Validation of the adaptive scan method in the quest for time-efficient methods of testing auditory processes.

A major barrier to the clinical application of psychophysical testing of central auditory processes is the time required to obtain precise estimates of different listening abilities. In this study, we validate a novel adaptive scan (AS) method of threshold estimation that is designed to adapt on a range of values around threshold rather than on a single threshold value. This method has the advantage of providing the listener with greater familiarity with the stimulus characteristics near threshold while maintaining precise measurement and increasing time-efficiency. Additionally, we explore the time-efficiency of AS through comparison with two more conventional adaptive algorithms and the method of constant stimuli in two common psychophysical tasks: the detection of a gap in noise and the detection of a tone in noise. Seventy undergraduates without hearing complaints were tested using all four methods. The AS method provided similar threshold estimates with similar precision to those from the other adaptive methods and, thus, it is a valid adaptive method of psychophysical testing. We also provide an analysis of the AS method based on precision metrics to propose a shortened version of the algorithm that maximizes the time/precision tradeoff and can achieve similar thresholds to the adaptive methods tested in the validation. This work lays the foundation for using AS across a wide variety of psychophysical assessments and experimental situations where different levels of precision and/or time-efficiency may be required.

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium.

Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity that contributes to working-memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal short-term potentiation (STP), a major form of short-term synaptic plasticity. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.

The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents.

Inhibition of phosphodiesterase 9 (PDE9) has been reported to enhance rodent cognitive function and may represent a potential novel approach to improving cognitive dysfunction in Alzheimer's disease. PF-04447943, (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a recently described PDE9 inhibitor, was found to have high affinity (Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1-8 and 10-11. PF-04447943 significantly increased neurite outgrowth and synapse formation (as indicated by increased synapsin 1 expression) in cultured hippocampal neurons at low (30-100 nM) but not high (300-1000 nM) concentrations. PF-04447943 significantly facilitated hippocampal slice LTP evoked by a weak tetanic stimulus at a concentration of 100 nM but failed to affect response to the weak tetanus at either 30 or 300 nM, or the LTP produced by a theta burst stimulus. Systemic administration of PF-04447943 (1-30 mg/kg p.o.) dose-dependently increased cGMP in the cerebrospinal fluid 30 min after administration indicating target engagement in the CNS of rats. PF-04447943 (1-3 mg/kg p.o.) significantly improved cognitive performance in three rodent cognition assays (mouse Y maze spatial recognition memory model of natural forgetting, mouse social recognition memory model of natural forgetting and rat novel object recognition with a scopolamine deficit). When administered at a dose of 3 mg/kg p.o., which improved performance in novel object recognition, PF-04447943 significantly increased phosphorylated but not total GluR1 expression in rat hippocampal membranes. Collectively these data indicate that PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor that increased indicators of hippocampal synaptic plasticity and improved cognitive function in a variety of cognition models in both rats and mice. Results with PF-04447943 are consistent with previously published findings using a structurally diverse PDE9 inhibitor, BAY73-6199, and further support the suggestion that PDE9 inhibition may represent a novel approach to the palliative remediation of cognitive dysfunction.

Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration.

Dopaminergic innervation of the frontal cortex in adults is important for a variety of cognitive functions and behavioral control. However, the role of frontal cortical dopaminergic innervation for neurobehavioral development has received little attention. In the current study, rats were given dopaminergic lesions in the frontal cortex with local micro-infusions of 6-hydroxydopamine (6-OHDA) at 1 week of age. The long-term behavioral effects of neonatal frontal cortical 6-OHDA lesions were assessed in a series of tests of locomotor activity, spatial learning and memory, and i.v. nicotine self-administration. In addition, neurochemical indices were assessed with tissue homogenization and HPLC in the frontal cortex, striatum, and nucleus accumbens of neonatal and adult rats after neonatal 6-OHDA lesions. In neonatal rats, frontal 6-OHDA lesions as intended caused a significant reduction in frontal cortical dopamine without effects on frontal cortical 5-HT and norepinephrine. The frontal cortical dopamine depletion increased 5-HT and norepinephrine levels in the nucleus accumbens. Locomotor activity assessment during adulthood in the figure-8 maze showed that lesioned male rats were hyperactive relative to sham-lesioned males. Locomotor activity of female rats was not significantly affected by the neonatal frontal 6-OHDA lesion. Learning and memory in the radial-arm maze was also affected by neonatal frontal 6-OHDA lesions. There was a general trend toward impaired performance in early maze acquisition and a paradoxical improvement at the end of cognitive testing. Nicotine self-administration showed significant lesion x sex interactions. The sex difference in nicotine self-administration with females self-administering significantly more nicotine than males was reversed by neonatal 6-OHDA frontal cortical lesions. Neurochemical studies in adult rats showed that frontal cortical dopamine and DOPAC levels significantly correlated with nicotine self-administration in the 6-OHDA-lesioned animals but not in the controls. Frontal cortical 5-HT and 5HIAA showed inverse correlations with nicotine self-administration in the 6-OHDA-lesioned animals but not in the controls. These results show that interfering with normal dopamine innervation of the frontal cortex during early postnatal development has persisting behavioral effects, which are sex-specific.

Measurement of auditory temporal processing using modified masking period patterns.

A common metric of auditory temporal processing is the difference in the threshold for a pure-tone signal masked by either unmodulated or amplitude-modulated noise. This technique may be viewed as a modification of the masking period pattern technique. Such measurements have been proposed as an efficient means of estimating auditory temporal resolution in a clinical setting, although in many cases threshold differences may reflect additional spectro-temporal processes. The primary purpose of the present experiment was to examine interactions among signal frequency and masker bandwidth and the effects of modulation frequency on modified masking period patterns. The results revealed unmodulated-modulated threshold differences that increased with increasing masker bandwidth and decreased with increasing modulation frequency. There was little effect of signal frequency for narrow-band noise maskers that were equal in absolute bandwidth across frequency. However, unmodulated-modulated threshold differences increased substantially with increasing signal frequency for bandwidths proportional to the signal frequency and for wideband maskers. Although the results are interpreted in terms of a combination of both within-channel and across-channel cues, the specific contributions of these cues in particular conditions are difficult to ascertain. Because modified masking period patterns depend strongly upon a number of specific stimulus parameters, and because it is difficult to determine with any precision the underlying perceptual processes, this technique is not recommended for use as a clinical measure of auditory temporal processing.

Monaural masking release in random-phase and low-noise noise.

Two masking-release paradigms thought to involve across-channel processing are comodulation masking release (CMR) and profile analysis. Similarities between these two paradigms were explored by comparing signal detection in maskers that varied only in degree of envelope fluctuation. The narrow-band-noise maskers were 10 Hz wide and their envelope fluctuations were manipulated using the low-noise noise algorithm of Pumplin [J. Acoust. Soc. Am. 78, 100-104 (1985)]. Masking conditions included the classic CMR conditions of an on-frequency band, multiple (five) incoherent bands, or multiple coherent bands. Detection was compared using both random-phase noise (RPN) and low-noise noise (LNN) maskers. In one set of conditions, the signal was identical to the on-frequency masker, yielding an intensity discrimination task. Conditions that included RPN maskers and tonal signals resembled the classic CMR paradigm, whereas conditions including LNN and noise signals more closely resembled the classic profile analysis paradigm. Other conditions may be considered hybrids. This combination of conditions provided a wide variety of within- and across-channel cues for detection. The results suggest that CMR and profile analysis could be based upon the same set of stimulus cues and perhaps the same perceptual processes.

Amplitude-modulation detection at low- and high-audio frequencies.

Estimates of temporal acuity under comparable conditions at low- and high-audio frequencies are rare. The present study used the amplitude-modulation detection paradigm to estimate temporal acuity over a range of audio frequencies from 800 to 12,800 Hz. Amplitude-modulation detection was measured as a function of modulation frequency for bandlimited noise carriers, and the resulting temporal modulation-transfer functions were used to characterize temporal acuity. The most important result from the two experiments reported is that systematic manipulations of carrier upper-cutoff frequency produced estimates of temporal acuity that did not vary from 800 to 12,800 Hz. When the modulated noise bands were filtered after modulation to control for potential spectral cues, the low-pass cutoff of the modulation-transfer function varied with the carrier bandwidth. However, when the standard stimulus was a quasifrequency-modulated (QFM) noise and the signal was an unfiltered, amplitude-modulated noise, the low-pass cutoff of the modulation-transfer function was independent of carrier bandwidth. These results are consistent with a growing body of evidence demonstrating that auditory temporal acuity is constant throughout most of the audible frequency range.

The influence of stimulus envelope and fine structure on the binaural masking level difference.

A masking level difference (MLD) paradigm was used to investigate the influence of stimulus envelope and stimulus fine-structure characteristics on monaural and binaural hearing. The degree of masker envelope fluctuation was manipulated by selecting narrow-band noises (50 Hz) on a continuum of values of the normalized fourth moment of the envelope. The noises were specified as low-noise noise (LNN), medium-noise noise (MNN), and high-noise noise (HNN). Fine-structure cues were studied by measuring thresholds at 500 and 4000 Hz, regions in which the availability of such cues to the auditory system differ substantially. In addition, thresholds were measured for Gaussian noise maskers (GN) and for maskers having a flat magnitude spectrum, termed equal-magnitude noise (EMN) maskers. The results indicated lower NoSo thresholds for LNN than for the other four masker types. Furthermore, there were no differences in threshold for maskers having moderate and high degrees of envelope fluctuation (MNN and HNN). The NoS pi thresholds were not significantly different across masker type and were characterized by large individual differences among the seven listeners. The results are considered in relation to models of monaural and binaural processing. Consistent with previous reports, the results indicate that binaural detection depends on interaural differences in the stimulus envelope and fine structure at low frequencies and changes in the envelope at high frequencies.

Comodulation masking release for single and multiple rates of envelope fluctuation.

Two experiments are presented that investigate the influence of envelope fluctuation rate upon the magnitude of comodulation masking release (CMR). In Experiment 1, thresholds were measured for a tonal signal centered in either one or five masker bands. The maskers were either narrow-band noises or 100% sinusoidally amplitude-modulated (SAM) tones. The five masker bands had either the same (coherent) or different (incoherent) envelopes. Envelope rate was varied by manipulating either the noise bandwidth (10-200 Hz) or the SAM rate (10-128 Hz). The CMR values were largest for slow envelope rates. In Experiment 2, envelope coherence was simultaneously manipulated at two rates by amplitude modulating (10 Hz) narrow-band noises (100 Hz). The modulation depth was 100%, 83%, or 50%. The CMR based on the coherence of the noise carriers was about 5 dB, regardless of the SAM coherence or the modulation depth. The CMR based on the SAM coherence decreased from about 19 to 2 dB as modulation depth decreased, regardless of the noise-carrier coherence. Thresholds were highest when the envelope fluctuations were incoherent at both rates and were lowest when the envelope fluctuations were coherent at both rates. These data suggest that the auditory system is able to make across-frequency envelope comparisons at both envelope rates simultaneously.

Potential impact on vaccination coverage levels by administering vaccines simultaneously and reducing dropout rates.

BACKGROUND: Retrospective immunization coverage surveys conducted during 1991 and 1992 demonstrated that coverage levels for the routine childhood vaccines by 24 months of age in selected urban areas of the United States ranged from 10% to 52%, far below the US Public Health Service goal of 90%. Therefore, appropriate programmatic changes must be identified and incorporated. METHODS: We analyzed coverage survey data collected from 21 sites to measure the potential impact on coverage levels of implementing selected changes in vaccination practices. In a multistaged cluster survey design, school health records of kindergarten or first-grade students were randomly selected and dates of vaccination assessed. We evaluated changes in the vaccination practices, such as eliminating missed opportunities for simultaneous administration of vaccines and ensuring that children initiated the vaccination series on time (ie, by 3 months of age). We then calculated potential increases in coverage levels for a best-case scenario. RESULTS: From 77% to 96% of all children in the 21 sites had received at least one vaccination by their first birthday. Children were 2.3 to 17 times more likely to be up to date on their vaccinations by 24 months of age if they were up to date at 3 months of age. Each child had many opportunities for the simultaneous administration of diphtheria and tetanus toxoids and pertussis (DTP) vaccine, oral polio vaccine (OPV), and measles-mumps-rubella (MMR) vaccine that, if used appropriately, could have potentially raised coverage levels by 12% to 22% (median, 17%). The highest coverage levels could have been attained if all children had started the series on time and if advantage had been taken of all opportunities for simultaneous vaccination. Coverage levels for four doses of DTP vaccine, three doses of OPV, and one dose of MMR vaccine would have increased from a baseline of 10% to 52% to levels of 54% to 83%. CONCLUSIONS: Although the majority of children received a vaccination by their first birthday, the coverage level at 24 months of age was low. Tracking systems are needed to ensure that children do not drop out of the system once they have begun the vaccination series. In addition, all children who are late in beginning their vaccination series are at increased risk of not completing the recommended vaccination series on time, and these children need intensive follow-up and recall efforts. Also, providers need to administer all needed vaccines simultaneously.

Spectral shape discrimination of narrow-band sounds.

Measurements are reported on the detectability of signals added to narrow-band sounds. The narrow-band sounds had a bandwidth of 20 Hz and were either Gaussian noise with flat amplitude spectra or sets of equal-amplitude sinusoidal components whose phases were chosen at random. Four different kinds of sinusoidal signals were used. Two signals produced symmetric changes in the audio spectrum adding a component either at the center of the spectrum or at both ends. The other two signals produced asymmetric changes adding a component at either end of the spectrum. The overall level of the sound was randomly varied on each presentation, so that the presence of a signal was largely unrelated to the absolute level of the signal component(s). A model is proposed that assumes the detection of the symmetric signals is based on changes in the shape of the power spectrum of the envelope. Such changes in the envelope power spectrum are probably heard as changes in the "roughness" or "smoothness" of the narrow-band sound. The predictions of this model were obtained from computer simulations. For the asymmetric signals, the most probable detection cues were changes in the pitch of the narrow-band sound. Results from a variety of different experiments using three listeners support these conjectures.

The detection of temporal gaps as a function of frequency region and absolute noise bandwidth.

Temporal gap detection was measured as a function of absolute signal bandwidth at a low-, a mid-, and a high-frequency region in six listeners with normal hearing sensitivity. Gap detection threshold decreased monotonically with increasing stimulus bandwidth at each of the three frequency regions. Given conditions of equivalent absolute bandwidth, gap detection thresholds were not significantly different for upper cutoff frequencies ranging from 600 to 4400 Hz. A second experiment investigated gap detection thresholds at two pressure-spectrum levels, conditions typically resulting in substantially different estimates of frequency selectivity. Estimates of frequency selectivity were collected at the two levels using a notched-noise masker technique. The gap threshold-signal bandwidth functions were almost identical at pressure-spectrum levels of 70 dB and 40 dB for the two subjects in experiment II, while estimates of frequency selectivity showed poorer frequency selectivity at the 70-dB level than at 40 dB. Data from both experiments indicated that gap detection in bandlimited noise was inversely related to signal bandwidth and that gap detection did not vary significantly with changes in signal frequency over the range of 600 to 4400 Hz. Over the range of frequencies investigated, the results indicated no clear relation between gap detection for noise stimuli and peripheral auditory filtering.

Gap detection as a function of stimulus bandwidth with fixed high-frequency cutoff in normal-hearing and hearing-impaired listeners.

Gap detection was measured as a function of noise bandwidth with constant high-frequency cutoff in both normal-hearing and cochlear-impaired listeners. Band-widening functions were measured in a low-frequency region (0.6-kHz upper cutoff) and a high-frequency region (2.2-kHz upper cutoff). Measures of frequency selectivity were also obtained in the two frequency regions. The results for the normal-hearing listeners indicated that, on a double logarithmic scale, gap thresholds improved more steeply with increasing bandwidth in the higher frequency region than in the lower. However, performance at the narrow bandwidths was independent of frequency region. For the cochlear-impaired listeners, gap thresholds were generally longer than normal in both frequency regions. However, in the higher frequency region, progressively more listeners approached normal values as bandwidth was increased. The elevated gap thresholds were due in part to the higher absolute thresholds and in part to poor ability to process stimulus fluctuation. No correspondence was found between gap detection performance and frequency selectivity.

Prevalence of rubella antibodies in Massachusetts schoolchildren.

In 1982, 1,871 (79%) of 2,368 eligible 6th, 10th and 12th grade students in Massachusetts participated in a statewide serosurvey for rubella antibodies. Sera were screened at the Centers for Disease Control (CDC) by a reference hemagglutination inhibition assay at 1:8, equivalent to approximately 15 International Units (IU)/ml. Sera negative by the CDC hemagglutination inhibition assay were retested using an enzyme immunoassay, a passive hemagglutination assay, and a commercial hemagglutination inhibition test. The approximate screening levels were 10 IU/ml, 7.5 IU/ml, and 5 IU/ml, respectively. Overall seroprevalence levels varied from 76.4% screening at 15 IU to 93.1% including seropositives from any of the tests. Persons with a school record of vaccination had significantly higher seroprevalence levels than persons without records. However, only 78.3% of persons with a record had antibody greater than or equal to 15 IU compared with 60.0% without records; considering any detectable antibody, the comparison is 95.6% versus 71.4%. The low titers in vaccinees appeared to be due to a falloff of antibody with time since vaccination. Of students with a single vaccination noted in the record with exact dates, 92.3% who were vaccinated 0-4 years prior to the study had antibody at 15 IU compared with less than 78% of students with antibody who were vaccinated five or more years prior to the study. In contrast, using more sensitive assays, there was no significant decline in seroprevalence with time since vaccination. Revaccination studies and epidemiologic data suggest that almost all persons with detectable antibody whether above or below 15 IU/ml are immune to rubella. Thus, immunity levels in Massachusetts schoolchildren in the 6th, 10th, and 12th grades are probably in excess of 90%.

Control of paralytic poliomyelitis in the United States.

The changing annual vaccination status of the population and the greater than 1,000-fold drop in reported annual incidence of paralytic poliomyelitis between the early 1950s and early 1970s indicate that the control of poliomyelitis in the United States must be attributed to the use of both the inactivated poliovirus vaccine and oral poliovirus vaccine. The containment, in 1972 and 1979, of rare epidemics in poorly vaccinated subpopulations and the existence of only three reported cases of paralytic poliomyelitis clearly attributable to wild poliovirus in the last three years document a major triumph for public health. The continuing occurrence of vaccine-associated paralysis (six or seven reported cases per year, 1980-1982) indicates the necessity, despite the accomplishments, for continued review of the current vaccination strategy.

Impact of measles in the United States.

Measles has had a severe impact on children in the United States since colonial times. In the early decades of the 20th century, thousands of fatal measles infections were reported each year. During the 1950s an annual average of greater than 500,000 cases of measles and nearly 500 deaths due to measles were reported in the United States. Surveys indicated that 95% of the population had been infected with measles by the age of 15 years. The introduction of measles vaccine and its widespread use, which began in 1963, has had a major impact on the occurrence of measles in the United States. Reported numbers of cases, deaths due to measles, and complications of measles (e.g., encephalitis) have declined dramatically. Accompanying the decline in reported incidence of measles and following it by approximately seven years, has been a decline in the reported incidence of subacute sclerosing panencephalitis (SSPE). In recent years, the incidence of measles has dropped to levels that are less than 1% of those seen in the prevaccine era. In 1981, provisional figures indicated that only 10% of counties in the United States reported any cases of measles. The reported incidence in 1981 was 1.3 cases per 100,000 population, compared with an average incidence of 336.3 cases per 100,000 population in the decade 1950-1959. Thus, the impact of measles in the United States has been markedly reduced, and it is anticipated that indigenous transmission will be eliminated entirely from the country within the year.

Elimination of indigenous measles from the United States.

In October 1978, a nationwide initiative to eliminate indigenous measles from the United States by October 1, 1982, was announced. The measles elimination program has three major elements: attaining and maintaining high immunization levels, aggressive and effective surveillance, and vigorous response to cases. In 1980, immunization levels in children entering school for the first time were 96%, indicating that the necessary levels have been attained in the age group. Mechanisms are in place to assure maintenance of these levels; these rely heavily on the use of immunization requirements for school attendance in each state. Aggressive surveillance systems have been developed for each state to detect suspected measles cases as soon as possible after they occur and to investigate them within 24 hr of notification. The clinical definition of measles used is fever of greater than or equal to 101 F (38.3 C); rash of three or more days duration; and cough, coryza, or conjunctivitis. The response to outbreaks involves identifying persons in the area who are at risk of contracting measles, determining those who are possibly susceptible, and ensuring that these persons are vaccinated. In school outbreaks, susceptible students are vaccinated or excluded from school until the outbreak is over. During 1981, measles morbidity reached a record low level of only 3,032 reported cases (provisional total). Epidemic measles occurred in only a few outbreaks of limited size and duration, and endemic cases were restricted to a small number. Imported cases averaged slightly more than two per week, occasionally producing limited outbreaks, but more often resulting in no secondary spread. Transmission of measles has been interrupted in most of the United States. With continued vigorous implementation of the current strategy and with additional measures to lessen the risk of importations, it appears likely that the goal to eliminate indigenous measles transmission will be attained by October 1982.