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PubMed2006

The role of adenosine A2A and A3 receptors on the differential modulation of norepinephrine and neuropeptide Y release from peripheral sympathetic nerve terminals.

The pre-synaptic sympathetic modulator role of adenosine was assessed by studying transmitter release following electrical depolarization of nerve endings from the rat mesenteric artery. Mesentery perfusion with exogenous adenosine exclusively inhibited the release of norepinephrine (NA) but did not affect the overflow of neuropeptide Y (NPY), establishing the basis for a differential pre-synaptic modulator mechanism. Several adenosine structural analogs mimicked adenosine's effect on NA release and their relative order of potency was: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride = 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-d-ribofuranuronamide = 5'-(N-ethylcarboxamido)adenosine >> adenosine > N(6)-cyclopentyladenosine. The use of selective receptor subtype antagonists confirmed the involvement of A(2A) and A(3) adenosine receptors. The modulator role of adenosine is probably due to the activation of both receptors; co-application of 1 nM 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride plus 1 nM 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide caused additive reductions in NA released. Furthermore, while 1 nM of an A(2A) or A(3) receptor antagonist only partially reduced the inhibitory action of adenosine, the combined co-application of the two antagonists fully blocked the adenosine-induced inhibition. Only the simultaneous blockade of the adenosine A(2A) plus A(3) receptors with selective antagonists elicited a significant increase in NA overflow. H 89 reduced the release of both NA and NPY. We conclude that pre-synaptic A(2A) and A(3) adenosine receptor activation modulates sympathetic co-transmission by exclusively inhibiting the release of NA without affecting immunoreactive (ir)-NPY and we suggest separate mechanisms for vesicular release modulation.

Adenosine↗
PubMedDate not supplied

Monitoring of the intracellular activation of 5-fluorouracil to deoxyribonucleotides in HT29 human colon cell line: application to modulation of metabolism and cytotoxicity study.

An HPLC method was developed for in vitro detection and monitoring of intracellular metabolites of [3H]-5-fluorouracil (FUra). Results showed a preferential activation of FUra to ribonucleoside and ribonucleotide derivatives (FURd, FUMP, FUDP and FUTP) in the human colorectal HT29 cell line. We screened various agents so as to determine if they could act as modulators of metabolism and/or toxicity of FUra by reversing the activation pathway of FUra from ribo- to deoxyribonucleotides, thus enhancing FdUMP formation. Different drugs (efflux inhibitors, catabolism inhibitors and enzymatic cofactors) were tested for enhancement of cytotoxicity when associated with FUra. The most promising agents were further studied by assessment of their ability to modulate intracellular activation of FUra to enhance thymidylate synthase (TS) inhibition by FUra and to increase the subsequent induction of apoptosis. 2'-Deoxyinosine (d-Ino), a deoxyribose 1-phosphate donor increasing thymidine phosphorylase activity, stood out as the best modulating agent we screened. Results showed an up to 30-fold increase of cytotoxicity along with a stronger inhibition of TS when FUra was associated with d-Ino, while FUra alone exhibited a lesser effect on TS activity. Besides, HPLC analysis revealed a complete reversal of the activation pathway of FUra, thus leading to an intracellular accumulation of deoxyribonucleotides. Assessment of cell cycle distribution showed a marked increase (+480%) of apoptosis in cells exposed to FUra/d-Ino compared to FUra alone. The HPLC method we developed is a convenient tool for assessing to what extent modulators will actually act on the intracellular activation of FUra. This study confirms the potentiality of d-Ino to modulate FUra metabolism in vitro. It proved to be an agent able to orientate the mechanism of action of FUra towards the inhibition of TS in cells where the normal activation pathway of the drug does not result in the intracellular accumulation of the active metabolite FdUMP.

Cell Cycle↗
PubMed1998

Distributed effects of dopamine modulation in the crustacean pyloric network.

It is now clear that neuromodulators can reconfigure a single motor network to allow the generation of a family of related movements. Using dopamine modulation of the 14-neuron pyloric network from the crustacean stomatogastric ganglion as an example, we describe two major mechanisms by which network output is modulated. First, the baseline electrophysiological properties of the network neurons can be altered. Dopamine can affect the activity of each neuron independently. For example, DA modulates IA in nearly every neuron in the pyloric network, but in opposite directions in different cells. Furthermore, DA usually modulates combinations of ionic currents. In some cases, currents with opposing actions on cell excitability are simultaneously affected, and the net response reflects the sum of these opposing effects. Second, neuromodulators can alter the strength of synaptic interactions within the network, quantitatively "rewiring" the network. Every synapse in the network is affected by DA, with some increased and others decreased in strength. DA acts both pre- and postsynaptically to affect transmission: these actions are frequently opposing in sign, and the net response arises as the sum of these opposing actions. Finally, spike-evoked and graded transmission at the same synapse can be oppositely affected by DA. These results emphasize the distributed nature of modulation in motor networks.

Animals↗
PubMed1968

Analysis of frequency-modulated and complex sounds by single auditory neurones of bats.

1. Single unit activity in the inferior colliculus of bats was studied in relation to the analysis of frequency-modulated (FM) and complex sounds. Complex sounds were composed of tone pulse I (pure or FM tone) delivered simultaneously with tone pulse II (pure or sometimes FM tone). It was assumed that in relevant complex sounds produced by animals, an important component (e.g. a formant in human speech) occurred at the best frequency (BF) of a given neurone. Tone pulse I represented such a component (called BF component). Tone pulse II was assumed to correspond to higher or lower components according to its relation to BF. Depending on characteristics of responses to tonal stimuli, collicular neurones were classified into five types: symmetrical, asymmetrical, FM-insensitive, FM-sensitive (or FM-specialized) and upper-threshold units.2. The symmetrical unit had a wide excitatory area and no inhibitory areas and it responded with equal thresholds to FM tone pulses sweeping in either directions. This type of neurone responded to all frequency modulations (e.g. transition in human speech) of the BF component, and the response was scarcely inhibited by other components.3. In the asymmetrical unit, the extent of frequency modulation of the BF component which could excite the neurone was limited by inhibitory areas on one or both sides of an excitatory area. Inhibitory areas on the lower frequency side tended to be larger than those on the high frequency side. The limitation was more severe for frequency sweeps toward the best frequency than for sweeps starting from it. The response to the BF component was inhibited by lower and/or higher components unless these were outside the inhibitory areas. In most of the asymmetrical units, lower components were more important than higher ones in determining whether the response to the BF component could occur.4. In the FM-insensitive unit with a narrow excitatory area, inhibitory areas on both sides of the excitatory area restricted the extent of frequency modulation of the BF components which could activate the neurone. Responses to frequency sweeps toward the best frequency were strongly limited by the inhibitory areas. When the lower and/or higher components were within the inhibitory areas, the response to the BF component was inhibited. This type of neurone responded to more restricted combinations of components than did the asymmetrical units.5. The FM-sensitive unit which had no excitatory area but a large inhibitory area responded only to FM components in a certain range. Evidence was obtained that not only the range and direction but rate and functional form of frequency sweep were important in determining the excitation of the neurone. Noise bursts with various band widths did not activate the neurones. Responses of the neurones were commonly inhibited by tones within an inhibitory area so wide as to involve even frequencies in the FM component which excited the neurone. Thus, the response of the FM-sensitive unit depended not only upon the characteristics of the FM component, but also on the frequencies of other components.6. The asymmetrical, FM-insensitive and FM-sensitive units required for their activation a certain structure in the complex sound. Some of the upper-threshold units did not respond to a sufficiently strong BF component and/or its frequency modulation. Furthermore, the response of the neurone to a weak BF component was inhibited by strong lower and/or higher components in a certain range. Some upper-threshold units also had asymmetrical or FM-sensitive characteristics. Those neurones appeared to be specialized for the analysis of sound structure not only in frequency, but in intensity.7. Although various types of behaviour of single neurones were found in the inferior colliculus, a strong tendency in the neural analysis of complex sound was the restriction of conditions under which single neurones were activated. Neurones at higher levels responded to more restricted sequences or sets of sound stimuli than did those at lower levels.

Action Potentials↗
PubMed1992

Role of K+ channels in the modulation of cholinergic neural responses in guinea-pig and human airways.

1. Several agonists modulate cholinergic neurotransmission in airways raising the possibility that there may be a common inhibitory mechanism, such as the activation of a common K+ channel in the nerve ending. To test this hypothesis, we examined whether blockers of K+ channels are able to depress the prejunctional inhibitory modulation of cholinergic contractile responses by various agonists in guinea-pig and human airways in vitro. 2. Electrical field stimulation (40 V, 0.5 ms) was applied to guinea-pig (0.5 Hz) or human (1 Hz) tracheal strips every 4 min to elicit cholinergic neural responses. The effects of the K+ channel blockers, charybdotoxin (ChTX, 10 nM), apamin (100 nM) and glibenclamide (1 microM), on the prejunctional inhibition of cholinergic contraction evoked by neuropeptide Y (NPY, 100 nM), an alpha 2-agonist, clonidine (10 nM), a mu-opioid agonist, [D-Ala2, NMePhe4, Gly-ol5]-enkephalin (DAMGO, 100 nM), and a KATP channel opener, lemakalim (300 nM) were tested in guinea-pigs. In human tissues, the effect of ChTX (10 nM) on the mu-opioid (DAMGO, 300 nM)-induced inhibition of cholinergic nerves was examined. 3. In guinea-pigs, ChTX (10 nM) significantly reversed the prejunctional inhibition of cholinergic contraction by NPY (84.2 +/- 16.2%), clonidine (71.9 +/- 22.4%), DAMGO (67.3 +/- 13.1%) and lemakalim (20.9 +/- 9.4%) (n = 5, P < 0.05, respectively), while apamin (100 nM) had no effect. Glibenclamide (10 microM) reduced only the lemakalim-induced inhibitory modulation. ChTX (10 nM) itself potentiated cholinergic contraction (24.6 +/- 9.4%, n = 5, P < 0.05) without affecting exogenously applied acetylcholine dose-response curves. Pretreatment with ChTX (10 nM) significantly reduced the inhibitory modulation of cholinergic nerves by NPY, clonidine and DAMGO, but not by lemakalim. 4. In human tissues, ChTX significantly reduced DAMGO-induced prejunctional inhibition of cholinergic contraction (13.6 +/- 8.5% with and 46.5 +/- 5.5% without ChTX, respectively; n = 5, P < 0.05). 5. These results may support a hypothesis that the activation of ChTX-sensitive K+ channels is involved in the inhibitory modulation of cholinergic neuro-transmission by agonists acting on presynaptic receptors in guinea-pig and human airways.

Adolescent↗
PubMed2002

Common principles of sensory encoding in spinal reflex modules and cerebellar climbing fibres.

An important step towards understanding the function of olivo-cerebellar climbing fibres must be to clarify what they signal. We suggest that climbing fibres projecting to paravermal cerebellum mediate highly integrated sensorimotor information derived from activity in spinal withdrawal reflex modules acting on single forelimb muscles. To test this hypothesis, cutaneous nociceptive receptive fields of spinal reflex modules were mapped and compared to those of climbing fibres. Quantitative methods were used both for mapping and for comparing receptive fields. The organization of muscle afferent input converging on individual climbing fibres was analysed in the light of results from receptive field comparisons. Individual cutaneous receptive fields in the two systems were readily matched. Matched pairs were highly similar with regard to detailed distributions of sensitivity: correlation coefficient r = 0.85; overlap of receptive field foci 72 % (average values). The olivary targets of muscle afferents from a given muscle were mainly climbing fibres with cutaneous receptive fields similar to that of the muscle itself, but to a lesser extent also other climbing fibres. In conclusion, paravermal climbing fibres apparently convey information integrating (i) cutaneous input to an individual spinal withdrawal reflex module, (ii) muscle afferent input from the output muscle of that module and (iii) muscle afferent input from muscles that constitute the output of functionally related modules. This suggests that an individual climbing fibre signals cutaneous sensory events reflecting activity of a single muscle conditional upon the functional state of the muscle itself and that of functionally related muscles.

Afferent Pathways↗
PubMed2003

Validation of intensity modulation on a commercial treatment planning system.

For two years now, a study on intensity modulated radiotherapy (IMRT) has been in progress at the Antoine Lacassagne Hospital Center for Cancer Therapy (in Nice) in collaboration with the University of Nice-Sophia Antipolis. The kind of intensity modulation that was used is the "step and shoot" technique in which the modulated beam is created both by adding andjoining elementary fields. Before carrying out clinical tests, several problems regarding the production of modulated beams has to be mastered. The current developments of our study enable us to dosimetrically produce (in water phantom and in the PMMA phantom) complexmodulated whose segmentation was calculated by one commercial treatment planning system (TPS). Nevertheless, we showed and studied some critical discrepancies between standard clinical calculations and the calculations using field segmentation. We showed that with nonoptimal conditions of segmentation the discrepancies, which are due to the type of algorithm used, could bring about significant errors inside the field of up to 10% of maximum dose. Another point of our study is the quantification and resolution of differences between measurements and calculations due to the internal segmentation of calculated modulated fields and their realization on Linac. Once again, in none optimal conditions of segmentation and inside the field we obtained discrepancies up to 20% of maximum dose between calculations using field segmentation and measurements. That was mainly due to the tongue and groove effect and penumbra phenomena. This study allows us to show that the discrepancies between segmentation calculations and standard clinical calculations should be solved by the use of penumbra models during segmentation calculations. We will introduce both the study and its near-future perspectives.

Algorithms↗
PubMed2006

Analytic IMRT dose calculations utilizing Monte Carlo to predict MLC fluence modulation.

A hybrid dose-computation method is designed which accurately accounts for multileaf collimator (MLC)-induced intensity modulation in intensity modulated radiation therapy (IMRT) dose calculations. The method employs Monte Carlo (MC) modeling to determine the fluence modulation caused by the delivery of dynamic or multisegmental (step-and-shoot) MLC fields, and a conventional dose-computation algorithm to estimate the delivered dose to a phantom or a patient. Thus, it determines the IMRT fluence prediction accuracy achievable by analytic methods in the limit that the analytic method includes all details of the MLC leaf transport and scatter. The hybrid method is validated and benchmarked by comparison with in-phantom film dose measurements, as well as dose calculations from two in-house, and two commercial treatment planning system analytic fluence estimation methods. All computation methods utilize the same dose algorithm to calculate dose to a phantom, varying only in the estimation of the MLC modulation of the incident photon energy fluence. Gamma analysis, with respect to measured two-dimensional (2D) dose planes, is used to benchmark each algorithm's performance. The analyzed fields include static and dynamic test patterns, as well as fields from ten DMLC IMRT treatment plans (79 fields) and five SMLC treatment plans (29 fields). The test fields (fully closed MLC, picket fence, sliding windows of different size, and leaf-tip profiles) cover the extremes of MLC usage during IMRT, while the patient fields represent realistic clinical conditions. Of the methods tested, the hybrid method most accurately reproduces measurements. For the hybrid method, 79 of 79 DMLC field calculations have gamma < 1 (3%/3 mm) for more than 95% of the points (per field) while for SMLC fields, 27 of 29 pass the same criteria. The analytic energy fluence estimation methods show inferior pass rates, with 76 of 79 DMLC and 24 of 29 SMLC fields having more than 95% of the test points with gamma < or = 1 (3%/3 mm). Paired one-way ANOVA tests of the gamma analysis results found that the hybrid method better predicts measurements in terms of both the fraction of points with gamma < or = 1 and the average gamma for both 2%/2 mm and 3%/3 mm criteria. These results quantify the enhancement in accuracy in IMRT dose calculations when MC is used to model the MLC field modulation.

Body Burden↗
PubMed1995

The influence of scatter on the design of optimized intensity modulations.

In contrast to the traditional treatment planning process where beam parameters are adjusted in order to produce a desired dose distribution, the inverse treatment planning technique starts from the desired dose distribution and employs mathematical inversion to derive a set of optimal intensity profiles for beams with predefined directions. Crucial to the success of the inverse technique is the mathematical inversion process that yields the optimized intensity modulation. This paper systematically investigates the influence of phantom scatter in the process of designing the optimized intensity modulation and assesses its clinical consequences through the resultant treatment plans. Optimized intensity modulations and the resultant dose distributions were calculated for four prostate patients and for a simple cubic phantom under two conditions: one includes scatter and the other ignores scatter in designing the optimized intensity modulation. The effects of scatter were assessed by comparing the isodose distributions, the dose-volume histograms of the target and of the critical organs, and the tumor control probabilities and the normal tissue complication probabilities of two set prostate treatment plans. The comparison reveals that the dose homogeneity to the target is significantly improved when scatter is included in the optimization process. For prostate patients, the dose to the volume enclosed by the outer rectal contour is concomitantly reduced. Our results suggest that it is important to include the scatter in the iterative design of the optimized intensity modulations.

Biophysical Phenomena↗
PubMed1996

Electron dose profile shaping by modulation of a scanning elementary beam.

The use of multiple high energy electron beams has been limited in the treatment of deep seated tumors. This is principally because of the rapid increase in the physical electron beam penumbra as a result of the rise in large angle scattering with depth in the patient. This decreases the transverse dose gradient between the target volume and sensitive dose limiting structures and diminishes the ability to conform electron isodose lines to the target volume. If the beam is flat in air, then its profile will become progressively more rounded with depth, due to the increase of scatter out of the beam edges. With a scanning elementary electron beam, such as produced by the Microtron MM50, the characteristics of a broad beam profile are determined by the scan pattern. Using an appropriate scan pattern one can create, at any depth within the range of electrons, various dose profiles with the sharpness not exceeding that of the elementary beam. The objective of this work was to study methods that produce the desired electron beam profile at the depth of the target volume, and to derive the surface fluence profile required. Two approaches were explored to modulate the elementary beam distribution: "amplitude modulation" (AM) and "frequency modulation" (FM). We calculated coordinate and intensity distributions of the 25, 40, and 50 MeV elementary beam pulses at the surface that would yield a flat field at various prescribed depths. The results are in good qualitative agreement with iterative deconvolution calculations by Brahme et al. [Acta Radiol. Oncol. 19, 305-319 (1980)]. The scattering penumbra between the 50%-90% isodose lines can be reduced by up to 40% by beam modulation. The modulation should also enable the combination of multiple electron beams so as to achieve the desired conformal isodose profile as is customarily seen with photon beam planning, but with greater normal tissue sparing due to higher electron longitudinal depth--dose gradients. The results can be also used for electron accelerators that do not use a scanning elementary beam.

Algorithms↗
PubMed1996

Intensity modulation optimization, lateral transport of radiation, and margins.

Intensity modulation provides greatly increased control, leading to superior dose distributions with a potential for improved clinical outcome. It also allows us to compensate for deviations from the expected patterns in dose distributions caused by the lateral transport of radiation. This is important not only to produce more homogeneous dose distributions in the target volume but also, more importantly, to allow a reduction in the margins for the penumbra and a corresponding reduction in the volume of normal tissue irradiated. Potentially, this would permit escalation of doses to higher levels and further improve local control for the same or lower normal tissue complications. The intensity-modulated treatment design process, regardless of the specific method used, involves the tracing of rays from the source of radiation through the target volume. Intensities of rays are adjusted iteratively in an attempt to produce a desired homogeneous dose within the target volume, while at the same time striving to maintain normal tissue exposure within the limits of tolerance. If the lateral transport of scattered radiation is ignored, as is commonly done because of the complexities of incorporating it, the resulting dose distribution within the target volume may be considerably different from the anticipated pattern. This would be particularly true if there are high gradients in fluence patterns within the field to shield a normal anatomic structure. Similarly, the lateral transport of radiation would lead to a dose deficit just inside the boundary of the planning target volume (PTV) and a dose excess just outside it. The conventional remedy to make up for the loss of dose near the boundaries, thereby ensuring complete coverage of the target volume, would be to employ a margin for the "penumbra." We demonstrate that, with intensity modulation, we have an important new tool to improve target coverage, namely an appropriate increase in fluence just inside the boundary. Most suitably, a combination of increased fluence and a smaller than conventional margin should be employed. We have used an iterative scheme to compensate for lateral transport in the intensity modulation optimization process. In each iteration, the intensity distribution is first designed ignoring lateral transport. At the end of each iteration, the dose distribution is calculated using a pencil beam convolution method, thereby incorporating lateral transport and revealing the deviations from the anticipated dose distribution caused by lateral transport. In the next iteration, ray intensities are further adjusted to rectify the deviations. In general, only a few iterations are needed to adequately account for the lateral transport of radiation. We have applied this method to intensity-modulated prostate treatment plans and demonstrate that this methodology allows the use of smaller margins, improves target dose homogeneity, and provides greater protection for normal tissues. We examine the variation of the magnitude of the gain from one patient to another. The methodology described in this paper has been introduced into routine clinical use.

Biophysical Phenomena↗
PubMed1997

Intensity-modulated radiotherapy by means of static tomotherapy: a planning and verification study.

There is currently much research interest in developing, evaluating, and verifying intensity-modulation techniques. Of particular interest is how well the delivery of intensity-modulated profiles can be simulated by planning algorithms, and how accurately these profiles can be delivered given the specification constraints of linear accelerators. In this paper we present a planning and verification study based on delivering radiation in "static-tomotherapy" mode via the NOMOS MIMiC (Multileaf intensity-modulation collimator), which sheds some light on these issues. An inverse-planning algorithm was used to compute intensity-modulated profiles for a 9-coplanar-field plan for a body phantom. The algorithm makes several approximations about the form of the elementary fluence profile through bixels during delivery. Specifically, it is independent of the state of adjacent bixels (i.e., open or closed) and obeys the superposition principle. From the standpoint of comparing the predicted versus the delivered dose, these assumptions were made irrelevant by a final one-step forward dose calculation performed using the optimized intensity profiles. This forward dose calculation took into account the penumbral characteristics of the delivery system by decomposing the intensity profiles into the set of delivery components. Each component was assigned the appropriate penumbral functions thereby ensuring that the calculated dose distribution closely predicted the delivered dose distribution. The nine intensity modulated fields were delivered to a perspex phantom with the same geometry, containing a verification film. In general good agreement was found between the predicted and the measured delivered dose distributions. All the main features of the predicted dose distribution are seen in the delivered. The 90% isodoses were consistently in spatial agreement to within 3 mm. At the 50% isodose level consistent spatial agreement was again found to within 3 mm, the largest deviation being about 5 mm. The close correspondence between the predicted and measured dose distribution demonstrates the potential of the MIMiC delivery system. Our results indicate the level of dose conformation that is achievable in practice and the accuracy of the dose computation algorithm. However, this study only concerned delivery of radiation to a 2 cm thick slice, and the dose distribution was only verified in the central plane of the phantom where the film was placed. We therefore cannot comment as yet on what happens to the dose distribution away from the central film-plane.

Algorithms↗
PubMed2003

Use of intensity modulation for missing tissue compensation of pediatric spinal fields.

Irradiation of the cranio-spinal axis is often one of the treatment modalities of certain childhood cancers, e.g., medulloblastoma. In order to achieve a uniform dose to the spinal cord, missing tissue compensators are required. In the past, our practice was to fabricate compensators out of strips of lead. We report on the use of intensity modulated fields to achieve the desired compensation. Seven cases of pediatric cancer whose treatment involved irradiation of the cranio-spinal axis had compensators designed using a beam intensity modulation method rather than making mechanical compensators. The compensators only adjusted for missing tissue along the spinal axis. Comparisons between calculated and measured doses were made at depth in phantoms and on the surface of the patient. The intensity modulated fields were delivered using a step-and-shoot delivery on an Elekta SL20 accelerator equipped with multileaf collimator. The intensity-modulated compensators provided more flexibility in design than the physical compensator method. Finer intensity steps were achievable, more accurate dose distributions were able to be calculated, and adjustments during treatment, e.g., junction changes, were more easily implemented. Convolution/superposition dose calculations were within +/-3% of measurements. Intensity modulated fields are a practical and more efficient method of delivering uniform doses to the spine in pediatric cancer treatments. They provide many advantages over mechanical compensators with regard to time and flexibility.

Algorithms↗
PubMed2001

Influence of rate of change of frequency on the overall pitch of frequency-modulated tones.

The mechanism(s) determining pitch may assign less weight to portions of a sound where the frequency is changing rapidly. The present experiments explored the possible effect of this on the overall pitch of frequency-modulated sounds. Pitch matches were obtained between an adjustable unmodulated sinusoid and a sinusoidal carrier that was frequency modulated using a highly asymmetric function with the form of a repeating U or inverted U shaped function. The amplitude was constant during the 400-ms presentation time of each stimulus, except for 10-ms raised-cosine onset and offset ramps. In experiment 1, the carrier level was 50 dB SPL and the geometric mean of the instantaneous frequency of the modulated carrier, fc, was either 0.5, 1, 2, or 8 kHz. The modulation rate (fm) was 5, 10, or 20 Hz. The overall depth (maximum to minimum) of the FM was 8% of fc. For all carrier frequencies, the matched frequency was shifted away from the mean carrier frequency, downwards for the U shaped function stimuli and upwards for the repeated inverted U shaped function stimuli. The shift was typically slightly greater than 1% of fc, and did not vary markedly with fc. The effect of fm was small, but there was a trend for the shifts to decrease with increasing fm for fc = 0.5 kHz and to increase with increasing fm for fc = 2 kHz. In experiment 2, the carrier level was reduced to 20 dB SL and matches were obtained only for fc = 2 kHz. Shifts in matched frequency of about 1% were still observed, but the trend for the shifts to increase with increasing fm no longer occurred. In experiment 3, matches were obtained for a 4-kHz carrier at 50 dB SPL. Shifts of about 1% again occurred, which did not vary markedly with fm. The shifts in matched frequency observed in all three experiments are not predicted by models based on the amplitude- or intensity-weighted average of instantaneous frequency (EWAIF or IWAIF). The shifts (and the pitch shifts observed earlier for two-tone complexes and for stimuli with simultaneous AM and FM) are consistent with a model based on the assumption that the overall pitch of a frequency-modulated sound is determined from a weighted average of period estimates, with the weight attached to a given estimate being inversely related to the short-term rate of change of period and directly related to a compressive function of the amplitude.

Adolescent↗
PubMed2002

Auditory stream segregation on the basis of amplitude-modulation rate.

In this study, auditory stream segregation based on differences in the rate of envelope fluctuations--in the absence of spectral and temporal fine structure cues--was tested. The temporal sequences to segregate were composed of fully amplitude-modulated (AM) bursts of broadband noises A and B. All sequences were built by the reiteration of a ABA triplet where A modulation rate was fixed at 100 Hz and B modulation rate was variable. The first experiment was devoted to measuring the threshold difference in AM rate leading subjects to perceive the sequence as two streams as opposed to just one. The results of this first experiment revealed that subjects generally perceived the sequences as a single perceptual stream when the difference in AM rate between the A and B noises was smaller than 0.75 oct, and as two streams when the difference was larger than about 1.00 oct. These streaming thresholds were found to be substantially larger than, and not related to, the subjects' modulation-rate discrimination thresholds. The results of a second experiment demonstrated that AM-rate-based streaming was adversely affected by decreases in AM depth, but that segregation remained possible as long as the AM of either the A or B noises was above the subject's AM-detection threshold. The results of a third experiment indicated that AM-rate-based streaming effects were still observed when the modulations applied to the A and B noises were set individually, either at a constant level in dB above AM-detection threshold, or at levels at which they were of the same perceived strength. This finding suggests that AM-rate-based streaming is not necessarily mediated by perceived differences in AM depth. Altogether, the results of this study indicate that sequential sounds can be segregated on the sole basis of differences in the rate of their temporal fluctuations in the absence of other temporal or spectral cues.

Adult↗
PubMed2002

Benefit of modulated maskers for speech recognition by younger and older adults with normal hearing.

To assess age-related differences in benefit from masker modulation, younger and older adults with normal hearing but not identical audiograms listened to nonsense syllables in each of two maskers: (1) a steady-state noise shaped to match the long-term spectrum of the speech, and (2) this same noise modulated by a 10-Hz square wave, resulting in an interrupted noise. An additional low-level broadband noise was always present which was shaped to produce equivalent masked thresholds for all subjects. This minimized differences in speech audibility due to differences in quiet thresholds among subjects. An additional goal was to determine if age-related differences in benefit from modulation could be explained by differences in thresholds measured in simultaneous and forward maskers. Accordingly, thresholds for 350-ms pure tones were measured in quiet and in each masker; thresholds for 20-ms signals in forward and simultaneous masking were also measured at selected signal frequencies. To determine if benefit from modulated maskers varied with masker spectrum and to provide a comparison with previous studies, a subgroup of younger subjects also listened in steady-state and interrupted noise that was not spectrally shaped. Articulation index (AI) values were computed and speech-recognition scores were predicted for steady-state and interrupted noise; predicted benefit from modulation was also determined. Masked thresholds of older subjects were slightly higher than those of younger subjects; larger age-related threshold differences were observed for short-duration than for long-duration signals. In steady-state noise, speech recognition for older subjects was poorer than for younger subjects, which was partially attributable to older subjects' slightly higher thresholds in these maskers. In interrupted noise, although predicted benefit was larger for older than younger subjects, scores improved more for younger than for older subjects, particularly at the higher noise level. This may be related to age-related increases in thresholds in steady-state noise and in forward masking, especially at higher frequencies. Benefit of interrupted maskers was larger for unshaped than for speech-shaped noise, consistent with AI predictions.

Adult↗
PubMed2003

Modulation rate discrimination for unresolved components: temporal cues related to fine structure and envelope.

The present study investigated the hypothesis that the cues for modulation rate discrimination for unresolved spectral components differ as a function of the spectral region occupied by the stimuli. Specifically, it was hypothesized that when components occupy relatively low spectral regions, phase locking both to the fine structure and to the envelope are useful cues. However, as the spectral region occupied by the components increases, phase locking to the fine structure becomes less robust, whereas phase locking to the envelope remains as a potentially strong cue. Observers were asked to detect a decrease in modulation rate for carrier frequencies between 1500 and 6000 Hz. Both amplitude-modulated (AM) and quasifrequency-modulated (QFM) tones were used in order to produce stimuli having strong and weak envelope cues, respectively. Although there were marked individual differences, the results showed an interaction between modulation type and spectral region, with AM and QFM performance being relatively similar at low spectral region, but with QFM showing a steeper reduction in performance as the spectral region of the carrier frequency increased. Overall, the data are consistent with an interpretation that pitch perception for unresolved components depends upon both fine structure and envelope cues, and that the relative importance of these cues depends upon the spectral region occupied by the stimuli.

Adult↗
PubMed2004

External and internal limitations in amplitude-modulation processing.

Three experiments are presented to explore the relative role of "external" signal variability and "internal" resolution limitations of the auditory system in the detection and discrimination of amplitude modulations (AM). In the first experiment, AM-depth discrimination performance was determined using sinusoidally modulated broadband-noise and pure-tone carriers. The AM index, m, of the standard ranged from -28 to -3 dB (expressed as 20 log m). AM-depth discrimination thresholds were found to be a fraction of the AM depth of the standard for standards down to -18 dB, in the case of the pure-tone carrier, and down to -8 dB, in the case of the broadband-noise carrier. For smaller standards, AM-depth discrimination required a fixed increase in AM depth, independent of the AM depth of the standard. In the second experiment, AM-detection thresholds were obtained for signal-modulation frequencies of 4, 16, 64, and 256 Hz, applied to either a band-limited random-noise carrier or a deterministic ("frozen") noise carrier, as a function of carrier bandwidth (8 to 2048 Hz). In general, detection thresholds were higher for the random- than for the frozen-noise carriers. For both carrier types, thresholds followed the pattern expected from frequency-selective processing of the stimulus envelope. The third experiment investigated AM masking at 4, 16, and 64 Hz in the presence of a narrow-band masker modulation. The variability of the masker was changed from entirely frozen to entirely random, while the long-term average envelope power spectrum was held constant. The experiment examined the validity of a long-term average quantity as the decision variable, and the role of memory in experiments with frozen-noise maskers. The empirical results were compared to predictions obtained with two modulation-filterbank models. The predictions revealed that AM-depth discrimination and AM detection are limited by a combination of the external signal variability and an internal "Weber-fraction" noise process.

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