... 7) Both yield and operational simplicity appear to distinguish this method from the alternati... more ... 7) Both yield and operational simplicity appear to distinguish this method from the alternatives.2,8 (8) JK Lindsay and CR Hauser, J. Org. ... and has not yet been determined under the conditions we employed for photochemical synthesis of 1. (IO) C. H. Niu and VI Stenberg, ...
Cochlear neuropathy, i.e. the loss of auditory nerve fibers (ANFs) without loss of hair cells, ma... more Cochlear neuropathy, i.e. the loss of auditory nerve fibers (ANFs) without loss of hair cells, may cause hearing deficits without affecting threshold sensitivity, particularly if the subset of ANFs with high thresholds and low spontaneous rates (SRs) is preferentially lost, as appears to be the case in both aging and noise-damaged cochleas. Because low-SR fibers may also be important drivers of the medial olivocochlear reflex (MOCR) and middle-ear muscle reflex (MEMR), these reflexes might be sensitive metrics of cochlear neuropathy. To test this hypothesis, we measured reflex strength and reflex threshold in mice with noise-induced neuropathy, as documented by confocal analysis of immunostained cochlear whole-mounts. To assay the MOCR, we measured contra-noise modulation of ipsilateral distortion-product otoacoustic emissions (DPOAEs) before and after the administration of curare to block the MEMR or curare + strychnine to also block the MOCR. The modulation of DPOAEs was 1) dominated by the MEMR in anesthetized mice, with a smaller contribution from the MOCR, and 2) significantly attenuated in neuropathic mice, but only when the MEMR was intact. We then measured MEMR growth functions by monitoring contra-noise induced changes in the wideband reflectance of chirps presented to the ipsilateral ear. We found 1) that the changes in wideband reflectance were mediated by the MEMR alone, and 2) that MEMR threshold was elevated and its maximum amplitude was attenuated in neuropathic mice. These data suggest that the MEMR may be valuable in the early detection of cochlear neuropathy.
Optogenetics provides a means to dissect the organization and function of neural circuits. Optoge... more Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior.
Advances in experimental medicine and biology, 2013
Both the performance of cochlear implant (CI) listeners and the responses of auditory neurons sho... more Both the performance of cochlear implant (CI) listeners and the responses of auditory neurons show limits in temporal processing at high frequencies. However, the upper limit of temporal coding of pulse-train stimuli in the inferior colliculus (IC) of anesthetized animals appears to be lower than that observed in corresponding perceptual tasks. We hypothesize that the neural rate limits have been underestimated due to the effect of anesthesia. To test this hypothesis, we developed a chronic, awake rabbit preparation for recording responses of single IC neurons to CI stimulation without the confound of anesthesia and compared these data with earlier recordings from the IC of anesthetized cats. Stimuli were periodic trains of biphasic pulses with rates varying from 20 to 1,280 pulses per second (pps). We found that the maximum pulse rates that elicited sustained firing and phase-locked responses were 2-3 times higher in the IC of awake rabbits than in anesthetized cats. Moreover, abou...
Fusiform cells in the dorsal cochlear nucleus (DCN) of barbiturate-anesthetized Mongolian gerbils... more Fusiform cells in the dorsal cochlear nucleus (DCN) of barbiturate-anesthetized Mongolian gerbils were characterized physiologically and labeled with neurobiotin. This report is based on 17 fusiform cells for which there was reasonable confidence in the association between physiological data and recovered anatomy. The qualitative morphology of these cells was no different from that reported in previous studies. The acoustic response properties were generally consistent with those described in the barbiturate-anesthetized cat. Most responses were of the pauser or buildup type, but a dependence on stimulus frequency and intensity was observed. Stimulus-evoked sustained depolarizations and large, long-lasting afterhyperpolarizations were common membrane potential features. The cells in this study showed a greater tendency to discharge regularly than did those of the cat, likely as a result of the longer interstimulus interval used. Barbiturate anesthesia appears to mask an interspecies...
The progression-free and median survival of patients with advanced ovarian cancer has not appreci... more The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with complete CA-125 response to initial platinum-based chemotherapy and subsequent elevation of CA-125 to ≥ 42 U/mL (> 2 × ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. This Green-Dahlberg study required 2 CA-125 responses in stage I (20 patients) to proceed to stage II (15 patients). The primary endpoint was CA-125 response (≥ 50% decrease from baseline, confirmed ≥ 21 days after initial evaluation). Eleven of 36 patients (31%) had a CA-125 response to pazopanib, with median time to response of 29 days and median response duration of 113 days. Overall response rate was 18% in patients with measurable disease at baseline. The most common adverse events leading to discontinuation of study drug were grade 3 ALT (8%) and AST (8%) elevation. Only 1 grade 4 toxicity (peripheral edema) was reported. Pazopanib monotherapy was relatively well tolerated, with toxicity similar to other small-molecule, oral angiogenesis inhibitors, and demonstrated promising single-agent activity in patients with recurrent ovarian cancer. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing.
... Ir Nat J 20:3740 Rivas-Martínez S (1976) Notes systématiques, chorologiques et écologiques s... more ... Ir Nat J 20:3740 Rivas-Martínez S (1976) Notes systématiques, chorologiques et écologiques sur des plantes d'Espagne, 1. Candollea 31:111117 Williams WM, Verry IM, Ellison NW (2006) A phylogenetic approach to germplasm use in clover breeding. ...
The primary aim of this study was to compare the perceptual sensation produced by bipolar electri... more The primary aim of this study was to compare the perceptual sensation produced by bipolar electrical stimulation of auditory brainstem implant (ABI) electrodes with the morphology of electrically evoked responses elicited by the same bipolar stimulus in the same unanesthetized, postsurgical state. Secondary aims were to (1) examine the relationships between sensations elicited by the bipolar stimulation used for evoked potential recording and the sensations elicited by the monopolar pulse-train stimulation used by the implant processor and (2) to examine the relationships between evoked potential morphology (elicited by bipolar stimulation) to the sensations elicited by monopolar stimulation. Electrically evoked early-latency and middle-latency responses to bipolar, biphasic low-rate pulses were recorded postoperatively in four adults with ABIs. Before recording, the perceptual sensations elicited by these bipolar stimuli were obtained and categorized as (1) auditory sensations only...
Optogenetics has become an important research tool and is being considered as the basis for sever... more Optogenetics has become an important research tool and is being considered as the basis for several neural prostheses. However, few studies have applied optogenetics to the auditory brainstem. This study explored whether optical activation of the cochlear nucleus (CN) elicited responses in neurons in higher centers of the auditory pathway, and it measured the evoked response to optical stimulation. Viral-mediated gene transfer was used to express channelrhodopsin-2 (ChR2) in the mouse CN. Blue light was delivered via an optical fiber placed near the surface of the infected CN and recordings were made in higher-level centers. Optical stimulation evoked excitatory multiunit spiking activity throughout the tonotopic axis of the central nucleus of the inferior colliculus (IC) and the auditory cortex (Actx). The pattern and magnitude of IC activity elicited by optical stimulation was comparable to that obtained with a 50dB SPL acoustic click. This broad pattern of activity was consistent with histological confirmation of green fluorescent protein (GFP) label of cell bodies and axons throughout the CN. Increasing pulse rates up to 320Hz did not significantly affect threshold or bandwidth of the IC responses, but rates higher than 50Hz resulted in desynchronized activity. Optical stimulation also evoked an auditory brainstem response, which had a simpler waveform than the response to acoustic stimulation. Control cases showed no responses to optical stimulation. These data suggest that optogenetic control of central auditory neurons is feasible, but opsins with faster channel kinetics may be necessary to convey information at rates typical of many auditory signals.
... 7) Both yield and operational simplicity appear to distinguish this method from the alternati... more ... 7) Both yield and operational simplicity appear to distinguish this method from the alternatives.2,8 (8) JK Lindsay and CR Hauser, J. Org. ... and has not yet been determined under the conditions we employed for photochemical synthesis of 1. (IO) C. H. Niu and VI Stenberg, ...
Cochlear neuropathy, i.e. the loss of auditory nerve fibers (ANFs) without loss of hair cells, ma... more Cochlear neuropathy, i.e. the loss of auditory nerve fibers (ANFs) without loss of hair cells, may cause hearing deficits without affecting threshold sensitivity, particularly if the subset of ANFs with high thresholds and low spontaneous rates (SRs) is preferentially lost, as appears to be the case in both aging and noise-damaged cochleas. Because low-SR fibers may also be important drivers of the medial olivocochlear reflex (MOCR) and middle-ear muscle reflex (MEMR), these reflexes might be sensitive metrics of cochlear neuropathy. To test this hypothesis, we measured reflex strength and reflex threshold in mice with noise-induced neuropathy, as documented by confocal analysis of immunostained cochlear whole-mounts. To assay the MOCR, we measured contra-noise modulation of ipsilateral distortion-product otoacoustic emissions (DPOAEs) before and after the administration of curare to block the MEMR or curare + strychnine to also block the MOCR. The modulation of DPOAEs was 1) dominated by the MEMR in anesthetized mice, with a smaller contribution from the MOCR, and 2) significantly attenuated in neuropathic mice, but only when the MEMR was intact. We then measured MEMR growth functions by monitoring contra-noise induced changes in the wideband reflectance of chirps presented to the ipsilateral ear. We found 1) that the changes in wideband reflectance were mediated by the MEMR alone, and 2) that MEMR threshold was elevated and its maximum amplitude was attenuated in neuropathic mice. These data suggest that the MEMR may be valuable in the early detection of cochlear neuropathy.
Optogenetics provides a means to dissect the organization and function of neural circuits. Optoge... more Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior.
Advances in experimental medicine and biology, 2013
Both the performance of cochlear implant (CI) listeners and the responses of auditory neurons sho... more Both the performance of cochlear implant (CI) listeners and the responses of auditory neurons show limits in temporal processing at high frequencies. However, the upper limit of temporal coding of pulse-train stimuli in the inferior colliculus (IC) of anesthetized animals appears to be lower than that observed in corresponding perceptual tasks. We hypothesize that the neural rate limits have been underestimated due to the effect of anesthesia. To test this hypothesis, we developed a chronic, awake rabbit preparation for recording responses of single IC neurons to CI stimulation without the confound of anesthesia and compared these data with earlier recordings from the IC of anesthetized cats. Stimuli were periodic trains of biphasic pulses with rates varying from 20 to 1,280 pulses per second (pps). We found that the maximum pulse rates that elicited sustained firing and phase-locked responses were 2-3 times higher in the IC of awake rabbits than in anesthetized cats. Moreover, abou...
Fusiform cells in the dorsal cochlear nucleus (DCN) of barbiturate-anesthetized Mongolian gerbils... more Fusiform cells in the dorsal cochlear nucleus (DCN) of barbiturate-anesthetized Mongolian gerbils were characterized physiologically and labeled with neurobiotin. This report is based on 17 fusiform cells for which there was reasonable confidence in the association between physiological data and recovered anatomy. The qualitative morphology of these cells was no different from that reported in previous studies. The acoustic response properties were generally consistent with those described in the barbiturate-anesthetized cat. Most responses were of the pauser or buildup type, but a dependence on stimulus frequency and intensity was observed. Stimulus-evoked sustained depolarizations and large, long-lasting afterhyperpolarizations were common membrane potential features. The cells in this study showed a greater tendency to discharge regularly than did those of the cat, likely as a result of the longer interstimulus interval used. Barbiturate anesthesia appears to mask an interspecies...
The progression-free and median survival of patients with advanced ovarian cancer has not appreci... more The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with complete CA-125 response to initial platinum-based chemotherapy and subsequent elevation of CA-125 to ≥ 42 U/mL (> 2 × ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. This Green-Dahlberg study required 2 CA-125 responses in stage I (20 patients) to proceed to stage II (15 patients). The primary endpoint was CA-125 response (≥ 50% decrease from baseline, confirmed ≥ 21 days after initial evaluation). Eleven of 36 patients (31%) had a CA-125 response to pazopanib, with median time to response of 29 days and median response duration of 113 days. Overall response rate was 18% in patients with measurable disease at baseline. The most common adverse events leading to discontinuation of study drug were grade 3 ALT (8%) and AST (8%) elevation. Only 1 grade 4 toxicity (peripheral edema) was reported. Pazopanib monotherapy was relatively well tolerated, with toxicity similar to other small-molecule, oral angiogenesis inhibitors, and demonstrated promising single-agent activity in patients with recurrent ovarian cancer. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing.
... Ir Nat J 20:3740 Rivas-Martínez S (1976) Notes systématiques, chorologiques et écologiques s... more ... Ir Nat J 20:3740 Rivas-Martínez S (1976) Notes systématiques, chorologiques et écologiques sur des plantes d'Espagne, 1. Candollea 31:111117 Williams WM, Verry IM, Ellison NW (2006) A phylogenetic approach to germplasm use in clover breeding. ...
The primary aim of this study was to compare the perceptual sensation produced by bipolar electri... more The primary aim of this study was to compare the perceptual sensation produced by bipolar electrical stimulation of auditory brainstem implant (ABI) electrodes with the morphology of electrically evoked responses elicited by the same bipolar stimulus in the same unanesthetized, postsurgical state. Secondary aims were to (1) examine the relationships between sensations elicited by the bipolar stimulation used for evoked potential recording and the sensations elicited by the monopolar pulse-train stimulation used by the implant processor and (2) to examine the relationships between evoked potential morphology (elicited by bipolar stimulation) to the sensations elicited by monopolar stimulation. Electrically evoked early-latency and middle-latency responses to bipolar, biphasic low-rate pulses were recorded postoperatively in four adults with ABIs. Before recording, the perceptual sensations elicited by these bipolar stimuli were obtained and categorized as (1) auditory sensations only...
Optogenetics has become an important research tool and is being considered as the basis for sever... more Optogenetics has become an important research tool and is being considered as the basis for several neural prostheses. However, few studies have applied optogenetics to the auditory brainstem. This study explored whether optical activation of the cochlear nucleus (CN) elicited responses in neurons in higher centers of the auditory pathway, and it measured the evoked response to optical stimulation. Viral-mediated gene transfer was used to express channelrhodopsin-2 (ChR2) in the mouse CN. Blue light was delivered via an optical fiber placed near the surface of the infected CN and recordings were made in higher-level centers. Optical stimulation evoked excitatory multiunit spiking activity throughout the tonotopic axis of the central nucleus of the inferior colliculus (IC) and the auditory cortex (Actx). The pattern and magnitude of IC activity elicited by optical stimulation was comparable to that obtained with a 50dB SPL acoustic click. This broad pattern of activity was consistent with histological confirmation of green fluorescent protein (GFP) label of cell bodies and axons throughout the CN. Increasing pulse rates up to 320Hz did not significantly affect threshold or bandwidth of the IC responses, but rates higher than 50Hz resulted in desynchronized activity. Optical stimulation also evoked an auditory brainstem response, which had a simpler waveform than the response to acoustic stimulation. Control cases showed no responses to optical stimulation. These data suggest that optogenetic control of central auditory neurons is feasible, but opsins with faster channel kinetics may be necessary to convey information at rates typical of many auditory signals.
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Papers by Kenneth Hancock