Adaptation of Binaural Processing in the Adult Brainstem Induced by Ambient Noise

Interaural differences in stimulus intensity and timing are major cues for sound localization. In mammals, these cues are first processed in the lateral and medial superior olive by interaction of excitatory and inhibitory synaptic inputs from ipsi- and contralateral cochlear nucleus neurons. To preserve sound localization acuity following changes in the acoustic environment, the processing of these binaural cues needs neuronal adaptation. Recent studies have shown that binaural sensitivity adapts to stimulation history within milliseconds, but the actual extent of binaural adaptation is unknown. In the current study, we investigated long-term effects on binaural sensitivity using extracellular in vivo recordings from single neurons in the dorsal nucleus of the lateral lemniscus that inherit their binaural properties directly from the lateral and medial superior olives. In contrast to most previous studies, we used a noninvasive approach to influence this processing. Adult gerbils were exposed for 2 weeks to moderate noise with no stable binaural cue. We found monaural response properties to be unaffected by this measure. However, neuronal sensitivity to binaural cues was reversibly altered for a few days. Computational models of sensitivity to interaural time and level differences suggest that upregulation of inhibition in the superior olivary complex can explain the electrophysiological data

Psychophysical and physiological evidence for fast binaural processing

The mammalian auditory system is the temporally most precise sensory modality: To localize low-frequency sounds in space, the binaural system can resolve time differences between the ears with microsecond precision. In contrast, the binaural system appears sluggish in tracking changing interaural time differences as they arise from a low-frequency sound source moving along the horizontal plane. For a combined psychophysical and electrophysiological approach, we created a binaural stimulus, called "Phasewarp," that can transmit rapid changes in interaural timing. Using this stimulus, the binaural performance in humans is significantly better than reported previously and comparable with the monaural performance revealed with amplitude-modulated stimuli. Parallel, electrophysiological recordings of binaural brainstem neurons in the gerbil show fast temporal processing of monaural and different types of binaural modulations. In a refined electrophysiological approach that was matched to the psychophysics, the seemingly faster binaural processing of the Phasewarp was confirmed. The current data provide both psychophysical and physiological evidence against a general, hard-wired binaural sluggishness and reconcile previous contradictions of electrophysiological and psychophysical estimates of temporal binaural performance

Adjustment of interaural-time-difference analysis to sound level

To localize low-frequency sound sources in azimuth, the binaural system compares the timing of sound waves at the two ears with microsecond precision. A similarly high precision is also seen in the binaural processing of the envelopes of high-frequency complex sounds. Both for low- and high-frequency sounds, interaural time difference (ITD) acuity is to a large extent independent of sound level. The mechanisms underlying this level-invariant extraction of ITDs by the binaural system are, however, only poorly understood. We use high-frequency pip trains with asymmetric and dichotic pip envelopes in a combined psychophysical, electrophysiological, and modeling approach. Although the dichotic envelopes cannot be physically matched in terms of ITD, the match produced perceptually by humans is very reliable, and it depends systematically on the overall sound level. These data are reflected in neural responses from the gerbil lateral superior olive and lateral lemniscus. The results are predicted in an existing temporal-integration model extended with a level-dependent threshold criterion. These data provide a very sensitive quantification of how the peripheral temporal code is conditioned for binaural analysis

Novel approaches for the investigation of sound localization in mammals

The ability to localize sounds in space is important to mammals in terms of awareness of the environment and social contact with each other. In many mammals, and particularly in humans, localization of sound sources in the horizontal plane is achieved by an extraordinary sensitivity to interaural time differences (ITDs). Auditory signals from sound sources, which are not centrally located in front of the listener travel different distances to the ears and thereby generate ITDs. These ITDs are first processed by binaural sensitive neurons of the superior olivary complex (SOC) in the brainstem. Despite decades of research on this topic, the underlying mechanisms of ITD processing are still an issue of strong controversy and the processing of concurrent sounds for example is not well understood. Here I used in vivo extra-cellular single cell recordings in the dorsal nucleus of the lateral lemniscus (DNLL) to pursue three novel approaches for the investigation of ITD processing in gerbils, a well-established animal model for sound localization. The first study focuses on the ITD processing of static pure tones in the DNLL. I found that the low frequency neurons of the DNLL express an ITD sensitivity that closely resembles the one seen in the SOC. Tracer injections into the DNLL confirmed the strong direct inputs of the SOC to the DNLL. These findings support the population of DNLL neurons as a suitable novel approach to study the general mechanism of ITD processing, especially given the technical difficulties in recording from neurons in the SOC. The discharge rate of the ITD-sensitive DNLL neurons was strongly modulated over the physiological relevant range of ITDs. However, for the majority of these neurons the maximal discharge rates were clearly outside this range. These findings contradict the possible encoding of physiological relevant ITDs by the maximal discharge of single neurons. In contrast, these data support the more recent hypothesis that the discharge rate averaged over a population of ITD-sensitive neurons encodes the location of low frequency sounds. In the second study, I investigated the ITD processing of two concurrent sound sources, extending the classical approach of using only a single sound source. As concurrent sound sources a pure tone and background noise were chosen. The data show that concurrent white noise has a high impact on the response to tones and vice versa. The discharge rate to tones was mostly suppressed by the noise. The discharge rate to the noise was suppressed or enhanced by the tone depending on the ITD of the tone. Investigating the responses to monaural stimulation and to tone stimulation with concurrent spectrally filtered noise, I found that the ITD sensitivity of DNLL neurons strongly depends on the spectral compositions, the ITDs, and the levels of the concurrent sound sources. Two different mechanisms that mediate these findings were identified: monaural across-frequency interactions and temporal interactions at the level of the coincidence detector. Simulations of simple coincidence detector models (in cooperation with Christian Leibold) suggested this interpretation. In the third study of my thesis, the temporal resolution of binaural motion was analyzed. Particularly, it was investigated how fast the neuronal system can follow changes of the ITD. Here, psychophysical experiments in humans and electrophysiological recordings in the gerbil DNLL were performed using identical acoustic stimulation. Although the binaural system has previously been described as sluggish, the binaural response of ITD-sensitive DNLL neurons was found to follow fast changes of ITDs. Furthermore, in psychophysical experiments in humans, the binaural performance was better than expected when using a novel plausible motion stimulus. These data suggest that the binaural system can follow changes of the binaural cues much faster than previously reported and almost as fast as the monaural system, given a physiological useful stimulus. In summary, the results presented here establish the ITD-sensitive DNLL neurons as a novel approach for the investigation of ITD processing. In addition, the usage of more complex and naturalistic stimuli is a promising and necessary approach for opening the field for further studies regarding a better understanding of the hearing process

Inhibiting the inhibition

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects

Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine KrasG12D-induced skin carcinogenesis in vivo

Background The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population, Pdx1-Cre mice were utilized to generate conditional oncogenic KrasG12D mice with ablation of Notch1 and/or Notch2. Methodology/Principal Findings Surprisingly, mice with activated KrasG12D and Notch1 but not Notch2 ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for Pdx1 expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes in vitro revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and β-catenin signaling inhibition capabilities. Conclusions/Significance Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using Pdx1-Cre transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors

Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer - A subgroup analysis of the pivotal NAPOLI-1 trial

Irinotecan liposomal; Pacients grans; Càncer de pàncreesIrinotecán liposomal; Pacientes mayores; Cáncer de páncreasLiposomal irinotecan; Older patients; Pancreatic cancerObjectives Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial ( NCT01494506 ) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. Materials and Methods This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [ .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions). Discussion Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients.The NAPOLI-1 trial (ClinicalTrials.govidentifier: NCT01494506) was sponsored by Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA; Medical writing support was provided by Laura McMahon of Physicians World Europe GmbH, Mannheim, Germany, and funded by Shire International, Zug, Switzerland. Correction and publication costs were funded by Global Medical Affairs, Servier, Suresnes, France

Lineage fate of ductular reactions in liver injury and carcinogenesis.

Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/&beta;-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs

NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors

BACKGROUND: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. PATIENTS AND METHODS: Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. RESULTS: The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57-0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. CONCLUSIONS: The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. CLINICAL TRIAL REGISTRATION NUMBER: NCT01494506