using in vivo optical coherence tomography, we demonstrated that apical-side vibrations peaked at a higher frequency, had different timing and were enhanced compared with those at the basilar membrane. These effects depend nonlinearly on the stimulus sound pressure level. The timing difference and enhancement of vibrations are important for explaining how the noise problem is circumvented.

  • 5.
    Dash-Wagh, Suvarna
    et al.
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jacob, Stefan
    Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Lindberg, Staffan
    Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
    Fridberger, Anders
    Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Langel, Ülo
    Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
    Ulfendahl, Mats
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Intracellular Delivery of Short Interfering RNA in Rat Organ of Corti Using a Cell-penetrating Peptide PepFect62012Ingår i: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RNA interference (RNAi) using short interfering RNA (siRNA) is an attractive therapeutic approach for treatment of dominant-negative mutations. Some rare missense dominant-negative mutations lead to congenital-hearing impairments. A variety of viral vectors have been tested with variable efficacy for modulating gene expression in inner ear. However, there is concern regarding their safety for clinical use. Here, we report a novel cell-penetrating peptide (CPP)-based nonviral approach for delivering siRNA into inner ear tissue using organotypic cultures as model system. PepFect6 (PF6), a variant of stearyl-TP10, was specially designed for improved delivery of siRNA by facilitating endosomal release. We show that PF6 was internalized by all cells without inducing cytotoxicity in cochlear cultures. PF6/siRNA nanoparticles lead to knockdown of target genes, a housekeeping gene and supporting cell-specific connexin 26. Interestingly, application of PF6/connexin 26 siRNA exhibited knockdown of both connexin 26 and 30 mRNA and their absence led to impaired intercellular communication as demonstrated by reduced transfer of calcein among the PF6/connexin 26-siRNA-treated cells. Thus, we conclude that PF6 is an efficient nonviral vector for delivery of siRNA, which can be applied as a tool for the development of siRNA-based therapeutic applications for hearing impairments.Molecular Therapy - Nucleic Acids (2012) 1, e61; doi:10.1038/mtna.2012.50; published online 11 December 2012.

  • 6.
    Duan, Maoli
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Bjelke, Börje
    Örebro University Hospital, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Counter, Allen
    Karolinska Institutet, Stockholm, Sweden.
    Klason, Tomas
    Karolinska Institutet, Stockholm, Sweden.
    Skjönsberg, Åsa
    Karolinska Institutet, Stockholm, Sweden.
    Herrlin, Petra
    Karolinska Institutet, Stockholm, Sweden.
    Borg, Erik
    Örebro University Hospital, Sweden.
    Laurell, Göran
    Karolinska Institutet, Stockholm, Sweden.
    Imaging of the guinea pig cochlea following round window gadolinium application2004Ingår i: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 15, nr 12, s. 1927-1930Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Precise, non-invasive determination of the aetiology and site of pathology of inner ear disorders is difficult. The aim of this study was to describe an alternative method for inner ear visualization, based on local application of the paramagnetic contrast agent gadolinium. Using a 4.7 T MRI scanner, high contrast images of all four cochlear turns were obtained 3.5 h after placing gadolinium on the round window membrane. Gadolinium cleared from the cochlea within 96 h. Auditory brainstem response measurements performed on a separate group of animals showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea.

  • 7. Felix, Richard A
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Leijon, Sara
    Berrebi, Albert S
    Magnusson, Anna K
    Sound rhythms are encoded by postinhibitory rebound spiking in the superior paraolivary nucleus2011Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, nr 35, s. 12566-12578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The superior paraolivary nucleus (SPON) is a prominent structure in the auditory brainstem. In contrast to the principal superior olivary nuclei with identified roles in processing binaural sound localization cues, the role of the SPON in hearing is not well understood. A combined in vitro and in vivo approach was used to investigate the cellular properties of SPON neurons in the mouse. Patch-clamp recordings in brain slices revealed that brief and well timed postinhibitory rebound spiking, generated by the interaction of two subthreshold-activated ion currents, is a hallmark of SPON neurons. The I(h) current determines the timing of the rebound, whereas the T-type Ca(2+) current boosts the rebound to spike threshold. This precisely timed rebound spiking provides a physiological explanation for the sensitivity of SPON neurons to sinusoidally amplitude-modulated (SAM) tones in vivo, where peaks in the sound envelope drive inhibitory inputs and SPON neurons fire action potentials during the waveform troughs. Consistent with this notion, SPON neurons display intrinsic tuning to frequency-modulated sinusoidal currents (1-15Hz) in vitro and discharge with strong synchrony to SAMs with modulation frequencies between 1 and 20 Hz in vivo. The results of this study suggest that the SPON is particularly well suited to encode rhythmic sound patterns. Such temporal periodicity information is likely important for detection of communication cues, such as the acoustic envelopes of animal vocalizations and speech signals.

  • 8.
    Flock, Å.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Flock, B.
    Karolinska Institute, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institute, Stockholm, Sweden.
    Jäger, W.
    Huddinge Hospital, Sweden.
    Methods for integrating fluorimetry in the study of hearing organ structure and function1997Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 106, nr 1-2, s. 29-38Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The measurement of function in the intact organ of Corti has up to now been achieved by three methods: electrophysiology, mechanical measurement and biochemical analysis. The two former methods have supplied information at the level of single identified cells. We have used a fourth method, optical fluorimetry, to measure hair cell function at the cellular level in the intact organ of Corti. Here we describe the methods involved in fluorescence labelling and video-enhanced microscopy in combination with electrophysiological recording of cochlear microphonic (CM) and summating potentials (SP). The guinea pig temporal bone containing an intact ear drum, ossicular chain and cochlea can be maintained in the isolated state by perfusion of the scala tympani with oxygenated tissue culture medium. Substances added to the perfusate readily diffuse through the basilar membrane into the organ of Corti. In this way cells in the organ can be stained by a number of fluorescent probes which label different structures and functions. Here we have used two dyes which label mitochondria and fluoresce with an intensity proportional to metabolic activity. By simultaneous measurement of CM and SP the functional state of the organ can be monitored.

  • 9.
    Flock, Å.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Scarfone, E.
    Université Montpellier II, France.
    Ulfendahl, M.
    Karolinska Sjukhuset, Stockholm, Sweden .
    Supporting cells contribute to control of hearing sensitivity1999Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 19, nr 11, s. 4498-4507Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mammalian hearing organ, the organ of Corti, was studied in an in vitro preparation of the guinea pig temporal bone. As in vivo, the hearing organ responded with an electrical potential, the cochlear microphonic potential, when stimulated with a test tone. After exposure to intense sound, the response to the test tone was reduced. The electrical response either recovered within 10-20 min or remained permanently reduced, thus corresponding to a temporary or sustained loss of sensitivity. Using laser scanning confocal microscopy, stimulus-induced changes of the cellular structure of the hearing organ were simultaneously studied. The cells in the organ were labeled with two fluorescent probes, a membrane dye and a cytoplasm dye, showing enzymatic activity in living cells. Confocal microscopy images were collected and compared before and after intense sound exposure. The results were as follows. (1) The organ of Corti could be divided into two different structural entities in terms of their susceptibility to damage: an inner, structurally stable region comprised of the inner hair cell with its supporting cells and the inner and outer pillar cells; and an outer region that exhibited dynamic structural changes and consisted of the outer hair cells and the third Deiters' cell with its attached Hensen's cells. (2) Exposure to intense sound caused the Deiters' cells and Hensen's cells to move in toward the center of the cochlear turn. (3) This event coincided with a reduced sensitivity to the test tone (i.e., reduced cochlear microphonic potential). (4) The displacement and sensitivity loss could be reversible. It is concluded that these observations have relevance for understanding the mechanisms behind hearing loss after noise exposure and that the supporting cells take an active part in protection against trauma during high-intensity sound exposure.

  • 10.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Sound-induced differential motion within the hearing organ2003Ingår i: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, nr 5, s. 446-448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hearing depends on the transformation of sound-induced basilar membrane vibration into deflection of stereocilia1 on the sensory hair cells, but the nature of these mechanical transformations is unclear. Using new techniques to visualize and measure sound-induced vibration deep inside the moving organ of Corti, we found that two functionally crucial structures, the basilar membrane and the reticular lamina, have different centers of rotation, leading to shearing motion and rapid deformation for the mechanoreceptive outer hair cells. Structural relations within the organ of Corti are much more dynamic than previously thought, which clarifies how outer hair cell molecular motors can have such a powerful effect.

  • 11.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet, Stockholm, Sweden.
    Internal shearing within the hearing organ evoked by basilar membrane motion2002Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 22, nr 22, s. 9850-9857Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The vibration of the hearing organ that occurs during sound stimulation is based on mechanical interactions between different cellular structures inside the organ of Corti. The exact nature of these interactions is unclear and subject to debate. In this study, dynamic structural changes were produced by stepwise alterations of scala tympani pressure in an in vitro preparation of the guinea pig temporal bone. Confocal images were acquired at each level of pressure. In this way, the motion of several structures could be observed simultaneously with high resolution in a nearly intact system. Images were analyzed using a novel wavelet-based optical flow estimation algorithm. Under these conditions, the reticular lamina moved as a stiff plate with a center of rotation in the region of the inner hair cells. Despite being enclosed in several types of supporting cells, the inner hair cells, together with the adjacent inner pillar cells, moved in a manner signifying high compliance. The outer hair cells displayed radial motion indicative of cellular bending. Together, these results show that shearing motion occurs between several parts of the organ, and that structural relationships within the organ change dynamically during displacement of the basilar membrane.

  • 12.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Karolinska Institutet, Stockholm, Sweden.
    Hu, Ning
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Zou, Yuan
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Ren, Tianying
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Nuttall, Alfred
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Organ of Corti potentials and the motion of the basilar membrane2004Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 24, nr 45, s. 10057-10063Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During sound stimulation, receptor potentials are generated within the sensory hair cells of the cochlea. Prevailing theory states that outer hair cells use the potential-sensitive motor protein prestin to convert receptor potentials into fast alterations of cellular length or stiffness that boost hearing sensitivity almost 1000-fold. However, receptor potentials are attenuated by the filter formed by the capacitance and resistance of the membrane of the cell. This attenuation would limit cellular motility at high stimulus frequencies, rendering the above scheme ineffective. Therefore, Dallos and Evans (1995a) proposed that extracellular potential changes within the organ of Corti could drive cellular motor proteins. These extracellular potentials are not filtered by the membrane. To test this theory, both electric potentials inside the organ of Corti and basilar membrane vibration were measured in response to acoustic stimulation. Vibrations were measured at sites very close to those interrogated by the recording electrode using laser interferometry. Close comparison of the measured electrical and mechanical tuning curves and time waveforms and their phase relationships revealed that those extracellular potentials indeed could drive outer hair cell motors. However, to achieve the sharp frequency tuning that characterizes the basilar membrane, additional mechanical processing must occur inside the organ of Corti.

  • 13.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, Å.
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Hospital, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Acoustic overstimulation increases outer hair cell Ca2+ concentrations and causes dynamic contractions of the hearing organ1998Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, nr 12, s. 7127-7132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dynamic responses of the hearing organ to acoustic overstimulation were investigated using the guinea pig isolated temporal bone preparation. The organ was loaded with the fluorescent Ca2+ indicator Fluo-3, and the cochlear electric responses to low-level tones were recorded through a microelectrode in the scala media. After overstimulation, the amplitude of the cochlear potentials decreased significantly. In some cases, rapid recovery was seen with the potentials returning to their initial amplitude. In 12 of 14 cases in which overstimulation gave a decrease in the cochlear responses, significant elevations of the cytoplasmic [Ca2+] in the outer hair cells were seen. [Ca2+] increases appeared immediately after terminating the overstimulation, with partial recovery taking place in the ensuing 30 min in some preparations. Such [Ca2+] changes were not seen in preparations that were stimulated at levels that did not cause an amplitude change in the cochlear potentials. The overstimulation also gave rise to a contraction, evident as a decrease of the width of the organ of Corti. The average contraction in 10 preparations was 9 microm (SE 2 microm). Partial or complete recovery was seen within 30-45 min after the overstimulation. The [Ca2+] changes and the contraction are likely to produce major functional alterations and consequently are suggested to be a factor contributing strongly to the loss of function seen after exposure to loud sounds.

  • 14.
    Fridberger, Anders
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Oregon Health and Science University, OR 97201 USA.
    Guinan, John J. Jr.
    Harvard MIT Div Health Science and Technology, MA USA; Massachusetts Eye and Ear Infirm, MA 02114 USA; Harvard University, MA 02115 USA.
    What Shapes the Stimulus to the Inner Hair Cell?: A Moderated Discussion2015Ingår i: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, nr 080006Konferensbidrag (Refereegranskat)
    Abstract [en]

    The following is an edited transcript of a recorded discussion session on the topic of "What Shapes the Stimulus to the Inner Hair Cell?". The discussion, moderated by the authors, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

  • 15.
    Fridberger, Anders
    et al.
    Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden.
    Ren, Tianying
    Oregon Hearing Research Center, Oregon Health & Science University, Portland, USA.
    Local mechanical stimulation of the hearing organ by laser irradiation2006Ingår i: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 17, nr 1, s. 33-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Light produces force when interacting with matter. Such radiation pressure may be used to accelerate small objects along the beam path of a laser. Here, we demonstrate that a moderately powerful laser can deliver enough force to locally stimulate the hearing organ, in the absence of conventional sound. Damped mechanical oscillations are observed following brief laser pulses, implying that the organ of Corti is locally resonant. This new method will be helpful for probing the mechanical properties of the hearing organ, which have crucial importance for the ear's ability to detect sound.

  • 16.
    Fridberger, Anders
    et al.
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden .
    Tomo, Igor
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Imaging hair cell transduction at the speed of sound: dynamic behavior of mammalian stereocilia2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 6, s. 1918-1923Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cochlea contains two types of sensory cells, the inner and outer hair cells. Sound-evoked deflection of outer hair cell stereocilia leads to fast force production that will enhance auditory sensitivity up to 1,000-fold. In contrast, inner hair cells are thought to have a purely receptive function. Deflection of their stereocilia produces receptor potentials, transmitter release, and action potentials in the auditory nerve. Here, we describe a method for rapid confocal imaging. The method was used to image stereocilia during simultaneous sound stimulation in an in vitro preparation of the guinea pig cochlea. We show that inner hair cell stereocilia move because they interact with the fluid surrounding the hair bundles, but stereocilia deflection occurs at a different phase of the stimulus than is generally expected. In outer hair cells, stereocilia deflections were approximately 1/3 of the reticular lamina displacement. Smaller deflections were found in inner hair cells. The ratio between stereocilia deflection and reticular lamina displacement is important for auditory function, because it determines the stimulus applied to transduction channels. The low ratio measured here suggests that amplification of hair-bundle movements may be necessary in vivo to preserve transduction fidelity at low stimulus levels. In the case of the inner hair cells, this finding would represent a departure from traditional views on their function.

  • 17.
    Fridberger, Anders
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Institute, Stockholm, Sweden.
    Acute mechanical overstimulation of isolated outer hair cells causes changes in intracellular calcium levels without shape changes1996Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 116, nr 1, s. 17-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Impaired auditory function following acoustic overstimulation, or noise, is mainly reported to be accompanied by cellular changes such as damage to the sensory hair bundles, but changes in the cell bodies of the outer hair cells have also been described. To investigate more closely the immediate cellular responses to overstimulation, isolated guinea pig outer hair cells were subjected to a 200 Hz oscillating water jet producing intense mechanical stimulation. The water jet was aimed at the cell body of the isolated outer hair cell. Cell shape changes were studied using video microscopy, and intracellular calcium concentration changes were monitored by means of the fluorescent calcium indicator Fluo-3. Cells exposed to a high-intensity stimulus showed surprisingly small light-microscopical alterations. The cytoplasmic calcium concentration increased in most cells, although some cells appeared very resistant to the mechanical stress. No correlation could be found be tween the calcium concentration changes and the cell length. The changes in calcium concentration reported here are suggested to be involved in the long-term pathogenesis of noise-induced hair cell damage.

  • 18.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    van Maarseveen, J.
    Rijksuniversiteit Groningen, the Netherlands.
    Scarfone, E.
    Université de Montpellier II, France.
    Ulfendahl, M.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, A.
    Karolinska Institutet, Stockholm, Sweden.
    Pressure-induced basilar membrane position shifts and the stimulus-evoked potentials in the low-frequency region of the guinea pig cochlea1997Ingår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 161, nr 2, s. 239-252Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have used the guinea pig isolated temporal bone preparation to investigate changes in the non-linear properties of the tone-evoked cochlear potentials during reversible step displacements of the basilar membrane towards either the scala tympani or the scala vestibuli. The position shifts were produced by changing the hydrostatic pressure in the scala tympani. The pressures involved were calculated from measurements of the fluid flow through the system, and the cochlear DC impedance calculated (1.5 x 10(11) kg m-4 s-1, n = 10). Confocal microscopic visualization of the organ of Corti showed that pressure increases in the scala tympani caused alterations of the position of the reticular lamina and stereocilia bundles. For low pressures, there was a sigmoidal relation between the DC pressure applied to the scala tympani (and thus the position shift of the organ of Corti) and the amplitude of the summating potential. The cochlear microphonic potential also showed a pronounced dependence on the applied pressure: pressure changes altered the amplitude of the fundamental as well as its harmonics. In addition, the sound pressure level at which the responses began to saturate was increased, implying a transition towards a linear behaviour. An increase of the phase lag of the cochlear microphonic potential was seen when the basilar membrane was shifted towards the scala vestibuli. We have also measured the intracochlear DC pressure using piezoresistive pressure transducers. The results are discussed in terms of changes in the non-linear properties of cochlear transduction. In addition, the implications of these results for the pathophysiology and diagnosis of Meniérè's disease are discussed.

  • 19.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    van Maarseveen, J.
    Rijksuniversiteit Groningen, The Netherlands.
    Ulfendahl, M.
    Karolinska Institutet, Stockholm, Sweden.
    An in vitro model for acoustic overstimulation1998Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 118, nr 3, s. 352-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although many studies have been performed on the effects of acoustic overstimulation on the inner ear, our knowledge about the cellular processes underlying reduced hearing sensitivity and auditory cell death is still limited. In order to further our understanding of cellular processes occurring in conjunction with acoustic trauma, we designed an in vitro model to study the effects of overstimulation directly on sensory hair cells isolated from the low-frequency part of the guinea pig cochlea. The isolated outer hair cells were subjected to pressure jets delivered by a glass micropipette positioned close to the cell, in order to mimic the pressure changes occurring in the intact inner ear during sound stimulation. A second micropipette coupled to a piezoresistive pressure transducer was used as a probe measuring the pressure at precise locations at and around the cell. In a previous study, we found that such stimulation gave rise to increases in the intracellular calcium concentration. The present study characterizes the stimulus, describes the computer-controlled setup used for calibration, and gives examples of different modes of overstimulation at the cellular level. The peak pressure that could be generated using the pressure jet was around 325 Pa, or 144 dB (re 20 microPa) at 140 Hz. The pressure jet elicited large mechanical vibrations of the cell bodies of isolated cells. The vibration mode of the cells often changed over time, implying that the stimulation caused changes of the cellular stiffness. However, most cells appeared quite resistant to the high intensity mechanical stimulation.

  • 20.
    Fridberger, Anders
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Von Tiedemann, Miriam
    Karolinska Institutet, Stockholm.
    Flock, Åke
    Karolinska Institutet, Stockholm.
    Flock, Britta
    Karolinska Institutet, Stockholm.
    Öfverstedt, Lars-Göran
    Karolinska Institutet, Stockholm.
    Skoglund, Ulf
    Karolinska Institutet, Stockholm.
    Three-dimensional structure of outer hair cell pillars2009Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, nr 9, s. 940-945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Conclusions. Electron tomography was used to generate three-dimensional reconstructions of the pillars that connect the cell membrane with the cytoskeleton of the outer hair cell. Results are consistent with the hypothesis that pillars are important for mechanically linking the membrane with the cytoskeleton.

    Objective: To make a qualitative assessment of the morphology of the sub-membrane pillars of cochlear outer hair cells.

    Materials and methods. Guinea pig cochleae were fixed and prepared for electron microscopy using protocols described previously. Sections were imaged on an electron microscope equipped with a goniometer. The specimens were tilted through a range of 120°, and an image was acquired at each tilt angle. Filtered back-projection was used to generate three-dimensional reconstructions.

    Results. Twelve individual pillars were successfully reconstructed. Pillars often connect to the cell membrane through a thin segment, and to the cytoskeleton through a forking structure that may form a central cavity.

  • 21.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Widengren, Jerker
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Measuring hearing organ vibration patterns with confocal microscopy and optical flow2004Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 86, nr 1 Pt 1, s. 535-543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new method for visualizing vibrating structures is described. The system provides a means to capture very fast repeating events by relatively minor modifications to a standard confocal microscope. An acousto-optic modulator was inserted in the beam path, generating brief pulses of laser light. Images were formed by summing consecutive frames until every pixel of the resulting image had been exposed to a laser pulse. Images were analyzed using a new method for optical flow computation; it was validated through introducing artificial displacements in confocal images. Displacements in the range of 0.8 to 4 pixels were measured with 5% error or better. The lower limit for reliable motion detection was 20% of the pixel size. These methods were used for investigating the motion pattern of the vibrating hearing organ. In contrast to standard theory, we show that the organ of Corti possesses several degrees of freedom during sound-evoked vibration. Outer hair cells showed motion indicative of deformation. After acoustic overstimulation, supporting cells contracted. This slowly developing structural change was visualized during simultaneous intense sound stimulation and its speed measured with the optical flow technique.

  • 22.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Oregon Health Sciences University, Portland, USA.
    Nuttall, Alfred
    University of Michigan, Ann Arbor, USA.
    Alterations of basilar membrane response phase and velocity after acoustic overstimulation2002Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 167, nr 1-2, s. 214-222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate the physiology of noise-induced hearing loss, the sound-induced vibrations of the basilar membrane (BM) of the inner ear were measured in living anesthetized guinea pigs before and after intense sound exposure. The vibrations were measured using a laser Doppler velocimeter after placing reflective glass beads on the BM. Pseudo-random noise waveforms containing frequencies between 4 and 24 kHz were used to generate velocity tuning curves. Before overstimulation, sharp response peaks were seen at stimulus frequencies between 15 and 17 kHz, consistent with the expected best frequency of the recording location. The response to low level stimuli lagged the high level ones by up to 90 degrees at the characteristic frequency. Following exposure to loud sound, the BM vibrations showed a pronounced reduction in amplitude, primarily at low stimulus levels, and the best frequency moved to approximately 12 kHz. At higher levels, the reduction was either absent or much smaller. In addition to the amplitude changes, increased phase lags were seen at frequencies near the characteristic frequency. In animals with more severe exposures, response phases were altered also at frequencies showing no change of the amplitude. The phase was independent of stimulus level after severe exposures.

  • 23.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Oregon Health & Science University, Portland, USA.
    Parthasarathi, Anand
    Bose Corporation, Framingham, Massachusetts, USA.
    Ren, Tianying
    Oregon Health & Science University, Portland, USA.
    Nuttall, Alfred
    Oregon Health & Science University, Portland, USA.
    Loud sound-induced changes in cochlear mechanics2002Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 88, nr 5, s. 2341-2348Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate the inner ear response to intense sound and the mechanisms behind temporary threshold shifts, anesthetized guinea pigs were exposed to tones at 100-112 dB SPL. Basilar membrane vibration was measured using laser velocimetry, and the cochlear microphonic potential, compound action potential of the auditory nerve, and local electric AC potentials in the organ of Corti were used as additional indicators of cochlear function. After exposure to a 12-kHz intense tone, basilar membrane vibrations in response to probe tones at the characteristic frequency of the recording location (17 kHz) were transiently reduced. This reduction recovered over the course of 50 ms in most cases. Organ of Corti AC potentials were also reduced and recovered with a time course similar to the basilar membrane. When using a probe tone at either 1 or 4 kHz, organ of Corti AC potentials were unaffected by loud sound, indicating that transducer channels remained intact. In most experiments, both the basilar membrane and the cochlear microphonic response to the 12-kHz overstimulation was constant throughout the duration of the intense stimulus, despite a large loss of cochlear sensitivity. It is concluded that the reduction of basilar membrane velocity that followed loud sound was caused by changes in cochlear amplification and that the cochlear response to intense stimulation is determined by the passive mechanical properties of the inner ear structures.

  • 24.
    Grosh, Karl
    et al.
    University of Michigan, MI 48109 USA.
    Ren, Tianying
    Oregon Health and Science University, OR 97201 USA.
    He, Wenxuan
    Oregon Health and Science University, OR 97201 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Li, Yizeng
    Johns Hopkins University, MD 21218 USA.
    Nankali, Amir
    University of Michigan, MI 48109 USA.
    Light-Induced Basilar Membrane Vibrations in the Sensitive Cochlea2015Ingår i: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, nr 070005Konferensbidrag (Refereegranskat)
    Abstract [en]

    The exceptional sensitivity of mammalian hearing organ is attributed to an outer hair cell-mediated active process, where forces produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. A physiologically based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity. The experiments and the theoretical analysis show that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex.

  • 25.
    Hakizimana, Pierre
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Brownell, William E
    Jacob, Stefan
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sound-induced length changes in outer hair cell stereocilia2012Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hearing relies on mechanical stimulation of stereocilia bundles on the sensory cells of the inner ear. When sound hits the ear, each stereocilium pivots about a neck-like taper near their base. More than three decades of research have established that sideways deflection of stereocilia is essential for converting mechanical stimuli into electrical signals. Here we show that mammalian outer hair cell stereocilia not only move sideways but also change length during sound stimulation. Currents that enter stereocilia through mechanically sensitive ion channels control the magnitude of both length changes and bundle deflections in a reciprocal manner: the smaller the length change, the larger is the bundle deflection. Thus, the transduction current is important for maintaining the resting mechanical properties of stereocilia. Hair cell stimulation is most effective when bundles are in a state that ensures minimal length change.

  • 26.
    Hakizimana, Pierre
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Effects of salicylate on sound-evoked outer hair cell stereocilia deflections2015Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, nr 9, s. 2021-2029Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hearing depends on sound-evoked deflections of the stereocilia that protrude from the sensory hair cells in the inner ear. Although sound provides an important force driving stereocilia, forces generated through mechanically sensitive ion channels and through the motor protein prestin have been shown to influence stereocilia motion in solitary hair cells. While a possible influence of prestin on mechanically sensitive ion channels has not been systematically investigated, a decrease in transducer currents is evident in solitary hair cells when prestin is blocked with salicylate, raising the question of whether a reduced prestin activity or salicylate itself affected the mechanotransduction apparatus. We used two- and three-dimensional time-resolved confocal imaging to visualize outer hair cell stereocilia during sound stimulation in the apical turn of cochlear explant preparations from the guinea pig. Surprisingly, following application of salicylate, outer hair cell stereocilia deflections increased, while cochlear microphonic potentials decreased. However, when prestin activity was altered with the chloride ionophore tributyltin, both the cochlear microphonic potential and the stereocilia deflection amplitude decreased. Neither positive nor negative current stimulation abolished the bundle movements in the presence of salicylate, indicating that the observed effects did not depend on the endocochlear potential. These data suggest that salicylate may alter the mechanical properties of stereocilia, decreasing their bending stiffness.

  • 27.
    He, Wenxuan
    et al.
    Oregon Health and Science University, Portland, USA.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Porsov, Edward
    Oregon Health and Science University, Portland, USA.
    Grosh, Karl
    University of Michigan, Ann Arbor, MI, USA .
    Ren, Tianying
    Oregon Health and Science University, Portland, USA.
    Reverse wave propagation in the cochlea2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 7, s. 2729-2733Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Otoacoustic emissions, sounds generated by the inner ear, are widely used for diagnosing hearing disorders and studying cochlear mechanics. However, it remains unclear how emissions travel from their generation sites to the cochlear base. The prevailing view is that emissions reach the cochlear base via a backward-traveling wave, a slow-propagating transverse wave, along the cochlear partition. A different view is that emissions propagate to the cochlear base via the cochlear fluids as a compressional wave, a fast longitudinal wave. These theories were experimentally tested in this study by measuring basilar membrane (BM) vibrations at the cubic distortion product (DP) frequency from two longitudinal locations with a laser interferometer. Generation sites of DPs were varied by changing frequencies of primary tones while keeping the frequency ratio constant. Here, we show that BM vibration amplitude and phase at the DP frequency are very similar to responses evoked by external tones. Importantly, the BM vibration phase at a basal location leads that at a more apical location, indicating a traveling wave that propagates in the forward direction. These data are in conflict with the backward- traveling-wave theory but are consistent with the idea that the emission comes out of the cochlea predominantly through compressional waves in the cochlear fluids.

  • 28. He, Wenxuan
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Porsov, Edward
    Ren, Tianying
    Fast reverse propagation of sound in the living cochlea2010Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, nr 11, s. 2497-2505Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The auditory sensory organ, the cochlea, not only detects but also generates sounds. Such sounds, otoacoustic emissions, are widely used for diagnosis of hearing disorders and to estimate cochlear nonlinearity. However, the fundamental question of how the otoacoustic emission exits the cochlea remains unanswered. In this study, emissions were provoked by two tones with a constant frequency ratio, and measured as vibrations at the basilar membrane and at the stapes, and as sound pressure in the ear canal. The propagation direction and delay of the emission were determined by measuring the phase difference between basilar membrane and stapes vibrations. These measurements show that cochlea-generated sound arrives at the stapes earlier than at the measured basilar membrane location. Data also show that basilar membrane vibration at the emission frequency is similar to that evoked by external tones. These results conflict with the backward-traveling-wave theory and suggest that at low and intermediate sound levels, the emission exits the cochlea predominantly through the cochlear fluids.

  • 29.
    Jacob, Stefan
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Johansson, Cecilia
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Noise-induced alterations in cochlear mechanics, electromotility, and cochlear amplification2013Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 465, nr 6, s. 907-917Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Loud sounds are a common cause of hearing loss. Very intense sounds may result in permanent hearing loss, but lower levels typically cause a transient decrease in auditory sensitivity. Studies have arrived at different conclusions as regards the physiological mechanisms underlying such temporary threshold shifts. Here, we investigated the effect of acoustic overstimulation on the mechanics of the low-frequency areas of the guinea pig cochlea. We demonstrate that brief loud sound exposure results in an increased phase lag and a paradoxical frequency-specific increase of sound-evoked displacement. Despite the increased displacement, electrically evoked motion is reduced. Because electromotility is important for amplifying low-level sounds, this change was associated with a decrease in measures of cochlear amplification. These changes recovered over the course of 30-40 min. Overstimulation also caused an increase in cytoplasmic calcium levels of both hair cells and supporting cells. These data suggest that reduced organ of Corti stiffness contributes to temporary threshold shifts.

  • 30. Jacob, Stefan
    et al.
    Johansson, Cecilia
    Ulfendahl, Mats
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    A digital heterodyne laser interferometer for studying cochlear mechanics2009Ingår i: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 179, nr 2, s. 271-277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Laser interferometry is the technique of choice for studying the smallest displacements of the hearing organ. For low intensity sound stimulation, these displacements may be below 1 nm. This cannot be reliably measured with other presently available techniques in an intact organ of Corti. In a heterodyne interferometer, light is projected against an object of study and motion of the target along the optical axis causes phase and frequency modulations of the back-reflected light. To recover object motion, the reflected light is made to interfere with a reference beam of artificially altered frequency, producing a beating signal. In conventional interferometers, this carrier signal is demodulated with analog electronics. In this paper, we describe a digital implementation of the technique, using direct carrier sampling. In order to obtain the necessary reference signal for demodulation we introduce an additional third light path. Together, this results in lower noise and reduces the cost of the system.

    Within the hearing organ, different structures may move in different directions. It is therefore necessary to precisely measure the angle of incidence of the laser light, and to precisely localize the anatomical structure where the measurement is performed. Therefore, the interferometer is integrated with a laser scanning confocal microscope that permits us to map crucial morphometric parameters in each experiment. We provide key construction parameters and a detailed performance characterization. We also show that the system accurately measures the diminutive vibrations present in the apical turn of the cochlea during low-level sound stimulation.

  • 31. Jacob, Stefan
    et al.
    Pienkowski, Martin
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    The endocochlear potential alters cochlear micromechanics2011Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, nr 11, s. 2586-2594Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acoustic stimulation gates mechanically sensitive ion channels in cochlear sensory hair cells. Even in the absence of sound, a fraction of these channels remains open, forming a conductance between hair cells and the adjacent fluid space, scala media. Restoring the lost endogenous polarization of scala media in an in vitro preparation of the whole cochlea depolarizes the hair cell soma. Using both digital laser interferometry and time-resolved confocal imaging, we show that this causes a structural refinement within the organ of Corti that is dependent on the somatic electromotility of the outer hair cells (OHCs). Specifically, the inner part of the reticular lamina up to the second row of OHCs is pulled toward the basilar membrane, whereas the outer part (third row of OHCs and the Hensen's cells) unexpectedly moves in the opposite direction. A similar differentiated response pattern is observed for sound-evoked vibrations: restoration of the endogenous polarization decreases vibrations of the inner part of the reticular lamina and results in up to a 10-fold increase of vibrations of the outer part. We conclude that the endogenous polarization of scala media affects the function of the hearing organ by altering its geometry, mechanical and electrical properties.

  • 32.
    Jacob, Stefan
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Tomo, Igor
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Rapid confocal imaging for measuring sound-induced motion of the hearing organ in the apical region2007Ingår i: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 12, nr 2, s. 021005-1-021005-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe a novel confocal image acquisition system capable of measuring the sound-evoked motion of the organ of Corti. The hearing organ is imaged with a standard laser scanning confocal microscope during sound stimulation. The exact temporal relation between each image pixel and the sound stimulus is quantified. The motion of the structures under study is obtained by fitting a Fourier series to the time dimension of a continuous sequence of acquired images. Previous versions of this acquisition system used a simple search to find pixels with similar phase values. The Fourier series approach permits substantially faster image acquisition with reduced noise levels and improved motion estimation. The system is validated by imaging various vibrating samples attached to a feedback-controlled piezoelectric translator. When using a rigid sample attached to the translator, the system is capable of measuring motion with peak-to-peak amplitudes smaller than 50 nm with an error below 20% at frequencies between 50 and 600 Hz. Examples of image sequences from the inner ear are given, along with detailed performance characteristics of the method.

  • 33.
    Neng, Lingling
    et al.
    Oregon Health & Science University, Portland, USA.
    Zhang, Wenjing
    Oregon Health & Science University, Portland, USA.
    Hassan, Ahmed
    Lawrence Berkeley National Laboratory, California, USA.
    Zemla, Marcin
    Lawrence Berkeley National Laboratory, California, USA.
    Kachelmeier, Allan
    Oregon Health & Science University, Portland, USA.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Auer, Manfred
    Lawrence Berkeley National Laboratory, California, USA.
    Shi, Xiaorui
    Oregon Health & Science University, Portland, USA.
    Isolation and culture of endothelial cells, pericytes and perivascular resident macrophage-like melanocytes from the young mouse ear2013Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 8, nr 4, s. 709-720Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This protocol describes a growth medium-based approach for obtaining cochlear endothelial cells (ECs), pericytes (PCs) and perivascular resident macrophage-like melanocytes (PVM/Ms) from the stria vascularis of mice aged between P10 and P15 (P, postnatal day). The procedure does not involve mechanical or enzymatic digestion of the sample tissue. Explants of stria vascularis, 'mini-chips', are selectively cultured in growth medium, and primary cell lines are obtained in 7-10 d. The method is simple and reliable, and it provides high-quality ECs, PVM/Ms and PCs with a purity >90% after two passages. This protocol is suitable for producing primary culture cells from organs and tissues of small volume and high anatomical complexity, such as the inner ear capillaries. The highly purified primary cell lines enable cell culture-based in vitro modeling of cell-cell interactions, barrier control function and drug action.

  • 34. Nuttall, Alfred L
    et al.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Instrumentation for studies of cochlear mechanics: from von Békésy forward2012Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 293, nr 1-2, s. 3-11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Georg von Békésy designed the instruments needed for his research. He also created physical models of the cochlea allowing him to manipulate the parameters (such as volume elasticity) that could be involved in controlling traveling waves. This review is about the specific devices that he used to study the motion of the basilar membrane thus allowing the analysis that lead to his Nobel Prize Award. The review moves forward in time mentioning the subsequent use of von Békésy's methods and later technologies important for motion studies of the organ of Corti. Some of the seminal findings and the controversies of cochlear mechanics are mentioned in relation to the technical developments.

  • 35.
    Ramamoorthy, Sripriya
    et al.
    Oregon Health and Science University, OR 97201 USA.
    Chen, Fangyi
    Oregon Health and Science University, OR 97201 USA; South University of Science and Technology China, Peoples R China.
    Zha, Dingjun
    Oregon Health and Science University, OR 97201 USA; Fourth Mil Medical University, Peoples R China.
    Jacques, Steven L.
    Oregon Health and Science University, OR 97201 USA.
    Wang, Ruikang
    University of Washington, WA 98195 USA.
    Choudhoury, Niloy
    Oregon Health and Science University, OR 97201 USA.
    Nuttall, Alfred L.
    Oregon Health and Science University, OR 97201 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Oregon Health and Science University, OR 97201 USA.
    The Second Filters Second Coming2015Ingår i: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, nr 040003Konferensbidrag (Refereegranskat)
    Abstract [en]

    We measured sound-evoked vibrations at the stereociliary side of inner and outer hair cells and their surrounding supporting cells, using optical coherence tomography interferometry in living anesthetized guinea pigs. Our measurements demonstrate a gradient in frequency tuning among different cell types, going from a high best frequency at the inner hair cells to a lower one at the Hensen cells. This causes the locus of maximum inner hair cell activation to be shifted toward the apex of the cochlea as compared to the outer hair cells. These observations show that additional processing and filtering of acoustic signals occurs within the organ of Corti prior to inner hair cell excitation, thus reinstating a transformed second filter as a mechanism contributing to cochlear frequency tuning.

  • 36.
    Ramamoorthy, Sripriya
    et al.
    Oregon Health and Science University, Portland, USA .
    Zha, Dingjun
    Oregon Health and Science University, Portland, USA.
    Chen, Fangyi
    Oregon Health and Science University, Portland, USA.
    Jacques, Steven L.
    Oregon Health and Science University, Portland, USA.
    Wang, Ruikang
    University of Washington, USA .
    Choudhury, Niloy
    Oregon Health and Science University, Portland, USA.
    Nuttall, Alfred L.
    Oregon Health and Science University, Portland, USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Filtering of Acoustic Signals within the Hearing Organ2014Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, nr 27, s. 9051-9058Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The detection of sound by the mammalian hearing organ involves a complex mechanical interplay among different cell types. The inner hair cells, which are the primary sensory receptors, are stimulated by the structural vibrations of the entire organ of Corti. The outer hair cells are thought to modulate these sound-evoked vibrations to enhance hearing sensitivity and frequency resolution, but it remains unclear whether other structures also contribute to frequency tuning. In the current study, sound-evoked vibrations were measured at the stereociliary side of inner and outer hair cells and their surrounding supporting cells, using optical coherence tomography interferometry in living anesthetized guinea pigs. Our measurements demonstrate the presence of multiple vibration modes as well as significant differences in frequency tuning and response phase among different cell types. In particular, the frequency tuning at the inner hair cells differs from other cell types, causing the locus of maximum inner hair cell activation to be shifted toward the apex of the cochlea compared with the outer hair cells. These observations show that additional processing and filtering of acoustic signals occur within the organ of Corti before inner hair cell excitation, representing a departure from established theories.

  • 37.
    Ramamoorthy, Sripriya
    et al.
    Oregon Health and Science University, OR 97239 USA.
    Zhang, Yuan
    Oregon Health and Science University, OR 97239 USA.
    Petrie, Tracy
    Oregon Health and Science University, OR 97239 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ren, Tianying
    Oregon Health and Science University, OR 97239 USA.
    Wang, Ruikang
    University of Washington, WA 98195 USA.
    Jacques, Steven L.
    Oregon Health and Science University, OR 97239 USA; Oregon Health and Science University, OR 97239 USA.
    Nuttall, Alfred L.
    Oregon Health and Science University, OR 97239 USA; University of Michigan, MI 48105 USA.
    Minimally invasive surgical method to detect sound processing in the cochlear apex by optical coherence tomography2016Ingår i: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 21, nr 2, s. 025003-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sound processing in the inner ear involves separation of the constituent frequencies along the length of the cochlea. Frequencies relevant to human speech (100 to 500 Hz) are processed in the apex region. Among mammals, the guinea pig cochlear apex processes similar frequencies and is thus relevant for the study of speech processing in the cochlea. However, the requirement for extensive surgery has challenged the optical accessibility of this area to investigate cochlear processing of signals without significant intrusion. A simple method is developed to provide optical access to the guinea pig cochlear apex in two directions with minimal surgery. Furthermore, all prior vibration measurements in the guinea pig apex involved opening an observation hole in the otic capsule, which has been questioned on the basis of the resulting changes to cochlear hydrodynamics. Here, this limitation is overcome by measuring the vibrations through the unopened otic capsule using phase-sensitive Fourier domain optical coherence tomography. The optically and surgically advanced method described here lays the foundation to perform minimally invasive investigation of speech-related signal processing in the cochlea. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.

  • 38.
    Ramamoorthy, Sripriya
    et al.
    Oregon Health and Science University, OR 97239 USA.
    Zhang, Yuan
    Oregon Health and Science University, OR 97239 USA.
    Petrie, Tracy
    Oregon Health and Science University, OR 97239 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ren, Tianying
    Oregon Health and Science University, OR 97239 USA.
    Wang, Ruikang
    University of Washington, WA 98195 USA.
    Jacques, Steven L.
    Oregon Health and Science University, OR 97239 USA; Oregon Health and Science University, OR 97239 USA.
    Nuttall, Alfred L.
    Oregon Health and Science University, OR 97239 USA; University of Michigan, MI 48105 USA.
    Two dimensional vibrations of the guinea pig apex organ of Corti measured in vivo using phase sensitive Fourier domain optical coherence tomography2015Ingår i: PHOTONIC THERAPEUTICS AND DIAGNOSTICS XI, Society of Photo-optical Instrumentation Engineers (SPIE) , 2015, Vol. 9303, nr 93031L, s. 93031L-Konferensbidrag (Refereegranskat)
    Abstract [en]

    In this study, we measure the in vivo apical-turn vibrations of the guinea pig organ of Corti in both axial and radial directions using phase-sensitive Fourier domain optical coherence tomography. The apical turn in guinea pig cochlea has best frequencies around 100 - 500 Hz which are relevant for human speech. Prior measurements of vibrations in the guinea pig apex involved opening the otic capsule, which has been questioned on the basis of the resulting changes to cochlear hydrodynamics. Here this limitation is overcome by measuring the vibrations through bone without opening the otic capsule. Furthermore, we have significantly reduced the surgery needed to access the guinea pig apex in the axial direction by introducing a miniature mirror inside the bulla. The method and preliminary data are discussed in this article.

  • 39.
    Ren, Tianying
    et al.
    Oregon Health and Science University, OR 97239 USA .
    He, Wenxuan
    Oregon Health and Science University, OR 97239 USA .
    Li, Yizeng
    University of Michigan, MI 48109 USA .
    Grosh, Karl
    University of Michigan, MI 48109 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Light-induced vibration in the hearing organ2014Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 4, s. 5941-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The exceptional sensitivity of mammalian hearing organs is attributed to an active process, where force produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these fundamental precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. This shows that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex. A physiologically-based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity.

  • 40.
    Simonoska, Rusana
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Stenberg, Annika E
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Duan, Maoli
    Karolinska Institutet, Stockholm, Sweden.
    Yakimchuk, Konstantin
    Karolinska Institutet, NOVUM, Huddinge, Sweden.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sahlin, Lena
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Gustafsson, Jan-Åke
    Karolinska Institutet, NOVUM, Huddinge, Sweden.
    Hultcrantz, Malou
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Inner ear pathology and loss of hearing in estrogen receptor-beta deficient mice2009Ingår i: Journal of Endocrinology, ISSN 1479-6805, Vol. 201, nr 3, s. 397-406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There are well known differences between males and females in hearing. In the present study, the role of estrogen receptor-beta (ER-beta; listed as ESR2 in the MGI Database) in hearing was investigated by comparing hearing and morphology of the inner ear in ER-beta knock-out mice (ER-beta(-/-)) with that of wild-type (WT) littermates. Hearing was analyzed with auditory brainstem response audiometry at 3 and 12 months. The ER-beta(-/-) mice were deaf at 1 year of age, and the morphological analysis showed absence of hair cells and loss of the whole organ of Corti initiated in the basal turn of the cochlea. Furthermore, in ER-beta(-/-), but not in WT mice, the spiral ganglion was lacking many of its neurons. Immunostaining showed the presence of both ER-alpha (listed as ESR1 in the MGI Database) and ER-beta in the nuclei of some neurons in the inner ear in WT mice, but no ER-beta was found in the ER-beta(-/-) mice as expected. ER-alpha staining was predominant in the nuclei of large neurons and ER-beta in nuclei of small neurons and fibroblasts. These results reveal that both ERs are present in the inner ear at specific localizations suggesting subtype-specific functions. It is concluded that ER-beta is important for the prevention of age-related hearing loss. These findings strengthen the hypothesis that estrogen has a direct effect on hearing functions.

  • 41.
    Strimbu, Clark Elliott
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Noise Alters Hair-Bundle Mechanics at the Cochlear Apex2015Ingår i: Mechanics of hearing: Protein to perception, American Institute of Physics (AIP), 2015, Vol. 1703, nr 030014, s. 030014-1-030014-5Konferensbidrag (Refereegranskat)
    Abstract [en]

    Exposure to loud sounds can lead to both permanent and short term changes in auditory sensitivity. Permanent hearing loss is often associated with gross changes in cochlear morphology including the loss of hair cells and auditory nerve fibers while the mechanisms of short term threshold shifts are much less well understood and may vary at different locations across the cochlea. Previous reports suggest that exposure to loud sounds leads to a decrease in the cochlear microphonic potential and in the stiffness of the organ of Corti. Because the cochlear microphonic reflects changes in the membrane potential of the hair cells, this suggests that hair-bundle motion should be reversibly altered following exposure to loud sounds. Using an in vitro preparation of the guinea pig temporal bone we investigate changes in the micro-mechanical response near the cochlear apex following a brief (up to 10 - 20 minutes) exposure to loud (similar to 120 dB) tones near the best frequency at this location. We use time-resolved confocal imaging to record the motion of outer hair cell bundles before and after acoustic overstimulation. We have also recorded larger-scale structural views of the organ of Corti before and after exposure to the loud sound. Conventional electrophysiological techniques are used measure the cochlear microphonic potential. As has been previously reported, following acoustic overexposure the cochlear microphonic declines in value and typically recovers on the order of 30 - 60 minutes. Hair-bundle trajectories are affected following the loud sound and typically recover on a somewhat faster time scale than the microphonic potential, although the results vary considerably across preparations. Preliminary results also suggest reversible changes in the hair cells resting potential following the loud sound.

  • 42.
    Tomo, Igor
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sound-evoked radial strain in the hearing organ2007Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 93, nr 9, s. 3279-3284Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hearing organ contains sensory hair cells, which convert sound-evoked vibration into action potentials in the auditory nerve. This process is greatly enhanced by molecular motors that reside within the outer hair cells, but the performance also depends on passive mechanical properties, such as the stiffness, mass, and friction of the structures within the organ of Corti. We used resampled confocal imaging to study the mechanical properties of the low-frequency regions of the cochlea. The data allowed us to estimate an important mechanical parameter, the radial strain, which was found to be 0.1% near the inner hair cells and 0.3% near the third row of outer hair cells during moderate-level sound stimulation. The strain was caused by differences in the motion trajectories of inner and outer hair cells. Motion perpendicular to the reticular lamina was greater at the outer hair cells, but inner hair cells showed greater radial vibration. These differences led to deformation of the reticular lamina, which connects the apex of the outer and inner hair cells. These results are important for understanding how the molecular motors of the outer hair cells can so profoundly affect auditory sensitivity.

  • 43.
    Tomo, Igor
    et al.
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Le Calvez, Sophie
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Maier, Hannes
    University of Hamburg, Germany.
    Boutet de Monvel, Jacques
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Ulfendahl, Mats
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Imaging the living inner ear using intravital confocal microscopy2007Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 35, nr 4, s. 1393-1400Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Confocal laser scanning microscopy permits detailed visualization of structures deep within thick fluorescently labeled specimen. This makes it possible to investigate living cells inside intact tissue without prior chemical sample fixation and sectioning. Isolated guinea pig temporal bones have previously been used for confocal experiments in vitro, but tissue deterioration limits their use to a few hours after the death of the animal. In order to preserve the cochlea in an optimal functional and physiological condition, we have developed an in vivo model based on a confocal microscopy approach. Using a ventral surgical approach, the inner ear is exposed in deeply anaesthetized, tracheotomized, living guinea pigs. To label the inner ear structures, scala tympani is perfused via an opening in the basal turn, delivering tissue culture medium with fluorescent vital dyes (RH 795 and calcein AM). An apical opening is made in the bony shell of cochlea to enable visualization using a custom-built objective lens. Intravital confocal microscopy, with preserved blood and nerve supply, may offer an important tool for studying auditory physiology and the pathology of hearing loss. After acoustic overstimulation, shortening and swelling of the sensory hair cells were observed.

  • 44.
    Ulfendahl, M.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Khanna, S. M.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Flock, Å.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Jäger, W.
    Karolinska Institutet, Stockholm, Sweden.
    Mechanical response characteristics of the hearing organ in the low-frequency regions of the cochlea1996Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 76, nr 6, s. 3850-3862Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1. With the use of an in vitro preparation of the guinea pig temporal bone, in which the apical turns of the cochlea are exposed, the mechanical and electrical responses of the cochlea in the low-frequency regions were studied during sound stimulation. 2. The mechanical characteristics were investigated in the fourth and third turns of the cochlea with the use of laser heterodyne interferometry, which allows the vibratory responses of both sensory and supporting cells to be recorded. The electrical responses, which can be maintained for several hours, were recorded only in the most apical turn. 3. In the most apical turn, the frequency locations and shapes of the mechanical and electrical responses were very similar. 4. The shapes of the tuning curves and the spatial locations of the frequency maxima in the temporal bone preparation compared very favorably with published results from in vivo recordings of hair cell receptor potentials and sound-induced vibrations of the Reissner's membrane. 5. Compressive nonlinearities were present in both the mechanical and the electrical responses at moderate sound pressure levels. 6. The mechanical tuning changed along the length of the cochlea, the center frequencies in the fourth and third turns being approximately 280 and 570 Hz, respectively. 7. The mechanical responses of sensory and supporting cells were almost identical in shape but differed significantly in amplitude radially across the reticular lamina.

  • 45. Videhult Pierre, Pernilla
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Wikman, Anders
    Alexanderson, Kristina
    Self-reported hearing difficulties, main income sources, and socio-economic status; a cross-sectional population-based study in Sweden2012Ingår i: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Hearing difficulties constitute the most common cause of disability globally. Yet, studies on people with hearing difficulties regarding socio-economic status (SES), work, long-term unemployment, sickness absence, and disability pension are scarce. The aim of the present study was to investigate the main income sources of men and women of working ages with and without self-reported hearing difficulties and associations with gender, age, SES, type of living area, and country of birth.

    METHODS: A cross-sectional population-based study, using information on self-reported hearing difficulties and SES of 19 045 subjects aged 20-64 years participating in Statistics Sweden's annual Living Conditions Surveys in any of the years 2004 through 2008. The information was linked to a nationwide database containing data on demographics and income sources. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated, using binary logistic regression analysis.

    RESULTS: Hearing difficulties increased with age and were more common in men (age-adjusted OR: 1.42 (95% CI: 1.30-1.56)) with an overall prevalence of 13.1% in men and 9.8% in women. Using working men as reference, the OR of having hearing difficulties was 1.23 (0.94-1.60) in men with unemployment benefits and 1.36 (1.13-1.65) in men with sickness benefits or disability pension, when adjusting for age and SES. The corresponding figures in women were 1.59 (1.17-2.16) and 1.73 (1.46-2.06). The OR of having sickness benefits or disability pension in subjects with hearing difficulties was 1.36 (1.12-1.64) in men and 1.70 (1.43-2.01) in women, when adjusting for age and SES and using men and women with no hearing difficulties as reference.

    CONCLUSIONS: Hearing difficulties were more prevalent in men. After adjustment with age and SES as well as with type of living area and country of birth, a significant association with unemployment benefits was found only in women, and the associations with long-term sickness absence and disability pension tended to be stronger in women.

  • 46.
    Videhult Pierre, Pernilla
    et al.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Johnson, Ann-Christin
    Karolinska Institute, Sweden.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Subjective and Clinically Assessed Hearing Loss; A Cross-Sectional Register-Based Study on a Swedish Population Aged 18 through 50 Years2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives Questionnaire studies suggest that hearing is declining among young adults. However, few studies have examined the reliability of hearing questionnaires among young adult subjects. This study examined the associations between pure tone audiometrically assessed (PTA) hearing loss and questionnaire responses in young to middle aged adults. Materials and Methods A cross-sectional study using questionnaire and screening PTA (500 through 6000 Hz) data from 15322 Swedish subjects (62% women) aged 18 through 50 years. PTA hearing loss was defined as a hearing threshold above 20 dB in both ears at one or more frequencies. Data were analysed with chi-square tests, nonlinear regression, binary logistic regression, and the generalized estimating equation (GEE) approach. Results The prevalence of PTA hearing loss was 6.0% in men and 2.9% in women (p less than 0.001). Slight hearing impairment was reported by 18.5% of the men and 14.8% of the women (p less than 0.001), whereas 0.5% of men and women reported very impaired hearing. Using multivariate GEE modelling, the odds ratio of PTA hearing loss was 30.4 (95% CI, 12.7-72.9) in men and 36.5 (17.2-77.3) in women reporting very impaired hearing. The corresponding figures in those reporting slightly impaired hearing were 7.06 (5.25-9.49) in men and 8.99 (6.38-12.7) in women. These values depended on the sound stimulus frequency (p = 0.001). The area under the ROC curve was 0.904 (0.892-0.915) in men and 0.886 (0.872-0.900) in women. Conclusions Subjective hearing impairment predicted clinically assessed hearing loss, suggesting that there is cause for concern as regards the future development of hearing in young to middle-aged people.

  • 47.
    Von Tiedemann, M.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, J.
    Karolinska Institutet, Stockholm, Sweden.
    Image adaptive point-spread function estimation and deconvolution for in vivo confocal microscopy2006Ingår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 69, nr 1, s. 10-20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Visualizing deep inside the tissue of a thick biological sample often poses severe constraints on image conditions. Standard restoration techniques (denoising and deconvolution) can then be very useful, allowing one to increase the signal-to-noise ratio and the resolution of the images. In this paper, we consider the problem of obtaining a good determination of the point-spread function (PSF) of a confocal microscope, a prerequisite for applying deconvolution to three-dimensional image stacks acquired with this system. Because of scattering and optical distortion induced by the sample, the PSF has to be acquired anew for each experiment. To tackle this problem, we used a screening approach to estimate the PSF adaptively and automatically from the images. Small PSF-like structures were detected in the images, and a theoretical PSF model reshaped to match the geometric characteristics of these structures. We used numerical experiments to quantify the sensitivity of our detection method, and we demonstrated its usefulness by deconvolving images of the hearing organ acquired in vitro and in vivo.

  • 48. von Tiedemann, Miriam
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Boutet de Monvel, Jacques
    Brightness-compensated 3-D optical flow algorithm for monitoring cochlear motion patterns2010Ingår i: Journal of biomedical optics, ISSN 1560-2281, Vol. 15, nr 5, s. 056012-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method for three-dimensional motion analysis designed for live cell imaging by fluorescence confocal microscopy is described. The approach is based on optical flow computation and takes into account brightness variations in the image scene that are not due to motion, such as photobleaching or fluorescence variations that may reflect changes in cellular physiology. The 3-D optical flow algorithm allowed almost perfect motion estimation on noise-free artificial sequences, and performed with a relative error of <10% on noisy images typical of real experiments. The method was applied to a series of 3-D confocal image stacks from an in vitro preparation of the guinea pig cochlea. The complex motions caused by slow pressure changes in the cochlear compartments were quantified. At the surface of the hearing organ, the largest motion component was the transverse one (normal to the surface), but significant radial and longitudinal displacements were also present. The outer hair cell displayed larger radial motion at their basolateral membrane than at their apical surface. These movements reflect mechanical interactions between different cellular structures, which may be important for communicating sound-evoked vibrations to the sensory cells. A better understanding of these interactions is important for testing realistic models of cochlear mechanics.

  • 49.
    Warren, Rebecca L.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    The Basilar Membrane Acts as a Passive Support Structure at the Cochlear Apex2015Ingår i: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, nr 040006Konferensbidrag (Refereegranskat)
    Abstract [en]

    The precise mechanical behavior of the basilar membrane (BM) at low frequencies is still unknown. To address this issue we use an in vitro preparation of the guinea pig temporal bone to investigate the mechanical behaviour of the organ of Corti at the apex of the cochlea. Confocal laser interferometry is used to record the nanometre displacements of both Hensens cells (HeC) and the BM in response to sound and electrical stimulation. We show that at low frequencies, the BM exhibits greatly reduced sound-evoked movement (similar to 35dB less) and no current-evoked movement, when compared to the HeC at the same position along the spiral. The BM best frequency is found to be an average of 52Hz (0.35 octave) higher than the HeC best frequency. In addition, we demonstrate that BM motion is not affected by inhibition of somatic electromotility or by blocking the mechanoelectrical transduction channels. We therefore propose that the BM primarily acts as a passive support structure at the cochlear apex. We suggest that the micromechanics of the cochlea that are vital to low-frequency amplification and frequency selectivity take place predominantly at the surface of the organ of Corti.

  • 50.
    Warren, Rebecca L.
    et al.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Ramamoorthy, Sripriya
    Indian Institute Technology, India.
    Ciganovic, Nikola
    Imperial Coll, England.
    Zhang, Yuan
    Oregon Health and Science University, OR 97239 USA.
    Wilson, Teresa M.
    Oregon Health and Science University, OR 97239 USA.
    Petrie, Tracy
    Oregon Health and Science University, OR 97239 USA.
    Wang, Ruikang K.
    University of Washington, WA 98195 USA; University of Washington, WA 98195 USA.
    Jacques, Steven L.
    Oregon Health and Science University, OR 97239 USA.
    Reichenbach, Tobias
    Imperial Coll, England.
    Nuttall, Alfred L.
    Oregon Health and Science University, OR 97239 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Oregon Health and Science University, OR 97239 USA.
    Minimal basilar membrane motion in low-frequency hearing2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 30, s. E4304-E4310Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low-frequency hearing is critically important for speech and music perception, but no mechanical measurements have previously been available from inner ears with intact low-frequency parts. These regions of the cochlea may function in ways different from the extensively studied high-frequency regions, where the sensory outer hair cells produce force that greatly increases the sound-evoked vibrations of the basilar membrane. We used laser interferometry in vitro and optical coherence tomography in vivo to study the low-frequency part of the guinea pig cochlea, and found that sound stimulation caused motion of a minimal portion of the basilar membrane. Outside the region of peak movement, an exponential decline in motion amplitude occurred across the basilar membrane. The moving region had different dependence on stimulus frequency than the vibrations measured near the mechanosensitive stereocilia. This behavior differs substantially from the behavior found in the extensively studied high-frequency regions of the cochlea.

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  • text
  • asciidoc
  • rtf