Analysis of temporal structure in sound by the human brain.

For over a century, models of pitch perception have been based on the frequency composition of the sound. Pitch phenomena can also be explained, however, in terms of the time structure, or temporal regularity, of sounds. To locate the mechanism for the detection of temporal regularity in humans, we used functional imaging and a 'delay-and-add' noise, which activates all frequency regions uniformly, like noise, but which nevertheless produces strong pitch perceptions and tuneful melodies. This stimulus has temporal regularity that can be systematically altered. We found that the activity of primary auditory cortex increased with the regularity of the sound. Moreover, a melody composed of delay-and-add 'notes' produced a distinct pattern of activation in two areas of the temporal lobe distinct from primary auditory cortex. These results suggest a hierarchical analysis of time structure in the human brain.

Encoding of the temporal regularity of sound in the human brainstem.

We measured the neural activity associated with the temporal structure of sound in the human auditory pathway from cochlear nucleus to cortex. The temporal structure includes regularities at the millisecond level and pitch sequences at the hundreds-of-milliseconds level. Functional magnetic resonance imaging (fMRI) of the whole brain with cardiac triggering allowed simultaneous observation of activity in the brainstem, thalamus and cerebrum. This work shows that the process of recoding temporal patterns into a more stable form begins as early as the cochlear nucleus and continues up to auditory cortex.

Right parietal cortex is involved in the perception of sound movement in humans.

Changes in the delay (phase) and amplitude of sound at the ears are cues for the analysis of sound movement. The detection of these cues depends on the convergence of the inputs to each ear, a process that first occurs in the brainstem. The conscious perception of these cues is likely to involve higher centers. Using novel stimuli that produce different perceptions of movement in the presence of identical phase and amplitude modulation components, we have demonstrated human brain areas that are active specifically during the perception of sound movement. Both functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) demonstrated the involvement of the right parietal cortex in sound movement perception with these stimuli.

Executive function and genetic predisposition to schizophrenia--the Maudsley family study.

Executive cognitive impairment has been found in families affected by schizophrenia and is a putative endophenotype. We wished to explore its genetic basis further by studying the association between impairment and genetic loading for schizophrenia. We studied 30 schizophrenia patients with a family history of schizophrenia, 53 of their nonpsychotic first-degree relatives (familial), 32 patients with schizophrenia but no known family history of psychosis, 52 of their first-degree relatives (nonfamilial), and 47 normal controls. They were tested using the National Adult Reading Test (NART), Trails A and B, Verbal fluency tasks, and a computerized version of the Wisconsin Card Sorting Test (WCST). Familial, but not nonfamilial, relatives were impaired on NART, letter fluency, Trails B, and WCST total errors. They were inferior to nonfamilial relatives on letter fluency and Trails A. Both sets of relatives were impaired on Trails B controlling for Trails A, and on WCST categories achieved. There were no significant differences between schizophrenia patients with and without a family history. Our results suggest that executive deficits qualitatively similar to those seen in those with schizophrenia reflect familial susceptibility, even taking early IQ and education into consideration, consistent with a genetic mechanism.

Human cortical areas selectively activated by apparent sound movement.

BACKGROUND: Positron emission tomography (PET) measures cerebral blood flow, an indicator of neural activity. PET has been used successfully to identify visual association areas in the human brain, which are involved in the analysis of different aspects of visual stimuli. However, comparable studies have not yet been carried out for the human auditory system. RESULTS: We have attempted to identify human cortical areas that are selectively activated during sound movement analysis. Using PET, we have identified cortical areas that appeared to be selectively activated while human subjects attended to the position of a moving sound image compared to when they attended to a stationary sound image. The areas are in the right insula, adjacent to the right posterior cingulate, and in the cerebellum. CONCLUSIONS: We suggest that the insula may be acting as an auditory association cortex involved in sound movement analysis, analogous to area V5 in the visual system.

Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers.

BACKGROUND: Developmental dyslexia is a specific disorder of reading and spelling that affects 3-9% of school-age children and adults. Contrary to the view that it results solely from deficits in processes specific to linguistic analysis, current research has shown that deficits in more basic auditory or visual skills may contribute to the reading difficulties of dyslexic individuals. These might also have a crucial role in the development of normal reading skills. Evidence for visual deficits in dyslexia is usually found only with dynamic and not static stimuli, implicating the magnocellular pathway or dorsal visual stream as the cellular locus responsible. Studies of such a dissociation between the processing of dynamic and static auditory stimuli have not been reported previously. RESULTS: We show that dyslexic individuals are less sensitive both to particular rates of auditory frequency modulation (2 Hz and 40 Hz but not 240 Hz) and to dynamic visual-motion stimuli. There were high correlations, for both dyslexic and normal readers, between their sensitivity to the dynamic auditory and visual stimuli. Nonword reading, a measure of phonological awareness believed crucial to reading development, was also found to be related to these sensory measures. CONCLUSIONS: These results further implicate neuronal mechanisms that are specialised for detecting stimulus timing and change as being dysfunctional in many dyslexic individuals. The dissociation observed in the performance of dyslexic individuals on different auditory tasks suggests a sub-modality division similar to that already described in the visual system. These dynamic tests may provide a non-linguistic means of identifying children at risk of reading failure.

Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies.

BACKGROUND: Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non-paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC-Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis. METHODS: The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow-up of at least 18 months are described here. RESULTS: All patients had negative testing for VGKC-Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures. CONCLUSION: These cases demonstrate that the absence of VGKC-Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen.

Reaction time and sustained attention in schizophrenia and its genetic predisposition.

Sustained attention is affected by schizophrenia. The simplest form of Continuous Performance Test (CPT-X) is a purer test of vigilance than more demanding variants but widely thought too insensitive to detect abnormalities in those with genetic predisposition to schizophrenia. We used a 7-minute CPT to compare 61 patients diagnosed with schizophrenia, 45 of their never-psychotic relatives, and 47 control subjects. We found a significant impairment in stimulus discrimination in both patients (p=0.001) and their relatives (p=0.006). There was no difference in stimulus discrimination between relatives of patients with impaired and unimpaired stimulus discrimination. Relatives of patients with unimpaired stimulus discrimination were still inferior to controls (p=0.02). Reactions slowed in all groups equally as the test progressed. Patients showed increased mean reaction time (p<0.0001) and interquartile range (p=0.003). Relatives showed slower reaction times (p=0.01) but normal interquartile range. Groups did not differ in respect of individuals' fastest reaction times. We conclude that genetic predisposition to schizophrenia reduces performance even during a task placing minimal cognitive load on working memory and perceptual processing, suggesting impaired vigilance. Increased reaction time in the disease and its predisposition appear to be due to changes in response distribution rather than by a limitation of maximum speed. Our results raise the possibility of separating the cognitive components of vigilance, working memory and perceptual processing tapped by more demanding variants of the CPT, and draw attention to the need for consideration of dynamic neurocognitive processes in schizophrenia.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Proton magnetic resonance spectroscopy in frontotemporal dementia.

This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.

Distinct mechanisms for processing spatial sequences and pitch sequences in the human auditory brain.

Perception of the acoustic world requires the simultaneous processing of the acoustic patterns associated with sound objects and their location in space. In this functional magnetic resonance experiment, we investigated the human brain areas engaged in the analysis of pitch sequences and sequences of acoustic spatial locations in a paradigm in which both could be varied independently. Subjects were presented with sequences of sounds in which the individual sounds were regular interval noises with variable pitch. Positions of individual sounds were varied using a virtual acoustic space paradigm during scanning. Sound sequences with changing pitch specifically activated lateral Heschl's gyrus (HG), anterior planum temporale (PT), planum polare, and superior temporal gyrus anterior to HG. Sound sequences with changing spatial locations specifically activated posteromedial PT. These results demonstrate directly that distinct mechanisms for the analysis of pitch sequences and acoustic spatial sequences exist in the human brain. This functional differentiation is evident as early as PT: within PT, pitch pattern is processed anterolaterally and spatial location is processed posteromedially. These areas may represent human homologs of macaque lateral and medial belt, respectively.

Effect of ultraviolet light on thymidine incorporation, DNA chain elongation and replicon initiation in wild-type and excision-deficient Chinese hamster ovary cells.

Wild-type Chinese hamster ovary cells (AA8) and five excision-deficient clones derived from the AA8 line (UV-4, UV-5, UV-20, UV-24 and UV-41) were exposed to ultraviolet light and then analyzed for their ability to incorporate [3H]thymidine and to initiate as well as elongate replicon-sized DNA fragments. After exposure to ultraviolet light, all cell lines exhibited a depression in the rate of thymidine incorporation. For exposures of 4.0 J/m2 or higher the wild-type cells recovered normal rates of thymidine incorporation within a few hours, while none of the excision-deficient lines exhibited complete recovery. For fluences below 4.0 J/m2 all but the UV-5 line exhibited at least some recovery. The ability to elongate DNA chains appeared to correlate with the thymidine incorporation data, with the UV-5 line exhibiting the strongest blockage of DNA chain elongation, the AA8 line exhibiting the least blockage, and the UV-20 line exhibiting an intermediate response. All cell lines exhibited a decrease in the distance between replication origins, thus supporting models which propose that exposure to ultraviolet light results in the use of alternative sites for the initiation of replication.

Effects of inhibitors of DNA synthesis and protein synthesis on the rate of DNA synthesis after exposure of mammalian cells to ultraviolet light.

Chinese hamster V-79 cells were treated with metabolic inhibitors o DNA or protein synthesis for various intervals of time after exposure of 3.0 or 5.0 J m-2. After removal of the metabolic block(s) the rate of DNA synthesis was followed by measuring the incorporation of [14C]thymidine into acid-insoluble material. A 2.5 or 5.0 h incubation with cycloheximide or hydroxyurea was effective in delaying the onset of the recovery in the rate of DNA synthesis that normally becomes evident several hours after exposure to ultraviolet light. By using concentrations of cycloheximide or hydroxyurea that inhibit DNA synthesis by a similar amount (70%), but protein synthesis by vastly different amounts (95% for cycloheximide; 0% for hydroxyurea), it was apparent that the delay in recovery caused by the treatment of cells with cycloheximide could be accounted for entirely by its inhibitory effect on DNA synthesis. This suggests that the recovery in DNA synthetic rates following exposure of V-79 cells to ultraviolet light does not appear to require de novo protein synthesis, and therefore does not appear to require the involvement of an inducible DNA repair process.

S-phase transit times as a function of age in human diploid fibroblasts.

The minimum time it takes a cell to pass completely through the S phase (MIN S) was examined in human diploid fibroblasts using a sequential [14C]thymidine, [3H]thymidine, [14C]thymidine labeling protocol. MIN S appeared to be around 6-8 h for both WI-38 and MRC-5 cells. In addition, MIN S did not increase in senescent cultures. Since damage to either DNA, its polymerases, or both would result in a reduction in the rate of DNA synthesis and a corresponding increase in MIN S, this suggests that in senescent cultures at least a portion of the cells contain DNA that is relatively undamaged and DNA polymerases that exhibit normal replicative kinetics.

DNA chain growth as a function of age in intact and permeabilized WI-38 and MRC-5 cells.

The rate of incorporation of deoxythymidine triphosphate (dTTP) into acid-precipitable material of permeabilized MRC-5 and WI-38 cells as well as the rate of DNA chain growth in both intact and permeabilized cells was examined as a function of cell age. Although both the total rate of dTTP incorporation and the percentage of labeled cells decreased as cultures aged, we could detect no decrease in the rate of DNA chain growth from passages 29 to 53 for MRC-5 and from passages 34 to 50 for WI-38 cells. Since the older passages were in phase III growth and since, in our hands, the WI-38 cells used for this study senesced at passage 51, we conclude that a decrease in the rate of DNA chain growth is not related to in vitro aging.

The effects of 5-fluorouracil and doxorubicin on expression of human immunodeficiency virus type 1 long terminal repeat.

Previous work by many groups has documented induction of the human immunodeficiency virus (HIV) long terminal repeat (LTR) following exposure of cells to ultraviolet light and other DNA damaging agents. Our experiments set out to determine the relative activation or repression of the HIV-LTR in response to two classes of chemotherapeutic agents: Doxorubicin is a DNA damage-inducing agent, and 5-fluorouracil has an antimetabolic mode of action. Using HeLa cells stably transfected with a construct in which HIV-LTR drives expression of the chloramphenicol acetyl transferase reporter gene, we demonstrated an up to ten-fold induction following doxorubicin treatment at 24 h post-treatment. This induction was repressed by treatment with salicylic acid, suggesting a role for prostaglandin/cyclo-oxygenase pathways and/or NF-kappa B in the inductive response. Induction by 5-fluorouracil, in contrast, was more modest (two-fold at most) though it was consistently elevated over controls.

Psychophysical evaluation of cochlear hair cell damage due to the A3243G mitochondrial DNA mutation.

Mitochondrial dysfunction is an important cause of human deafness, implicated in genetic deafness, toxin and noise damage. We assessed the mechanism of cochlear dysfunction in a population of 11 subjects with a specific mitochondrial disorder caused by the A3243G mitochondrial DNA mutation. Psychophysical tests were carried out to assess the inner and outer hair cell functions in vivo. Inner hair cell function was assessed using a measure of hearing threshold in the presence of "threshold-equalizing noise" which can indicate "dead regions" where the transduction mechanism fails. Outer hair cell function was assessed by using the notched-noise method to measure auditory filter width, dependent on active mechanisms in the outer hair cell. The results support the conclusion that this mitochondrial disorder causes both inner and outer hair cell dysfunctions. Evidence of inner hair cell dysfunction was found mainly in basal (high frequency) regions of the cochlea and occurred even in some subjects with only mild hearing loss. Evidence of outer hair cell dysfunction was found in some instances where pure tone threshold was at or close to normal. The common occurrence of dead regions in the basal cochlea has treatment implication for this form of deafness; such people may not be helped by amplification of high frequencies.

Effect of UVC light on growth, incorporation of thymidine, and DNA chain elongation in cells derived from the Indian meal moth and the cabbage looper.

After exposure to 10 or 20 J/m2 UVC light, cells of the UMN-PIE-1181 line, an embryonic cell line derived from the Indian meal moth, Plodia interpunctella, exhibited a rapid and prolonged depression in the rate of incorporation of [3H]thymidine, whereas cells of the TN-368 line, an ovarian cell line derived from Trichoplusia ni, the cabbage looper, showed only a slight drop in incorporation and a rapid recovery after exposure to 10 or 40 J/m2 UVC light. The extent of this depression was not correlated to the amount of cell killing by UVC light in these cell lines or in IAL-PID2 cells. Blockage of fork progression was correlated to the depression in thymidine incorporation. TN-368 cells exhibited little blockage after exposure to 10 or 20 J/m2 UVC light, whereas UMN-PIE-1181 cells exhibited significant blockage at these fluences. Photoreactivation did not entirely relieve blockage, depression in thymidine incorporation, or cell killing, indicating that, although the (5-6) dimer appears to be the major lesion responsible for these effects, other lesions such as the (6-4) photoproduct may play a role.

Delayed inhibition of subchromosomal DNA synthesis in V-79 Chinese hamster cells after gamma irradiation.

Existence of a substantial fraction of replicon initiation events refractory to the effects of X irradiation in Chinese hamster cells has been reported by several laboratories. The work reported here examined whether this apparently refractive fraction resulted from a delayed inhibition of initiation events. Data obtained from velocity sedimentation studies indicated that the extent of inhibition increased over the first hour after irradiation from 35% inhibition immediately following exposure to 3 kR to 75% inhibition of initiation 1 hr after irradiation. Analysis of subsequent recovery of initiation radiosensitivity was performed using DNA fiber autoradiograms prepared from cells incubated up to 4 hr between 2-kR exposures. The data from these experiments indicated that some recovery occurs within 1 hr of irradiation and thus separation of the inhibition and recovery processes in V-79 cells may not be feasible.