1. Rob van der Willigen http://www.mbfys.ru.nl/staff/r.vanderwilligen/CNP04/COLLEGES/2008/P5/AudPerc_2008_P5_Anatomy_Physiology_V1.ppt Auditory Perception

2. General Outline P4 P4: Auditory Perception - Cochlear Mechanotransduction - Physiology of the Auditory Nerve P5: Auditory Perception

3. Sensory Coding and Transduction Cochlear Mechanotransduction Mammalian Auditory Pathway Recapitulation previous lectures

4. 6 critical steps Sensory Coding and Transduction Recapitulation previous lectures

5. Peripheral Auditory System Sensory Coding and Transduction The Organ of Corti mediates mechanotransduction: The cochlea is filled with a watery liquid, which moves in response to the vibrations coming from the middle ear via the oval window. As the fluid moves, thousands of hair cells are set in motion, and convert that motion to electrical signals that are communicated via neurotransmitters to many thousands of nerve cells.

6. Cochlear nonlinearity Active processing of sound The response of the BM at location most sensitive for ~ 9 KHz tone (CF). The level of the tone varied from 3 to 80 dB SPL (iso-intensity contours). Figure 3. Vertical lines mark the responses to a tone at either 4.5 or 9 kHz. BM input-output function for a tone at CF (~9 kHz, solid line) and a tone one octave below (~4.5 kHz) taken from the iso-intensity contour plot. INPUT level (dB SPL) OUTPUT Response in dB CF= 9 kHz ~4.5kHz Frequency [kHz]

7. Cochlear nonlinearity Hair cell function IHC: Principal Sensor Sends frequency-specific information to the brain based on the vibratory pattern of the basilar membrane OHC: Effector (Cochlear amplifier) Provides frequency-specific energy to the basilar membrane. 10  m

8. Cochlear nonlinearity Hair cell physiology IHCs are responsible for turning the movement of the basilar membrane into changes in the firing rate of the auditory nerve. OHCs are anatomically and physiologically quite different from inner hair cells. OHCs act as tiny motors that amplify the mechanical movement of the basilar membrane. 10  m

9. 1. Nucleus 2. Stereocilia 3. Cuticular plate 4. Radial afferent ending (dendrite of type I neuron) 5. Lateral efferent ending 6. Medial efferent ending 7. Spiral afferent ending (dendrite of type II neuron) Cochlear nonlinearity Hair cell anatomy IHC OHC

10. Cochlear nonlinearity IHC Innervation The IHC is synaptically connected to all type I spiral ganglion neurons forming the radial afferent system (blue) going to the cochlear nuclei (CN). The lateral efferent system (red) arising from small neurons in the ipsilateral lateral superior olivary complex (LSO) brings a feedback control to the IHC/type I afferent synapse.

11. Cochlear nonlinearity OHC Innervation OHC synapses with a few (at least in basal and mid- portions of the cochlea) small endings from type II spiral ganglion neurons, forming the spiral afferent system (green). In turn, large neurons of the medial efferent system (red), from both sides of the medial superior olivary complex (MSO), form axo-somatic synapses with the OHC.

12. Cochlear nonlinearity Cochlear Innervation type 1 type 2 Inner hair cells: Main source of afferent signal in auditory nerve. (~ 10 afferents per hair cell) Outer hair cells: Primarily receiving efferent inputs. Type I neurons (95% of all ganglion cells) have a single ending radially connected to IHCs. Type II small, unmyelinated neurons spiral basally after entering the organ of Corti and branch to connect about ten OHCs, in the same row.

13. Cochlear nonlinearity Total Cochlear Innervation Each IHC is innervated by approximately 10 Type-I 8 th nerve fibers. Each Type II 8 th nerve fiber synapses with about 10 OHCs but each outer hair cell synapses with several nerve fibers. There are also approximately 900 efferent fibers (fibers that come into the cochlea from more central locations). Innervation is both Ipsilateral and Contralateral.

14. Cochlear nonlinearity In Vivo Cochlear Innervation Cochlear Innervation by Temporally Regulated Neurotrophin Expression The Journal of Neuroscience, 2001, 21(16):6170–6180

15. Cochlear nonlinearity Hair cell numbers and life time In the human cochlea, there are 3,500 IHCs and about 12,000 OHCs. This number is low, when compared to the millions of photo-receptors in the retina or chemo-receptors in the nose! In addition, hair cells share with neurons an inability to proliferate they are differentiated. Thus, the final number of hair cells is reached very early in development (around 10 weeks of fetal gestation); from this stage on our cochlea can only lose hair cells.

16. Cochlear nonlinearity Hair cell function IHC: Principal Sensor Sends frequency-specific Information to brain based on the vibratory pattern of the basilar membrane OHC: Effector (Cochlear amplifier) Provides frequency-specific energy to the basilar membrane.. 10  m

17. Cochlear nonlinearity Functional relationship IHC and OHC

18. Cochlear nonlinearity The response of the healthy mammalian basilar membrane (BM) to sound (1) is sharply tuned, (2) highly nonlinear, and (3) compressive. Damage to the outer hair cells (OHCs) results in changes to all three attributes: in the case of total OHC loss, the response of the BM becomes broadly tuned and linear. Many of the differences in auditory perception and performance between normal-hearing and hearing impaired listeners can be explained in terms of these changes in BM response. Loss of OHCs affects nonlinearity

19. Cochlear nonlinearity Cochlea is highly compressive: In the mid-level region a change in input sound pressure of 40 dB (from 40 to 80 dB SPL) leads to a change of slightly less than 10 dB in the velocity of the BM. A change in velocity by a factor of 10 corresponds to a 20-dB change in response. This is equivalent to a compression ratio of approximately 5:1, compared to the essentially linear (1:1) relationship between sound pressure and BM velocity in the case of the post mortem cochlea. GAIN equals  Amplitude of motion divided by  Amplitude of stimulus pressure No nonlinearity post mortem Basilar-membrane intensity-velocity coding functions for a chinchilla using a tone at the 10 kHz Rugero et al. (1997)

20. Cochlear nonlinearity OHC motor driven by Tectorial membrane OHCs have a unique type of motility. They convert receptor potentials into cell length changes at acoustic frequencies. The activation of the outer hair cell motor driven by the motion of the tectorial membrane into which the tips of the tallest stereocilia are inserted. OHCs contract when depolarized (-60 mV) OHC lengthen when hyperpolarized (-70 mV) A second class of sensory receptors, the outer hair cells couple visco-elastically the reticular lamina to the basilar membrane through their supporting Deiters' cells (yellow).

21. Cochlear nonlinearity OHC motor driven by the Tectorial membrane A virtuous loop. Sound evoked perturbation of the organ of Corti elicits a motile response from outer hair cells, which feeds back onto the organ of Corti amplifying the basilar membrane motion.

22. Cochlear nonlinearity OHC Boost BM vibrations at Vmax OHCs are proposed to generate positive (cell-body shortening) forces during maximum BM velocity toward scala media (a) and negative (cell body lengthening) forces during maximum BM velocity toward scala tympani (b) K. E. Nilsen and I. J. Russell. (2000) Scala Media a b Vmax Scala Media Scala Tympani

23. Cochlear nonlinearity OHC Activity OHC activity: Increases sensitivity (lowers thresholds) Increases selectivity (reduces bandwidth of auditory filter) Produces a non-linear amplitude response Produce Otoacoustic emissions

24. Cochlear nonlinearity Nonlinearity is an active process From Pickles (1988) Cochlear Tuning is sharp and the responses are highly nonlinear Base Apex

25. Cochlear Transduction IHC mechanotransduction

26. Cochlear Transduction IHC mechanotransduction (1) Kinocilia / Stereocilia Linked (2) Displacement Opens K + Channels (3) Depolarization (inward current) Less negative membrane potential → release of glutamate (4) K + flows through cell (5) Vesicle release in synaptic cleft Glutamate → increase spike rate in auditory nerve Positive displacement Depolarization

27. Cochlear Transduction IHC mechanotransduction (1) Kinocilia / Stereocilia Linked (2) Displacement Closes K + Channels (3) Hyperpolarization (outward current) Less positive membrane potential → inhibits release of glutamate (4) K + flows ceases (5) Decreases spike rate in auditory nerve Negative displacement Hyperpolarization

28. Cochlear nonlinearity Hair cell anatomy

29. To enhance frequency tuning: Mechanical resonance of hair bundles: Like a tuning fork, hair bundles near base of cochlea are short and stiff, vibrating at high frequencies; hair bundles near the tip of the cochlea are long and floppy, vibrating at low frequencies. Electrical resonance of cell membrane potential. Cochlear Transduction IHC mechanotransduction

30. Cochlear Transduction IHC mechanotransduction Very fast (responding from 10 Hz – 100 kHz 10  sec accuracy).

31. Cochlear Transduction IHC stimulus response relationship At low frequencies the membrane potential of the IHC follows every cycle of the stimulus (AC response, top). At high frequencies the membrane potential is unable to follow individual cycles, but instead remains depolarized throughout the duration of the stimulus (DC response, bottom). At intermediate frequencies the membrane potential exhibits a “mixed” AC + DC response. Inner hair cells are thus responsible for turning mechanical movement of the basilar membrane into membrane potential changes NOT action potentials.

32. Cochlear Transduction IHC mechanotransduction R eflect s Ca++ entry into the cell. Motion of the Kinocilia modulates K+ influx, which causes Ca++ influx, but there is also background Ca++ leakage, so vesicles are released even without sound input. The release rate varies among synaptic terminals, resulting in variation in sensitivity. The auditory neurons that synapse on the IHC use AMPA receptors and have a very short time constant (~200 μsec). Vesicle release

33. Cochlear Transduction IHC activity and Action Potentials Action Potentials are generated in the auditory nerve cells NOT in the IHCs and mostly when the basilar membrane moves upward.

34. Cochlear nonlinearity nonlinearity is an active process Depends on the endolymphatic cochlear battery Furosemide decreases [K + ], stops process. Not present in post-mortem cochlear preparations (in vitro). Requires metabolic energy.

35. Stria-Vascularis (dark red area) “battery” maintains the potential difference and powers the active process in a living animal. SV ST SM Disruption of electrical equilibrium via: drugs Electrical stimulation blood supply effects hearing Cochlear nonlinearity Endolymphatic cochlear battery SMScala media STScala tempany SVScala vestibuli Drawing from www.the-cochlea.info 0 mV K + low

36. Cochlear Transduction IHC versus OHC mechanotransduction Fluid movement bends the hairs of the IHCs. Tectorial membrane shearing (b) moves the tallest stereocilia that are inserted in the tectorial membrane.

37. Cochlear Transduction IHC versus OHC mechanotransduction The OHCs are depolarized in the same way as the IHCs When an OHC depolarizes, the entire cell contracts and shortens, thereby literally pulling the basilar membrane towards the cell, because the OHCs are affixed to the basilar membrane through the supporting Deiter cells This phenomenon, which is known as electromotility, causes the OHCs to actively feed mechanical energy back into the system! Electromotility it is powered by a specialized protein (Prestin), lodged in the OHCs’ membrane

38. Cochlear Transduction IHC versus OHC mechanotransduction

39. The Auditory Nerve Anatomy Neural information from inner hair cells: carried by cochlear division of the VIII Cranial Nerve, 30,000 myelinated fibers in Humans (cats have 50,000). The auditory nerve is formed by the axons of spiral ganglion cells, of which there are two types. Type I neurons have myelinated cell bodies and innervate IHCs. In humans, each IHC forms synaptic terminals with about 10 Type I fibers. Type II neurons are unmyelinated and innervate many OHCs longitudinally distributed along the cochlea. Both types of neurons project to the cochlear nucleus, albeit to different types of cells. Type I neurons form the vast majority of the AN population (95% in cats). All existing physiological data are from Type I neurons.

40. The Auditory Nerve Function The auditory nerve conveys information about sound from the ear to the brain, which decodes this information to control behavior. Data on responses of the auditory nerve to sound are useful both to infer the processing performed by the ear, and to assess the brain’s performance in various perceptual tasks against that of an ideal observer operating on auditory-nerve information.

41. The Auditory Nerve Spontaneous rate / All-or-none potentials Depolarizing currents exceeding a threshold produce a large, “all-or-none” action potential which travels along the axon without attenuation.

42. The Auditory Nerve Statistical analysis of neural discharges Histograms: Because neural discharges (action potential or "spikes") occur at discrete, punctuate instants in time, histograms are used to analyze and display the temporal discharge patterns. Histograms estimate the distribution of spike times along a temporal dimension which is divided into small time intervals or "bins". http://web.mit.edu/hst.723/www/Labs/LabANF.htm

43. The Auditory Nerve Raster plot. A single occurrence of an action potential (spike) is represented by a single dot as a function of time after stimulus onset. Representing firing rates Post-stimulus histogram (PSTH). A count of the average number of spikes in each bin (10 ms in this case) following stimulus presentation, and normalization to the number of presentations and the bin size, produces the normalized PSTH. Normalization gives the firing rate (or probability per unit time of firing ) as a function of time. http://mulab.physiol.upenn.edu/analysis.ht ml#Introduction

44. The Auditory Nerve Raster plot. A single occurrence of an action potential (spike) is represented by a single dot as a function of time after stimulus onset. Representing firing rates Post-stimulus histogram (PSTH). A count of the average number of spikes in each bin (10 ms in this case) following stimulus presentation, and normalization to the number of presentations and the bin size, produces the normalized PSTH. Normalization gives the firing rate (or probability per unit time of firing ) as a function of time.

45. The Auditory Nerve Spontaneous firing (Kiang et al., 1965)

46. The Auditory Nerve Time Coding Spike train of spontaneous activity of a single nerve fiber and 5 tonal responses (Kiang et al., 1965) PSTH of the spike train. Notice the adaptation after ~20 msec. Adaptation improves sensitivity to transients, can adjust sensitivity to preserve dynamic range of stimulus-response. Post-stimulus time histogram

47. The Auditory Nerve Time Coding: Phase locking In response to low-frequency (< 5 kHz) pure tones, spike discharges tend to occur at a particular phase within the stimulus cycle. However, spikes do not always occur on every cycle, i.e. there can be 2, 3, or more cycles between consecutive spikes. Phase locking can be quantified using period histograms (PSTH), which display the distribution of spikes within a stimulus cycle. With perfect phase locking, the period histogram would be an impulse. Period histograms of AN fibers for low-frequency pure tones are nearly sinusoidal at near-threshold level, and become more peaky at moderate and high levels. See Evans, E. (1975). The cochlear nerve and cochlear nucleus. In D. N. WD Keidel (Ed.), Handbook of Sensory Physiology (pp. 1-109). Heidelberg: Springer.

48. The Auditory Nerve Time Coding: Phase locking Alternatively, phase locking can be visualized from interspike interval histograms (ISIH). This analysis is appealing from the viewpoint of central auditory processing because, unlike period histograms, it does not require an absolute time reference locked to each stimulus cycle.

49. The Auditory Nerve Time Coding: Phase locking Alternatively, phase locking can be visualized from interspike interval histograms (ISIH). Here, phase locking shows up as modes at integer multiples of the stimulus period, i.e. at 1/f, 2/f, 3/f, etc for a pure tone of frequency f. This analysis is appealing from the viewpoint of central auditory processing because, unlike period histograms, it does not require an absolute time reference locked to each stimulus cycle. See Evans, E. (1975). The cochlear nerve and cochlear nucleus. In D. N. WD Keidel (Ed.), Handbook of Sensory Physiology (pp. 1-109). Heidelberg: Springer.

50. The Auditory Nerve Time Coding: Phase locking Synchrony coding: For very low-frequency pure tones, period histograms can show severe deviations from a sinusoidal waveform, with sometimes two peaks per cycle (“peak splitting”). Period histograms for higher frequency tones show less distortion. The synchronization index (vector strength) is a measure of the degree of phase locking varying for 0 for a flat period histogram (no phase locking) to 1 for a pulsatile histogram (perfect phase locking). Synchronization index falls rapidly with frequency for pure tones above 1 kHz. Above 5-6 kHz, the synchronization index reaches the noise floor of the measurements. There is no absolute upper frequency limit to phase locking. See Johnson, D. H. (1980). The relationship between spike rate and synchrony in responses of auditory-nerve fibers to single tones. J. Acoust. Soc. Am., 68(4), 1115-1122.

51. The Auditory Nerve Time Coding: CF See Evans, E. (1975). The cochlear nerve and cochlear nucleus. Handbook of Sensory Physiology (pp. 1-109). Heidelberg: Springer. Each vertical bar represents one spike (action potential) recorded from an AN fiber in response to a pure tone swept in frequency at different intensities. Spike discharges occur in all conditions: There is spontaneous activity. For low intensities, discharge rate increases above spontaneous only for a narrow range of frequencies.

52. The Auditory Nerve Time Coding: CF As intensity increases, so does the range of frequencies to which the fiber responds. The outline of the response area (red) represents the pure tone tuning curve or frequency threshold curve. The frequency for which threshold in dB is minimum is the characteristic frequency (CF). RECEPTIVE FIELD See Evans, E. (1975). The cochlear nerve and cochlear nucleus. Handbook of Sensory Physiology (pp. 1-109). Heidelberg: Springer.

53. The Auditory Nerve CF curve versus iso-intensity contours

54. The Auditory Nerve Time Coding: CF, IHC are critical Outer hair cell destruction decreases the sensitivity and broadens the tuning of auditory nerve fibers. Tuning curves show the threshold for response in an auditory nerve fiber as a function of frequency Kanamycin is a drug which can produce a specific lesion of outer hair cells, leaving inner hair cells normal.

55. Place Theory: Place of maximum vibration along basilar membrane. Tuning curves (or FTC=Frequency Threshold Curve) Tuning curves measured by finding the pure tone amplitude that produces a criterion response in an 8th nerve fiber. Tuning curves for four different fibers (A-D) are shown. The Auditory Nerve Time Coding

56. The Auditory Nerve Time Coding: Summary Responses of individual AN fibers to different frequencies are related to their place along the cochlear partition (Basilar menbrane). Frequency selectivity: Clearest when sounds are very faint. Threshold Tuning Curve: Map plotting thresholds of a neuron or fiber in response to sine waves with varying frequencies at lowest intensity that will give rise to a response.

57. The Auditory Nerve Time Coding versus Audition The Place Theory stipulates that frequencies are encoded by activity across the tonotopic array of fibers in the AN, as well as in tonotopic nuclei along the auditory pathway within the brain. The Timing Theory posits that temporal information conveyed through phase locking provides the dominant cue to frequency information. Upper limit is 5-6 kHz. Neither the Place nor the Timing Theory can account for all psychophysical data. For example the human hearing range is from 200 up to 20,000 Hz.

58. The Auditory Nerve Rate code: The Volley Principle Because of refractory intervals, no individual fiber can fire with a period equal to that of the input signal. Individual fibers catch a cycle, miss one or more, catch another one, miss a few, etc. The period of the input signal is not preserved on any individual fiber, but it is reflected in the most common interspike interval of a population of fibers.

59. The Auditory Nerve Rate code: The Volley Principle The volley theory is oversimplified since it requires neurons to always firing at the time when the signal amplitude reaches a peak. This is not the case since the entire hair cell-nerve fiber relationship is probabilistic rather than deterministic. The point of maximum amplitude is the time when the probability of a pulse is greatest (though not guaranteed). However, if the fiber is most likely to fire at the amplitude peak, the most common interspike interval (of a population of fibers) will equal the period of the input signal.

60. The Auditory Nerve Time Coding versus Audition So, we have a Place or Tonotopic Code: Frequency is coded by the place along the BM where 8 th N electrical activity is greatest (base=high freq; apex=low freq, etc.) We also have a Synchrony Code (with the Volley Principle tacked on to make it work even with the limits imposed by refractory intervals) based on the timing of 8 th N pulses: Frequency is coded by the interspike interval of a population of fibers (short interspike interval=high freq; long interspike interval=low freq). Is one of these theories right and the other one wrong? Probably not. Commonly Held View ~15 to ~400 Hz:Mainly synchrony ~400 to ~5000:Combination of place and synchrony above ~5000:Only place

61. The thresholds of auditory nerve fibers vary regularly with low threshold fibers on the pillar side of the inner hair cell and high threshold fibers on the modiolar side. The low threshold fibers have high spontaneous activity rates, while the high threshold fibers have low spontaneous activity rates. Spontaneous Activity and Threshold The Auditory Nerve High spontaneous + low threshold Low Spontaneous + high threshold Pillar Modiolar

62. The distribution of spontaneous discharge rates (SR) is bimodal, separating AN fibers into two groups. The high-SR group (SR > 18 spikes/s) forms 60% of the fiber population. The remaining fibers are further subdivided into a low-SR group (SR < 0.5 sp/s, ~15%) and a medium-SR group (0.5 < SR < 18 sp/s, ~25%). High-SR fibers form a large synaptic terminal on the “pillar” side of inner hair cells, while low- and medium-SR fibers form smaller terminals on the “modiolar” side. Spontaneous discharge rate is inversely related to threshold at the CF, high-SR fibers being the most sensitive. The auditory nerve can be thought of as a two-dimensional array of fibers organized by CF (cochlear place) and sensitivity or threshold (spontaneous rate). Low-SR fibers are more sharply tuned than high-SR fibers, even though the same inner hair cell is innervated by fibers from both groups. This is consistent with the compressive nonlinearity in basilar-membrane motion. Spontaneous Activity and Threshold The Auditory Nerve

63. Intensity Information Rate versus Level Functions Example of a Low-SR fibers with a high threshold. Data is represented by curve (c) in the right plot. Curves (a), (b) and (c) are typical of what is observed for neurons with High, Medium and Low SRs, respectively.

64. The Auditory Nerve Intensity Information