Measured Detection Thresholds Research Articles

A molecular psychophysical approach to identify cues for tone-in-noise detection in simultaneous masking

Experiments involving the detection of a tone presented in noise form the basis of many models of psychophysics that are used to estimate frequency resolution and cochlear compression for listeners with normal and impaired hearing. Despite the wide-spread application of tone-in-noise experiments, the cues used by listeners to detect the tone are a matter of debate. Here we adopt a molecular psychophysics approach – decision variable correlation (DVC) – to evaluate the extent to which trial-by-trial responses are consistent with candidate decision variables, including stimulus energy or the temporal envelope. We measured detection thresholds in normal-hearing adults for a 1000-Hz tone presented in one-third octave noise centered on the tone frequency. The tone and noise were gated simultaneously and thresholds were measured for durations of 10, 20, 50, and 100ms. We limited the reliability of energy-based cues by incorporating a roving-level paradigm. Similarly, the use of short tones (e.g., 10 ms) limited the reliability of envelope-based cues. Our results reveal that listeners adopted a strategy that emphasized energy-based cues for short-duration tones and envelope-based cues for long-duration tones. This finding suggests that models of human psychophysics may benefit from incorporating a decision device that adjusts cue weights based on stimulus duration.

Detection and discrimination of electrical stimuli from an upper limb cuff electrode in M. Mulatta

Objective. Peripheral nerve interfaces seek to restore nervous system function through electrical stimulation of peripheral nerves. In clinical use, these devices should function reliably for years or decades. In this study, we assessed evoked sensations from multi-channel cuff electrode stimulation in macaque monkeys up to 711 d post-implantation. Approach. Three trained macaque monkeys received multi-channel cuff electrode implants at the median or ulnar nerves in the upper arm. Electrical stimuli from the cuff interfaces evoked sensations, which we measured via standard psychophysical tasks. We adjusted pulse amplitude or pulse width for each block with various electrode channel configurations to examine the effects of stimulus parameterization on sensation. We measured detection thresholds and just-noticeable differences (JNDs) at irregular, near-daily intervals for several months using Bayesian inferencing from trial data. We examined data trends using classical models such as Weber’s Law and the strength-duration relationship using linear regression. Main results. Detection thresholds were similar between blocks with pulse width modulation and blocks with pulse amplitude modulation when represented as charge per pulse, the product of the amplitude and the pulse width. Conversely, Weber fractions—calculated as the slope of the regression between JND charge values and reference stimulus charge—were significantly different between pulse width and pulse amplitude modulation blocks for the discrimination task. Significance. Weber fractions were lower in blocks with amplitude modulation than in blocks with pulse width modulation, suggesting that pulse amplitude modulation allows finer resolution of sensory encoding above threshold. Consequently, amplitude modulation may enable a greater dynamic range for sensory perception with neuroprosthetic devices.

Achromatic and chromatic perceived contrast are reduced in the visual periphery.

The loss of contrast sensitivity with eccentricity is well documented, and is steeper for higher spatial frequencies, and for L/M cone-opponent stimuli compared to achromatic or S-cone-opponent. Here, we ask how perceived contrast depends on eccentricity when stimuli are presented at suprathreshold contrasts, and test two opposing predictions. Contrast constancy predicts no loss in perceived contrast across the visual field regardless of changes in detection threshold - appearance depends only on physical contrast. Conversely, perceived contrast may be scaled in the same way as detection threshold, reflecting the proportional increase in stimulus contrast above threshold. We measured perceived contrast for L/M cone-opponent, S-cone opponent, and Ach stimuli up to 18 degrees of eccentricity using a 2AFC contrast matching method between fovea and periphery. We tested a range of reference contrasts from low (close to detection threshold) to high suprathreshold contrasts and we relate suprathreshold perceived contrast to measured detection thresholds. We find evidence for a hybrid model in which apparent contrast is reduced with eccentricity for stimuli in the low and mid contrast range, with contrast constancy only attained at the highest contrasts. When equated for similar sensitivity losses, we find no difference between chromatic and Ach contrast responses.

Exercise does not enhance short-term deprivation-induced ocular dominance plasticity: evidence from dichoptic surround suppression

The input from the two eyes is combined in the brain. In this combination, the relative strength of the input from each eye is determined by the ocular dominance. Recent work has shown that this dominance can be temporarily shifted. Covering one eye with an eye patch for a few hours makes its contribution stronger. It has been proposed that this shift can be enhanced by exercise. Here, we test this hypothesis using a dichoptic surround suppression task, and with exercise performed according to American College of Sport Medicine guidelines. We measured detection thresholds for patches of sinusoidal grating shown to one eye. When an annular mask grating was shown simultaneously to the other eye, thresholds were elevated. The difference in the elevation found in each eye is our measure of relative eye dominance. We made these measurements before and after 120 min of monocular deprivation (with an eye patch). In the control condition, subjects rested during this time. For the exercise condition, 30 min of exercise were performed at the beginning of the patching period. This was followed by 90 min of rest. We find that patching results in a shift in ocular dominance that can be measured using dichoptic surround suppression. However, we find no effect of exercise on the magnitude of this shift. We further performed a meta-analysis on the four studies that have examined the effects of exercise on the dominance shift. Looking across these studies, we find no evidence for such an effect.

Reducing Behavioral Detection Thresholds per Electrode via Synchronous, Spatially-Dependent Intracortical Microstimulation.

Intracortical microstimulation (ICMS) has shown promise in restoring quality of life to patients suffering from paralysis, specifically when used in the primary somatosensory cortex (S1). However, these benefits can be hampered by long-term degradation of electrode performance due to the brain’s foreign body response. Advances in microfabrication techniques have allowed for the development of neuroprostheses with subcellular electrodes, which are characterized by greater versatility and a less detrimental immune response during chronic use. These probes are hypothesized to enable more selective, higher-resolution stimulation of cortical tissue with long-term implants. However, microstimulation using physiologically relevant charges with these smaller-scale devices can damage electrode sites and reduce the efficacy of the overall device. Studies have shown promise in bypassing this limitation by spreading the stimulation charge between multiple channels in an implanted electrode array, but to our knowledge the usefulness of this strategy in laminar arrays with electrode sites spanning each layer of the cortex remains unexplored. To investigate the efficacy of simultaneous multi-channel ICMS in electrode arrays with stimulation sites spanning cortical depth, we implanted laminar electrode arrays in the primary somatosensory cortex of rats trained in a behavioral avoidance paradigm. By measuring detection thresholds, we were able to quantify improvements in ICMS performance using a simultaneous multi-channel stimulation paradigm. The charge required per site to elicit detection thresholds was halved when stimulating from two adjacent electrode sites, although the overall charge used by the implant was increased. This reduction in threshold charge was more pronounced when stimulating with more than two channels and lessened with greater distance between stimulating channels. Our findings suggest that these improvements are based on the synchronicity and polarity of each stimulus, leading us to conclude that these improvements in stimulation efficiency per electrode are due to charge summation as opposed to a summation of neural responses to stimulation. Additionally, the per-site charge reductions are seen regardless of the cortical depth of each utilized channel. This evocation of physiological detection thresholds with lower stimulation currents per electrode site has implications for the feasibility of stimulation regimes in future advanced neuroprosthetic devices, which could benefit from reducing the charge output per site.

A psychophysical performance-based approach to the quality assessment of image processing algorithms.

Image processing algorithms are used to improve digital image representations in either their appearance or storage efficiency. The merit of these algorithms depends, in part, on visual perception by human observers. However, in practice, most are assessed numerically, and the perceptual metrics that do exist are criterion sensitive with several shortcomings. Here we propose an objective performance-based perceptual measure of image quality and demonstrate this by comparing the efficacy of a denoising algorithm for a variety of filters. For baseline, we measured detection thresholds for a white noise signal added to one of a pair of natural images in a two-alternative forced-choice (2AFC) paradigm where each image was selected randomly from a set of n = 308 on each trial. In a series of experimental conditions, the stimulus image pairs were passed through various configurations of a denoising algorithm. The differences in noise detection thresholds with and without denoising are objective perceptual measures of the ability of the algorithm to render noise invisible. This was a factor of two (6dB) in our experiment and consistent across a range of filter bandwidths and types. We also found that thresholds in all conditions converged on a common value of PSNR, offering support for this metric. We discuss how the 2AFC approach might be used for other algorithms including compression, deblurring and edge-detection. Finally, we provide a derivation for our Cartesian-separable log-Gabor filters, with polar parameters. For the biological vision community this has some advantages over the more typical (i) polar-separable variety and (ii) Cartesian-separable variety with Cartesian parameters.

Harmonicity aids hearing in noise

Hearing in noise is a core problem in audition, and a challenge for hearing-impaired listeners, yet the underlying mechanisms are poorly understood. We explored whether harmonic frequency relations, a signature property of many communication sounds, aid hearing in noise for normal hearing listeners. We measured detection thresholds in noise for tones and speech synthesized to have harmonic or inharmonic spectra. Harmonic signals were consistently easier to detect than otherwise identical inharmonic signals. Harmonicity also improved discrimination of sounds in noise. The largest benefits were observed for two-note up-down “pitch” discrimination and melodic contour discrimination, both of which could be performed equally well with harmonic and inharmonic tones in quiet, but which showed large harmonic advantages in noise. The results show that harmonicity facilitates hearing in noise, plausibly by providing a noise-robust pitch cue that aids detection and discrimination.Supplementary InformationThe online version contains supplementary material available at 10.3758/s13414-021-02376-0.

Layer-specific parameters of intracortical microstimulation of the somatosensory cortex

Objective. Intracortical microstimulation of the primary somatosensory cortex (S1) has shown great progress in restoring touch sensations to patients with paralysis. Stimulation parameters such as amplitude, phase duration, and frequency can influence the quality of the evoked percept as well as the amount of charge necessary to elicit a response. Previous studies in V1 and auditory cortices have shown that the behavioral responses to stimulation amplitude and phase duration change across cortical depth. However, this depth-dependent response has yet to be investigated in S1. Similarly, to our knowledge, the response to microstimulation frequency across cortical depth remains unexplored. Approach. To assess these questions, we implanted rats in S1 with a microelectrode with electrode-sites spanning all layers of the cortex. A conditioned avoidance behavioral paradigm was used to measure detection thresholds and responses to phase duration and frequency across cortical depth. Main results. Analogous to other cortical areas, the sensitivity to charge and strength–duration chronaxies in S1 varied across cortical layers. Likewise, the sensitivity to microstimulation frequency was layer dependent. Significance. These findings suggest that cortical depth can play an important role in the fine-tuning of stimulation parameters and in the design of intracortical neuroprostheses for clinical applications.

Relationships between subjective taste sensations and electrogustometry

<h3>Objectives</h3> The purpose of this study was to examine the relationships between subjective taste sensations and electrogustometry (EGM) results in patients with taste disorders according to the presence of burning mouth symptoms. <h3>Methods</h3> Forty-six patients (11 men, 53.5 ± 19.5 years; 35 women, 52.9 ± 12.9 years) with taste disturbances as a chief complaint were included. They were asked to complete a questionnaire including subjective taste sensations of 4 basic taste qualities and the pattern of taste disorders such as ageusia, hypogeusia, and dysgeusia. EGM was performed to measure detection thresholds of the chorda tympani, glossopharyngeal, and greater petrosal nerve areas in both sides. To examine the influence of burning mouth symptoms, they were divided into 2 groups: patients with (20 patients; 2 men and 18 women) and without (26 patients; 9 men and 17 women) burning mouth symptoms. The Mann-Whitney <i>U</i> or Kruskal-Wallis test was used to compare variables between the groups. The chi-square test or Fisher exact test for categorical variables and the Spearman correlation analysis for continuous variables were used to investigate associations. <h3>Results</h3> There were no significant differences in age and sex distribution according to the presence of burning mouth symptoms. Compared with the patients with burning mouth symptoms, those without burning mouth symptoms reported significantly lower levels of subjective taste sensations in all taste qualities and showed higher correlation levels between subjective taste sensations and EGM thresholds. Hypogeusia was the most common in both groups. Dysgeusia was more common than ageusia in the patients with burning mouth symptoms and vice versa in those without burning mouth symptoms. The pattern of taste disorders also showed more significant associations with the levels of subjective taste sensations in the patients without burning mouth symptoms than those with burning mouth symptoms. <h3>Conclusions</h3> Patients with taste disorder without burning mouth symptoms had a more severe level of taste disturbances than those with burning mouth symptoms. The pathophysiology of taste disturbances could differ according to the presence of burning mouth symptoms.

Imperceptible manipulation of lateral camera motion for improved virtual reality applications

We measure detection thresholds for lateral translation gains of virtual camera motion in response to the corresponding head motion under natural viewing. We propose three applications for our method, addressing three key problems in virtual reality, and validate their improvement when our manipulation technique is applied.

Imperceptible manipulation of lateral camera motion for improved virtual reality applications

Virtual Reality (VR) systems increase immersion by reproducing users' movements in the real world. However, several works have shown that this real-to-virtual mapping does not need to be precise in order to convey a realistic experience. Being able to alter this mapping has many potential applications, since achieving an accurate real-to-virtual mapping is not always possible due to limitations in the capture or display hardware, or in the physical space available. In this work, we measure detection thresholds for lateral translation gains of virtual camera motion in response to the corresponding head motion under natural viewing, and in the absence of locomotion, so that virtual camera movement can be either compressed or expanded while these manipulations remain undetected. Finally, we propose three applications for our method, addressing three key problems in VR: improving 6-DoF viewing for captured 360° footage, overcoming physical constraints, and reducing simulator sickness. We have further validated our thresholds and evaluated our applications by means of additional user studies confirming that our manipulations remain imperceptible, and showing that (i) compressing virtual camera motion reduces visible artifacts in 6-DoF, hence improving perceived quality, (ii) virtual expansion allows for completion of virtual tasks within a reduced physical space, and (iii) simulator sickness may be alleviated in simple scenarios when our compression method is applied.

Local reliability weighting explains identification of partially masked objects in natural images

A fundamental natural visual task is the identification of specific target objects in the environments that surround us. It has long been known that some properties of the background have strong effects on target visibility. The most well-known properties are the luminance, contrast, and similarity of the background to the target. In previous studies, we found that these properties have highly lawful effects on detection in natural backgrounds. However, there is another important factor affecting detection in natural backgrounds that has received little or no attention in the masking literature, which has been concerned with detection in simpler backgrounds. Namely, in natural backgrounds the properties of the background often vary under the target, and hence some parts of the target are masked more than others. We began studying this factor, which we call the “partial masking factor,” by measuring detection thresholds in backgrounds of contrast-modulated white noise that was constructed so that the standard template-matching (TM) observer performs equally well whether or not the noise contrast modulates in the target region. If noise contrast is uniform in the target region, then this TM observer is the Bayesian optimal observer. However, when the noise contrast modulates then the Bayesian optimal observer weights the template at each pixel location by the estimated reliability at that location. We find that human performance for modulated noise backgrounds is predicted by this reliability-weighted TM (RTM) observer. More surprisingly, we find that human performance for natural backgrounds is also predicted by the RTM observer.

Relationships between subjective taste sensations and electrogustometry findings in patients with taste disorders

This study aimed to examine the relationships between subjective taste sensations and electrogustometry (EGM) findings in patients with taste disturbances according to the presence of burning mouth (BM) symptoms. Forty-six patients were included and asked to complete a questionnaire that contained questions on subjective taste sensations for the four basic taste qualities and the pattern of taste disorders such as ageusia, hypogeusia and dysgeusia. EGM was performed to measure detection thresholds. To examine the influence of BM symptoms, patients were divided into two groups: patients with and without BM symptoms. The patients consisted of 11 men and 35 women. The group without BM symptoms (n=26) had significantly lower degrees of subjective taste sensations for all taste qualities and higher correlation levels between subjective taste sensations and EGM thresholds than the group with BM symptoms (n=20). The patterns of taste disorders also showed more significant associations with the levels of subjective taste sensations in the patients without BM symptoms compared with those with BM symptoms. In conclusion, patients with taste disorders without BM symptoms had more severe taste disturbances than those with BM symptoms. The pathophysiology of taste disturbances differs according to the presence or absence of BM symptoms.

Associations between sweet taste function, oral complex carbohydrate sensitivity, liking and consumption of ad libitum sweet and non-sweet carbohydrate milkshakes among female adults.

Excess energy intake is recognised as a strong contributing factor to the global rise of being overweight and obese. The aim of this paper was to investigate if oral sensitivity to complex carbohydrate relates to ad libitum consumption of complex carbohydrate foods in a sample group of female adults. Participants' ((n 51 females): age 23·0 (sd 0·6) years (range 20·0-41·0 years); excluding restrained eaters) sensitivity towards maltodextrin (oral complex carbohydrate) and glucose (sweet taste) was assessed by measuring detection threshold (DT) and suprathreshold intensity perception (ST). A crossover design was used to assess consumption of two different iso-energetic preload milkshakes and ad libitum milkshakes - (1) glucose-based milkshake, (2) maltodextrin-based milkshake. Ad libitum intake (primary outcome) and eating rate, liking, hunger, fullness and prospective consumption ratings were measured. Participants who were more sensitive towards complex carbohydrate (maltodextrin DT) consumed significantly more maltodextrin-based milkshake in comparison with less-sensitive participants (P = 0·01) and this was independent of liking. Participants who had higher liking for glucose-based milkshake consumed significantly more glucose-based milkshake in comparison with participants with lower hedonic ratings (P = 0·049). The results provide support regarding the role of the oral system sensitivity (potentially taste) to complex carbohydrate and the prospective to overconsume complex carbohydrate-based milkshake in a single sitting.

Masking of short tones in noise: Evidence for envelope-based, rather than energy-based detection

A short tone added to a longer simultaneous masker may be detected by observing an increase in overall acoustic energy. This detection scheme predicts probe thresholds to be independent of the masker’s temporal envelope. A recent study [Jennings et al., J. Assoc. Res. Oto. 19, 717–727 (2018)] revealed that probe thresholds were 10 dB higher for maskers with flattened compared to fluctuating envelopes, suggesting an envelope-based detection strategy. This study test the hypothesis that probe thresholds are proportional to envelope power by measuring detection thresholds for a 4-kHz, 6-ms probe in one of three temporal positions within a 400-ms masker in normal-hearing listeners. The narrow-band, low-fluctuating noise masker was preceded by flattened or fluctuating noise precursors. The precursor’s offset was delayed from the masker’s onset by -2, 0, 10, 25, 100, or 250 ms. Probe thresholds were positively correlated with envelope power (R-squared = 0.75), consistent with masking from precursor envelope fluctuations and from fluctuations introduced by precursor and masker ramps. These findings suggest that future modeling efforts for short probes presented in longer maskers should consider a decision variable based on envelope fluctuations.

Harmonicity aids detection of speech and other sounds in noise

Acoustic grouping cues, such as the tendency of frequencies to be harmonic, are used to segregate multiple sounds, as when listening to one of several concurrent speakers. However, we often must listen to sound sources in noise. Here we investigate the role of traditional acoustic grouping cues in detecting sound sources in noise. We measured detection thresholds for several types of sounds embedded in noise: speech, musical instruments, and synthetic complex tones. In each case the sounds were resynthesized with harmonic and inharmonic carrier frequencies to test the importance of harmonic frequency structure for hearing in noise. We found that harmonic signals were consistently easier to detect in noise than otherwise similar inharmonic signals. This harmonic advantage persisted even when the phases of harmonic components were randomized, such that the advantage is unlikely to reflect differences in the depth of modulation (from beating). Near threshold, harmonic signals were readily audible in conditions where inharmonic signals could not be heard. These results suggest that harmonicity is critical for detecting real-world signals in noise, demonstrating its relevance to another important aspect of auditory scene analysis.

Model of parafoveal chromatic and luminance temporal contrast sensitivity of humans and monkeys.

Rhesus monkeys are a valuable model for studies of primate visual contrast sensitivity. Their visual systems are similar to that of humans, and they can be trained to perform detection tasks at threshold during neurophysiological recording. However, the stimulus dependence of rhesus monkey contrast sensitivity has not been well characterized. Temporal frequency, color, and retinal eccentricity affect the contrast sensitivity of humans in reasonably well-understood ways. To ask whether these factors affect monkey sensitivity similarly, we measured detection thresholds of two monkeys using a two-alternative, forced-choice task and compared them to thresholds of two human subjects who performed the same task. Stimuli were drifting Gabor patterns that varied in temporal frequency (1–60 Hz), L- and M-cone modulation ratio, and retinal eccentricity (2°–14° from the fovea). Thresholds were fit by a model that assumed a pair of linear detection mechanisms: a luminance contrast detector and a red-green contrast detector. Analysis of model fits indicated that the sensitivity of these mechanisms varied across the visual field, but their temporal and spectral tuning did not. Human and monkey temporal contrast sensitivity was similar across the conditions tested, but monkeys were twofold less sensitive to low-frequency, luminance modulations.

Natural Regularity of Correlated Acoustic Frequency and Intensity in Music and Speech: Auditory Scene Analysis Mechanisms Account for Integrality of Pitch and Loudness

ABSTRACTDynamic changes in acoustic intensity can produce perceptual changes in pitch as large as half an octave. Here we investigate the functional roots behind these large distortions. We propose a natural acoustic regularity in which sound sources that change in fundamental frequency (f0) typically congruently change in intensity, and vice versa. It is therefore adaptive for the auditory system to capitalize on this statistical regularity by integrally perceiving changes in pitch and loudness. This regularity could then provide a redundant cue that facilitates parsing and tracking of individual sources during auditory scene analysis. In three initial experiments testing music and speech, we find support for the proposed statistical correlation between changes in f0 and intensity. In a fourth experiment, we utilize an adaptive staircase procedure to measure detection thresholds for tone-glides that changed in f0, intensity, or both. The lowest detection threshold levels occurred when f0 and intensity changed in the same direction. Our findings confirm an acoustical correlation between changes in f0 and intensity in domains of music and speech, and support that listeners can parse and hear sounds better when they are consistent with this natural regularity.

The Associations Between Oral Complex Carbohydrate Sensitivity, BMI, Liking, and Consumption of Complex Carbohydrate Based Foods

Recent work suggests that humans may perceive complex carbohydrates and that their sensitivity to simple carbohydrates (i.e., glucose and sucrose) is independent from tasting complex carbohydrates. The aim of this study was to confirm whether humans could sense complex carbohydrates from a range of concentration levels; and if their oral sensitivity to complex carbohydrate relates to their BMI, liking, and consumption of complex carbohydrate-based foods using a large sample group of adults. Participants' (n = 92 females, age 23.7 ± 0.5 yr [range, 19 to 47 yr]) oral sensitivity towards complex carbohydrate (maltodextrin) and sweet taste function (glucose) was assessed by measuring detection threshold and suprathreshold intensity perception (gLMS). Participants were asked to complete an online version of a Food Frequency Questionnaire and a Likes and Dislikes Questionnaire. Hedonic ratings for complex carbohydrate and sweet solutions, as well as for a range of complex carbohydrate and sweet prototypical foods, were also measured. Consistent with previous findings, there was large interindividual variation in detection and intensity measures for maltodextrin and glucose. No significant associations were found between oral complex carbohydrate sensitivity, Body Mass Index (BMI), and frequency of consumption of complex carbohydrate-based foods measured. Similarly, no differences were observed between liking of complex carbohydrates, BMI, and food intake. All in, these results from a large sample group further support the proposition that complex carbohydrates are not invisible to the human palate, and can be sensed in the oral cavity even at low concentration levels.

Cyclophosphamide-Induced Disruptions to Appetitive Qualities and Detection Thresholds of NaCl: Comparison of Single-Dose and Dose Fractionation Effects.

Chemotherapy is one of the most common treatments for cancer; however, a side effect is often altered taste. This study examined how cyclophosphamide, a chemotherapy drug, affects salt taste in mice. On the basis of previous findings, it was predicted that cyclophosphamide-induced disruptions in salt taste would be observed near days 2-4, 8-12, and 22-24 posttreatment, and that multiple, smaller doses would cause more severe disruptions to taste. To test these predictions, two experiments were performed, one using brief access testing to measure appetitive qualities, and another using operant conditioning to measure detection thresholds. After a single 100 mg/kg cyclophosphamide injection, peak alterations in brief access lick rates were seen near days 5-8 and 15 posttreatment, whereas peak alterations in detection thresholds were seen days 6, 14, and 20 posttreatment. After five 20 mg/kg injections of cyclophosphamide, brief access lick rates revealed disruptions only on postinjection day 8 whereas thresholds appeared to cycle, gradually increased to and decreased from peak elevations on posttreatment days 4, 10, 15, 20, and 23. Although salt taste functions were disrupted by cyclophosphamide, the patterns of these disruptions were less severe and shorter than expected from cell morphology studies, suggesting a functional adjustment to maintain behavioral accuracy. Fractionation of cyclophosphamide dosing had minimum effect on brief access responses but caused longer, cyclic-like disruptions of detection thresholds compared to single-dose administration.