Thin-film micro-electrode stimulation of the cochlea in rats exposed to aminoglycoside induced hearing loss.

The multi-channel cochlear implant (CI) provides sound and speech perception to thousands of individuals who would otherwise be deaf. Broad activation of auditory nerve fibres when using a CI results in poor frequency discrimination. The CI also provides users with poor amplitude perception due to elicitation of a narrow dynamic range. Provision of more discrete frequency perception and a greater control over amplitude may allow users to better distinguish speech in noise and to segregate sound sources. In this research, thin-film (TF) high density micro-electrode arrays and conventional platinum ring electrode arrays were used to stimulate the cochlea of rats administered sensorineural hearing loss (SNHL) via ototoxic insult, with neural responses taken at 434 multiunit clusters in the central nucleus of the inferior colliculus (CIC). Threshold, dynamic range and broadness of response were used to compare electrode arrays. A stronger current was required to elicit CIC threshold when using the TF array compared to the platinum ring electrode array. TF stimulation also elicited a narrower dynamic range than the PR counterpart. However, monopolar stimulation using the TF array produced more localised CIC responses than other stimulation strategies. These results suggest that individuals with SNHL could benefit from micro stimulation of the cochlea using a monopolar configuration which may provide discrete frequency perception when using TF electrode arrays.

Engineering a multimodal nerve conduit for repair of injured peripheral nerve.

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair.

Midbrain responses to micro-stimulation of the cochlea using high density thin-film arrays.

A broader activation of auditory nerve fibres than normal using a cochlear implant contributes to poor frequency discrimination. As cochlear implants also deliver a restricted dynamic range, this hinders the ability to segregate sound sources. Better frequency coding and control over amplitude may be achieved by limiting current spread during electrical stimulation of the cochlea and positioning electrodes closer to the modiolus. Thin-film high density microelectrode arrays and conventional platinum ring electrode arrays were used to stimulate the cochlea of urethane-anaesthetized rats and responses compared. Neurophysiological recordings were taken at 197 multi-unit clusters in the central nucleus of the inferior colliculus (CIC), a site that receives direct monaural innervation from the cochlear nucleus. CIC responses to both the platinum ring and high density electrodes were recorded and differences in activity to changes in stimulation intensity, thresholds and frequency coding of neural activation were examined. The high density electrode array elicited less CIC activity at nonspecific frequency regions than the platinum ring electrode array. The high density electrode array produced significantly lower thresholds and larger dynamic ranges than the platinum ring electrode array when positioned close to the modiolus. These results suggest that a higher density of stimulation sites on electrodes that effectively 'aim' current, combined with placement closer to the modiolus would permit finer control over charge delivery. This may equate to improved frequency specific perception and control over amplitude when using future cochlear implant devices.

Inhibition of smooth muscle cell adhesion and proliferation on heparin-doped polypyrrole.

We have investigated the application of polypyrrole (pPy) as a material to influence neointimal cell behaviour. The physico-chemical properties of pPy doped with heparin (Hep), para-toluene sulfonate, poly(2-methoxyaniline-5-sulfonic acid) (pMAS) and nitrate ions were studied in addition to cell adhesion and proliferation studies of neointimal relevant cell lines cultured on the pPy substrates. Both smooth muscle (hSMC) and endothelial (hEC) cell types adhered and proliferated best on the smooth, hydrophilic pPy/pMAS material. Moreover, pPy/Hep is able to support the proliferation of hECs on the surface but inhibits hSMC proliferation after 4 days of culture. The inhibitory effect on hSMCs is most likely due to the well-known antiproliferative effect of heparin on hSMC growth. The results presented indicate that surface exposed heparin binds to the putative heparin receptor of hSMCs and is sufficient to inhibit proliferation. The application of galvanostatically synthesized pPy/Hep to stent surfaces presents a novel bioactive control mechanism to control neointimal cell growth.

Creating conductive structures for cell growth: growth and alignment of myogenic cell types on polythiophenes.

Conducting polymers provide suitable substrates for the in vitro study of excitable cells, including skeletal muscle cells, due to their inherent conductivity and electroactivity. The thiophene family of conducting polymers offers unique flexibility for tailoring of polymer properties as a result of the ease of functionalization of the parent monomer. This article describes the preparation of films and electrospun fibers from an ester-functionalized organic solvent-soluble polythiophene (poly-octanoic acid 2-thiophen-3-yl-ethyl ester) and details the changes in properties that result from post-polymerization hydrolysis of the ester linkage. The polymer films supported the proliferation and differentiation of both primary and transformed skeletal muscle myoblasts. In addition, aligned electrospun fibers formed from the polymers provided scaffolds for the guided differentiation of linearly aligned primary myotubes, suggesting their suitability as three-dimensional substrates for the in vitro engineering of skeletal muscle tissue.

3D finite element analyses of insertion of the Nucleus standard straight and the Contour electrode arrays into the human cochlea.

Previous experimental studies of insertion of the Nucleus standard straight and the Contour arrays into the scala tympani have reported that the electrode arrays cause damage to various cochlear structures. However, the level of insertion-induced damage by these electrode arrays to cochlear structures (the spiral ligament, the basilar membrane and the osseous spiral lamina) has not been quantified. Although it has been suggested that rotation can overcome this resistance and prevent the basilar membrane from being pierced by the tip of the Nucleus standard straight array, there has not been any attempt to study the relationship between the rotation and the reduction of damage to the basilar membrane. In this study, 3D finite element analyses of insertions of the Nucleus standard straight array and the Contour array into the scala tympani have been undertaken. The perforation of the basilar membrane by the tip of the Nucleus standard straight array at the region of 11-14 mm from the round window appears to be compounded by the geometry of the spiral passage of the scala tympani. Anti-clockwise rotations between 25 degrees and 90 degrees applied at the basal end of the electrode array (for the right cochlea) were shown to significantly reduce the contact stresses exerted by the tip on the basilar membrane which support the practice of applying small rotation partway through insertion of electrode array to minimize damage to the basilar membrane. Although the Contour array (with its stylet intact) is stiffer than the Nucleus standard straight array, a slight withdrawal of the stylet from the Contour array before insertion was found to significantly reduce damage by the electrode array to the spiral ligament and the basilar membrane.

Reporting recommendations for tumor marker prognostic studies (remark).

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often, initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute - European Organisation for Research and Treatment of Cancer (NCI - EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

REporting recommendations for tumour MARKer prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen.

PURPOSE: To determine whether the hormone receptor status of the primary breast cancer (PBC) is predictive of the hormone receptor status of the subsequent contralateral breast cancer (CBC). PATIENTS AND METHODS: We identified patients in our database with known estrogen receptor (ER; n = 193) and/or progesterone receptor (PgR; n = 178) status in their PBC and in their subsequent CBC. One hundred twenty-six of these patients had received no adjuvant therapy, 34 had received adjuvant tamoxifen, and 33 had received adjuvant chemotherapy alone. The median interval between the first diagnosis of PBC and the development of the subsequent CBC was 3 years. ER and PgR assays were assessed biochemically in two central reference laboratories using identical quality-controlled ligand-binding methods. RESULTS: Among systemically untreated patients (n = 126), 88% of patients with ER-positive PBC and 75% of patients with ER-negative PBC developed an ER-positive CBC (P = .11). Among the tamoxifen-treated patients, those with an ER-positive PBC were almost equally likely to develop an ER-positive (47%) or ER-negative (53%) CBC (P = .99). PgR status was similar. In the untreated group (n = 112), 59% of patients with a PgR-positive PBC and 66% with a PgR-negative PBC developed a PgR-positive CBC (P = .48). Among tamoxifen-treated patients (n = 33), 50% of patients with a PgR-positive PBC versus 27% of patients with a PgR-negative PBC developed a PgR-positive CBC (P = .28). CONCLUSION: ER and PgR status of the primary tumor does not predict the hormone receptor status of the subsequent CBC in the absence of selective pressure of adjuvant therapy. Thus, other reasons should be considered to clarify the failure of tamoxifen to reduce the incidence of CBC in patients with a receptor-negative PBC.

Stiffness properties for Nucleus standard straight and contour electrode arrays.

Trauma and damage during insertion of electrode arrays into the human cochlea are strongly related to the stiffness of the array. The stiffness properties of electrode arrays, which were determined by three-point flexural bending and buckling tests, are reported in this paper. To date there has been limited publication on mechanical properties of these electrode arrays. Previous studies mainly focused on characterizing the stiffness of the tip of the Nucleus straight array with little emphasis on characterizing the stiffness of its whole length. In this study, stiffnesses of the Nucleus straight and contour electrode arrays have been determined along their length. Young's modulus of elasticity of the Nucleus straight array has been found to increase from the tip (182 MPa) to the rear end (491 MPa), whereas the stiffness of the contour array is greatest near the tip (480 MPa) and is fairly uniform in the middle and rear sections of the electrode array (380-400 MPa). Buckling experiments have shown that the contour array has much higher critical buckling load (about four times) than the Nucleus straight array. The results from three-point flexural bending and buckling experiments provide significant data for the development of electrode arrays, from which new array designs with improved flexibility can be developed. The results of stiffness properties are also important input for use in finite element models to predict the trajectories during insertion and to help evaluate the effects of different electrode array designs on damage sustained during insertion.

A study of intra-cochlear electrodes and tissue interface by electrochemical impedance methods in vivo.

This paper presents methods, results and analysis for measurements of the electrochemical impedance of platinum electrodes (approximately 0.43 mm2) over a 6-month implantation in the cat cochlea. The study aimed to improve our understanding of the effects of tissue response on impedance behaviour. An increase in impedance in the post-operative period was evident with a rise of the distorted arc at high frequencies in the complex plane, correlating to anomalous charge transport at the electrode-tissue interface. The impedance at low frequencies generally showed a capacitive dispersion modelled as a constant phase element, indicating a blocking characteristic of the electrodes. The study suggests that a reduction and changes in composition of perilymph or extracellular fluid adjacent to the electrodes, as a consequence of tissue response, causes the elevated "contact impedance". This affects the efficiency and quality of neural stimulating electrodes and neural recording electrodes. The finding of the crucial role of perilymph or extracellular fluid thin layer provides a new strategy for surface materials of neural electrodes, which is discussed in the paper. The interface characteristics must be considered during interpretation of studies undertaken in vitro or in acute experiments in vivo, where physiological fluid is abundant.

Cyclo-oxygenase-2 (COX-2) mRNA expression correlates with progesterone receptor positivity in human breast cancer.

BACKGROUND: We previously presented evidence showing that cyclo-oxygenase 2 (COX-2) plays an important role in mammary carcinogenesis and angiogenesis in human breast cancer. The present study aims to compare COX-2 mRNA expression with hormone receptor status, S-phase fraction, telomerase activity, and DNA ploidy in human breast cancer. METHODS: Total cellular RNA was extracted from frozen breast tissue samples according to standard methodology. The mRNA copy numbers for COX-2 were determined in 18 infiltrating carcinomas using quantitative RT-PCR and TaqMan methodology. The oestrogen receptor (ER) and progesterone receptor (PgR) status was determined using the ligand-binding technique (ER+ = > 3 fmol/mg, PgR+ = > 5 fmol/mg). We also determined DNA ploidy status (diploid or aneuploid), S-phase fraction (< 6% = low, 6-10% = intermediate, > 10% = high), and telomerase activity (total protein generated by TRAP assay). RESULTS: The median COX-2 mRNA copy number per micro g of RNA was 126 713 (range = 15 717-2 022 050). COX-2 expression was significantly associated with PgR positivity (p = 0.013). The association between COX-2 and DNA diploidy failed to reach a statistical significance (p = 0.085). No significant association was detected between COX-2 and S-phase fraction, ER status, or telomerase activity. CONCLUSIONS: COX-2 mRNA expression is associated with PgR positivity in human breast cancer. This observation is consistent with the hypothesis that COX-2 upregulates aromatase activity.

Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer.

BACKGROUND: More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen. PATIENTS AND METHODS: Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review. RESULTS: At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) >or=6 months] was 34.3% for idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms. CONCLUSIONS: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.

Evaluation of trajectories and contact pressures for the straight nucleus cochlear implant electrode array - a two-dimensional application of finite element analysis.

A two-dimensional (2D) finite element analysis has been used in this study to model the insertion of the Nucleus electrode array with different stiffness properties in order to evaluate the propensity of damage by visualizing the predicted trajectories and by comparing the buckling stresses and the contact pressures at the tip (and its distribution along the length) of the electrode array. Previous temporal bone studies have shown that damage during insertion of an electrode array around the basal turn of the cochlear spiral could be related to the design and the stiffness properties of the electrode array. However, it is difficult to evaluate different designs of electrode arrays purely by experimental methods as the experimental conditions and their results are difficult to reproduce. Three electrode arrays with different mechanical properties, i.e. uniform stiffness, graded stiffness, and a soft tip have been modelled. Buckling stress and contact pressure at the tip of the electrode array were found to be highest for the arrays with uniform stiffness. The contact pressures at the tip of the electrode array appeared strongly influenced by the stiffness profile and were optimal for graded stiffness. The results indicate the importance of the electrode array design and stiffness properties in minimizing trauma. However, there are a number of limitations in the present 2D evaluation which will require further analysis using a three-dimensional model to obtain definitive results.

Short-term auditory memory in children using cochlear implants and its relevance to receptive language.

The aim of this study was to assess auditory sequential, short-term-memory (SSTM) performance in young children using cochlear implants (CI group) and to examine the relationship of this performance to receptive language performance. Twenty-four children, 5 to 11 years old, using the Nucleus 22-electrode cochlear implant, were tested on a number of auditory and visual tasks of SSTM. The auditory memory tasks were designed to minimize the effect of auditory discrimination ability. Stimuli were chosen that children with cochlear implants could accurately identify with a reaction time similar to that of a control group of children with normal hearing (NH group). All children were also assessed on a receptive language test and on a nonverbal intelligence scale. As expected, children using cochlear implants demonstrated poorer auditory and visual SSTM skills than their hearing peers when the stimuli were verbal or were pictures that could be readily labeled. They did not differ from their peers with normal hearing on tasks where the stimuli were less likely to be verbally encoded. An important finding was that the CI group did not appear to have a sequential memory deficit specific to the auditory modality. The difference scores (auditory minus visual memory performance) for the CI group were not significantly different from those for the NH group. SSTM performance accounted for significant variance in the receptive language performance of the CI group. However, a forward stepwise regression analysis revealed that visual spatial memory (one of the subtests of the nonverbal IQ test) was the main predictor of variance in the language scores of the children using cochlear implants.

Rate-of-processing ability in children using cochlear implants and its relevance to speech perception.

The aim was to assess the ability of young children using cochlear implants to process a change in place of stimulation under conditions of shortened stimulus duration and shortened interstimulus interval. The study investigated whether or not this ability accounted for a significant amount of the variance in the speech performance of the children additional to the variance accounted for by electrode discrimination ability (measured in a previous study). An adaptation of the play audiometry procedure was used to assess 'rate-of-processing' ability in 17 children aged between 4 and 10 years. Initially the child was required to respond with a game-like motor response when a repeating stimulation on a reference electrode 'changed' to a different electrode in relatively 'slow' conditions. The child was then required to respond to the 'change', when the duration of the stimuli and the time interval between the stimuli were decreased. All but one of the children using cochlear implants scored significantly above chance for all conditions of stimulus duration and interstimulus interval assessed. That is, they were able to discriminate place pitch changes when these changes occurred more rapidly in time. A stepwise regression was computed to determine the relative contributions of a number of variables, including rate-of-processing ability, in accounting for variance in the children's speech perception performance (measured in a previous study). Rate-of-processing ability did not account for any variance additional to that accounted for by electrode discrimination ability, which was found to be the most significant predictor of speech perception performance for this group of children in the previous study.

Synchronization of the neural response to noisy periodic synaptic input.

The timing information contained in the response of a neuron to noisy periodic synaptic input is analyzed for the leaky integrate-and-fire neural model. We address the question of the relationship between the timing of the synaptic inputs and the output spikes. This requires an analysis of the interspike interval distribution of the output spikes, which is obtained in the gaussian approximation. The conditional output spike density in response to noisy periodic input is evaluated as a function of the initial phase of the inputs. This enables the phase transition matrix to be calculated, which relates the phase at which the output spike is generated to the initial phase of the inputs. The interspike interval histogram and the period histogram for the neural response to ongoing periodic input are then evaluated by using the leading eigenvector of this phase transition matrix. The synchronization index of the output spikes is found to increase sharply as the inputs become synchronized. This enhancement of synchronization is most pronounced for large numbers of inputs and lower frequencies of modulation and also for rates of input near the critical input rate. However, the mutual information between the input phase of the stimulus and the timing of output spikes is found to decrease at low input rates as the number of inputs increases. The results show close agreement with those obtained from numerical simulations for large numbers of inputs.

The role of radiographic phase-contrast imaging in the development of intracochlear electrode arrays.

OBJECTIVE: This study describes the application of a new radiographic imaging modality, phase-contrast radiography, to in vitro human temporal bone imaging and investigates its use in the development of new electrode arrays for cochlear implants. BACKGROUND: The development of perimodiolar electrode arrays for cochlear implants requires detailed information from postoperative radiologic assessment on the position of the array in relation to the cochlear structures. Current standard radiographic techniques provide only limited details. MATERIALS AND METHODS: Nucleus standard electrode arrays and perimodiolar Contour electrode arrays were implanted into the scala tympani of 11 human temporal bones. Both conventional and phase-contrast radiographs were taken of each temporal bone for comparative purposes. RESULTS: Phase-contrast imaging provides better visualization of anatomic details of the inner ear and of the structure of the intracochlear electrode array, and better definition of electrode location in relation to cochlear walls. CONCLUSION: Phase-contrast radiography offers significant improvement over conventional radiography in images of in vitro human temporal bones. It seems to be a valuable tool in the development of intracochlear electrode arrays and cochlear implant research. However, this new radiographic technique still requires certain computational and physics challenges to be addressed before its clinical use can be established.

Delay analysis in the auditory brainstem of the rat: comparison with click latency.

Many cells in the auditory brainstem 'phase lock' to tone stimuli. From the changing phase relationship between the stimulus and the neural response in phase-locking cells, the delay between them can be estimated. This delay, however, is consistently greater than the latency measured in response to click stimuli, an important discrepancy. In this paper the different measures of delay, namely phase delay, group delay and signal-front delay are re-examined. An improved method for computing the average group delay is presented, which accounts for the cyclical nature of the phase data. Data were collected from units in successive processing sites of auditory pathway: the auditory nerve, the cochlear nucleus, the trapezoid body and the medial nucleus of the trapezoid body. Low-characteristic frequency (CF) units gave multimodal post-stimulus-time histograms in response to clicks, and showed stepwise decreases in latency with increasing intensity, with the appearance of earlier peaks in the response, rather than shifts in the timing of the peaks. The separation of peaks corresponded to the inverse of the unit's CF. High-CF units also showed a decline in click latency with intensity, but to a lesser degree than low CF units. We present an analysis which explains the difference between click latency and delay, and which in contrast to previous accounts is experimentally testable. We demonstrate that this new framework accounts for the discrepancy between the two measures of delay, and in addition accounts for the observed stepwise shifts in click latency for low-CF units.