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Accurate timing is an integral aspect of sensory and motor processes such as the perception of speech and music and the execution of skilled movement. Neuropsychological studies of time perception in patient groups and functional neuroimaging studies of timing in normal participants suggest common neural substrates for perceptual and motor timing. A timing system is implicated in core regions of the motor network such as the cerebellum, inferior olive, basal ganglia, pre-supplementary, and supplementary motor area, pre-motor cortex as well as higher-level areas such as the prefrontal cortex. In this article, we assess how distinct parts of the timing system subserve different aspects of perceptual timing. We previously established brain bases for absolute, duration-based timing and relative, beat-based timing in the olivocerebellar and striato-thalamo-cortical circuits respectively (Teki et al., 2011). However, neurophysiological and neuroanatomical studies provide a basis to suggest that timing functions of these circuits may not be independent. Here, we propose a unified model of time perception based on coordinated activity in the core striatal and olivocerebellar networks that are interconnected with each other and the cerebral cortex through multiple synaptic pathways. Timing in this unified model is proposed to involve serial beat-based striatal activation followed by absolute olivocerebellar timing mechanisms.

A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between cognitive performance and cerebellar integrity in a specific degeneration of the cerebellar cortex: Spinocerebellar Ataxia type 6 (SCA6). The results demonstrate a critical relationship between verbal working memory and grey matter density in superior (bilateral lobules VI and crus I of lobule VII) and inferior (bilateral lobules VIIIa and VIIIb, and right lobule IX) parts of the cerebellum. We demonstrate that distinct cerebellar regions subserve different components of the prevalent psychological model for verbal working memory based on a phonological loop. The work confirms the involvement of the cerebellum in verbal working memory and defines specific subsystems for this within the cerebellum., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Synesthesia is a rare condition in which stimulation in one modality leads to a secondary experience in another sensory modality. Varying accounts attribute the condition to either neuroanatomical differences between the synesthetes and non-synesthetes or functional differences in how sensory brain regions interact. This study employed voxel-based morphometry to examine whether synesthetes who experience both grapheme-color and tone-color synesthesia as their evoked sensation show neuroanatomical differences in gray matter volume compared to non-synesthetes. We observed that synesthetes showed an increase in gray matter volume in left posterior fusiform gyrus (FG), but a concomitant decrease in anterior regions of left FG and left MT/V5. These findings imply that synesthesia for color is linked to neuroanatomical changes between adjacent regions of the visual system.

In this work, we show that electrophysiological responses during pitch perception are best explained by distributed activity in a hierarchy of cortical sources and, crucially, that the effective connectivity between these sources is modulated with pitch strength. Local field potentials were recorded in two subjects from primary auditory cortex and adjacent auditory cortical areas along the axis of Heschl's gyrus (HG) while they listened to stimuli of varying pitch strength. Dynamic causal modeling was used to compare system architectures that might explain the recorded activity. The data show that representation of pitch requires an interaction between nonprimary and primary auditory cortex along HG that is consistent with the principle of predictive coding.

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

Natural sounds are characterized by their spectral content and the modulation of energy over time. Using functional magnetic resonance imaging in awake macaques, we observed topographical representations of these spectral and temporal dimensions in a single structure, the inferior colliculus, the principal auditory nucleus in the midbrain. These representations are organized as a map with two approximately perpendicular axes: one representing increasing temporal rate and the other increasing spectral frequency.

Research on interval timing strongly implicates the cerebellum and the basal ganglia as part of the timing network of the brain. Here we tested the hypothesis that the brain uses differential timing mechanisms and networks--specifically, that the cerebellum subserves the perception of the absolute duration of time intervals, whereas the basal ganglia mediate perception of time intervals relative to a regular beat. In a functional magnetic resonance imaging experiment, we asked human subjects to judge the difference in duration of two successive time intervals as a function of the preceding context of an irregular sequence of clicks (where the task relies on encoding the absolute duration of time intervals) or a regular sequence of clicks (where the regular beat provides an extra cue for relative timing). We found significant activations in an olivocerebellar network comprising the inferior olive, vermis, and deep cerebellar nuclei including the dentate nucleus during absolute, duration-based timing and a striato-thalamo-cortical network comprising the putamen, caudate nucleus, thalamus, supplementary motor area, premotor cortex, and dorsolateral prefrontal cortex during relative, beat-based timing. Our results support two distinct timing mechanisms and underlying subsystems: first, a network comprising the inferior olive and the cerebellum that acts as a precision clock to mediate absolute, duration-based timing, and second, a distinct network for relative, beat-based timing incorporating a striato-thalamo-cortical network.

Frontotemporal lobar degeneration (FTLD) is generally recognised as a disorder with presenile onset (that is before 65 years of age) with only occasional cases presenting later than this. We set out to determine what proportion of cases of FTLD had late onset of disease and whether such cases of FTLD had distinctive clinical and neuropathological features as compared to cases with presenile onset. Within a combined Manchester and Newcastle autopsy series of 117 cases with pathologically confirmed FTLD (109/117 cases also met Lund Manchester clinical criteria for FTLD), we identified 30 cases (onset age range 65-86 years), comprising 25% of all FTLD cases ascertained in these two centres over a 25-year period. Neuropathologically, the 30 elderly cases presented features of several FTLD histological subgroups [FTLD-TDP (types 1, 2 and 3, 19 cases (63%)], FLTD-tau [MAPT, PiD and CBD, 10 cases (33%)] and FTLD-UPS (1 case), similar in range of phenotypes to that seen in the presenile group, though patients with MAPT, but not PGRN, mutation, or FUS pathology, were notably absent or fewer in the elderly group. Hippocampal sclerosis (HS) was present in 13/30 of the elderly FTLD cases (43%) compared with 14/79 (18%) (P = 0.012) in the presenile FTLD patients. Lobar atrophy present in most of the younger patients was prominent in only 25% of the elderly subjects. Prospective and retrospective psychiatric and medical case note analysis showed that the majority of the elderly FTLD patients, like their younger counterparts, had behavioural features consistent with frontotemporal dementia. FTLD is common amongst elderly persons and all or most of the major clinical and histological subtypes present in younger individuals can be seen in the older group.

During auditory perception, we are required to abstract information from complex temporal sequences such as those in music and speech. Here, we investigated how higher-order statistics modulate the neural responses to sound sequences, hypothesizing that these modulations are associated with higher levels of the peri-Sylvian auditory hierarchy. We devised second-order Markov sequences of pure tones with uniform first-order transition probabilities. Participants learned to discriminate these sequences from random ones. Magnetoencephalography was used to identify evoked fields in which second-order transition probabilities were encoded. We show that improbable tones evoked heightened neural responses after 200 ms post-tone onset during exposure at the learning stage or around 150 ms during the subsequent test stage, originating near the right temporoparietal junction. These signal changes reflected higher-order statistical learning, which can contribute to the perception of natural sounds with hierarchical structures. We propose that our results reflect hierarchical predictive representations, which can contribute to the experiences of speech and music., (Published by Elsevier Inc.)

Auditory figure-ground segregation, listeners' ability to selectively hear out a sound of interest from a background of competing sounds, is a fundamental aspect of scene analysis. In contrast to the disordered acoustic environment we experience during everyday listening, most studies of auditory segregation have used relatively simple, temporally regular signals. We developed a new figure-ground stimulus that incorporates stochastic variation of the figure and background that captures the rich spectrotemporal complexity of natural acoustic scenes. Figure and background signals overlap in spectrotemporal space, but vary in the statistics of fluctuation, such that the only way to extract the figure is by integrating the patterns over time and frequency. Our behavioral results demonstrate that human listeners are remarkably sensitive to the appearance of such figures. In a functional magnetic resonance imaging experiment, aimed at investigating preattentive, stimulus-driven, auditory segregation mechanisms, naive subjects listened to these stimuli while performing an irrelevant task. Results demonstrate significant activations in the intraparietal sulcus (IPS) and the superior temporal sulcus related to bottom-up, stimulus-driven figure-ground decomposition. We did not observe any significant activation in the primary auditory cortex. Our results support a role for automatic, bottom-up mechanisms in the IPS in mediating stimulus-driven, auditory figure-ground segregation, which is consistent with accumulating evidence implicating the IPS in structuring sensory input and perceptual organization.

CEREBELLAR FUNCTIONS IN TWO TYPES OF PERCEPTUAL TIMING WERE ASSESSED: the absolute (duration-based) timing of single intervals and the relative (beat-based) timing of rhythmic sequences. Continuous transcranial magnetic theta-burst stimulation (cTBS) was applied over the medial cerebellum and performance was measured adaptively before and after stimulation. A large and significant effect was found in the TBS (n = 12) compared to the SHAM (n = 12) group for single-interval timing but not for the detection of a regular beat or a deviation from it. The data support the existence of distinct perceptual timing mechanisms and an obligatory role of the cerebellum in absolute interval timing with a functional dissociation from relative timing of interval within rhythmic sequences based on a regular beat.

Pitch is a fundamental percept with a complex relationship to the associated sound structure. Pitch perception requires brain representation of both the structure of the stimulus and the pitch that is perceived. We describe direct recordings of local field potentials from human auditory cortex made while subjects perceived the transition between noise and a noise with a regular repetitive structure in the time domain at the millisecond level called regular-interval noise (RIN). RIN is perceived to have a pitch when the rate is above the lower limit of pitch, at approximately 30 Hz. Sustained time-locked responses are observed to be related to the temporal regularity of the stimulus, commonly emphasized as a relevant stimulus feature in models of pitch perception (e.g., [1]). Sustained oscillatory responses are also demonstrated in the high gamma range (80-120 Hz). The regularity responses occur irrespective of whether the response is associated with pitch perception. In contrast, the oscillatory responses only occur for pitch. Both responses occur in primary auditory cortex and adjacent nonprimary areas. The research suggests that two types of pitch-related activity occur in humans in early auditory cortex: time-locked neural correlates of stimulus regularity and an oscillatory response related to the pitch percept., (Copyright 2010 Elsevier Ltd. All rights reserved.)

This work tests the hypothesis that the cerebellum is critical to the perception of the timing of sensory events. Auditory tasks were used to assess two types of timing in a group of patients with a stereotyped specific degeneration of the cerebellum: the analysis of single time intervals requiring absolute measurements of time, and the holistic analysis of rhythmic patterns based on relative measures of time using an underlying regular beat. The data support a specific role for the cerebellum only in the absolute timing of single subsecond intervals but not in the relative timing of rhythmic sequences with a regular beat. The findings support the existence of a stopwatch-like cerebellar timing mechanism for absolute intervals that is distinct from mechanisms for entrainment with a regular beat.

Work by Agus and colleagues in this issue of Neuron defines a human mechanism for the rapid learning of novel noises. The noises do not have a verbal label, and are stored accurately for weeks., (Copyright 2010 Elsevier Inc. All rights reserved.)

Congenital amusia (amusia, hereafter) is a developmental disorder that impacts negatively on the perception of music. Psychophysical testing suggests that individuals with amusia have above average thresholds for detection of pitch change and pitch direction discrimination; however, a low-level auditory perceptual problem cannot completely explain the disorder, since discrimination of melodies is also impaired when the constituent intervals are suprathreshold for perception. The aim of the present study was to test pitch memory as a function of (a) time and (b) tonal interference, in order to determine whether pitch traces are inherently weaker in amusic individuals. Memory for the pitch of single tones was compared using two versions of a paradigm developed by Deutsch (1970a). In both tasks, participants compared the pitch of a standard (S) versus a comparison (C) tone. In the time task, the S and C tones were presented, separated in time by 0, 1, 5, 10, and 15 s (blocked presentation). In the interference task, the S and C tones were presented with a fixed time interval (5 s) but with a variable number of irrelevant tones in between 0, 2, 4, 6, and 8 tones (blocked presentation). In the time task, control performance remained high for all time intervals, but amusics showed a performance decrement over time. In the interference task, controls and amusics showed a similar performance decrement with increasing number of irrelevant tones. Overall, the results suggest that the pitch representations of amusic individuals are less stable and more prone to decay than those of matched non-amusic individuals.

Non-human-primate fMRI is becoming increasingly recognised as the missing link between the widely applied methods of human imaging and intracortical animal electrophysiology. A crucial requirement for the optimal application of this method is the precise knowledge of the time course of the Blood Oxygenation Level Dependent (BOLD) signal. We mapped the BOLD signal time course in the inferior colliculus (IC), medial geniculate body (MGB) and in tonotopically defined fields in the auditory cortex of two macaques. The results show little differences in the BOLD-signal time courses within the auditory pathway. However, we observed systematic differences in the magnitude of the change in the BOLD signal with significantly stronger signal changes in field A1 of the auditory cortex compared to field R. The measured time course of the signal was in good agreement with similar studies in human auditory cortex but showed considerable differences to data reported from macaque visual cortex. Consistent with the studies in humans we measured a peak in the BOLD response around 4 s after the onset of 2-s broadband noise stimuli while previous studies recorded from the primary visual cortex of the same species reported the earliest peaks to short visual stimuli several seconds later. The comparison of our results with previous studies does not support differences in haemodynamic responses within the auditory system between human and non-human primates. Furthermore, the data will aid optimal design of future auditory fMRI studies in non-human primates., (Copyright 2009 Elsevier Inc. All rights reserved.)

Auditory object analysis requires two fundamental perceptual processes: the definition of the boundaries between objects, and the abstraction and maintenance of an object's characteristic features. Although it is intuitive to assume that the detection of the discontinuities at an object's boundaries precedes the subsequent precise representation of the object, the specific underlying cortical mechanisms for segregating and representing auditory objects within the auditory scene are unknown. We investigated the cortical bases of these two processes for one type of auditory object, an "acoustic texture," composed of multiple frequency-modulated ramps. In these stimuli, we independently manipulated the statistical rules governing (1) the frequency-time space within individual textures (comprising ramps with a given spectrotemporal coherence) and (2) the boundaries between textures (adjacent textures with different spectrotemporal coherences). Using functional magnetic resonance imaging, we show mechanisms defining boundaries between textures with different coherences in primary and association auditory cortices, whereas texture coherence is represented only in association cortex. Furthermore, participants' superior detection of boundaries across which texture coherence increased (as opposed to decreased) was reflected in a greater neural response in auditory association cortex at these boundaries. The results suggest a hierarchical mechanism for processing acoustic textures that is relevant to auditory object analysis: boundaries between objects are first detected as a change in statistical rules over frequency-time space, before a representation that corresponds to the characteristics of the perceived object is formed.

We understand speech from different speakers with ease, whereas artificial speech recognition systems struggle with this task. It is unclear how the human brain solves this problem. The conventional view is that speech message recognition and speaker identification are two separate functions and that message processing takes place predominantly in the left hemisphere, whereas processing of speaker-specific information is located in the right hemisphere. Here, we distinguish the contribution of specific cortical regions, to speech recognition and speaker information processing, by controlled manipulation of task and resynthesized speaker parameters. Two functional magnetic resonance imaging studies provide evidence for a dynamic speech-processing network that questions the conventional view. We found that speech recognition regions in left posterior superior temporal gyrus/superior temporal sulcus (STG/STS) also encode speaker-related vocal tract parameters, which are reflected in the amplitude peaks of the speech spectrum, along with the speech message. Right posterior STG/STS activated specifically more to a speaker-related vocal tract parameter change during a speech recognition task compared with a voice recognition task. Left and right posterior STG/STS were functionally connected. Additionally, we found that speaker-related glottal fold parameters (e.g., pitch), which are not reflected in the amplitude peaks of the speech spectrum, are processed in areas immediately adjacent to primary auditory cortex, i.e., in areas in the auditory hierarchy earlier than STG/STS. Our results point to a network account of speech recognition, in which information about the speech message and the speaker's vocal tract are combined to solve the difficult task of understanding speech from different speakers.

This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (Wechsler Adult Intelligence Scale-III, Wechsler Memory Scale-III, Delis and Kaplan Executive Function System, Brixton Spatial Anticipation test). The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance.

Background: The Retinal Pigmented Epithelium (RPE) is juxtaposed with the photoreceptor outer segments of the eye. The proximity of the photoreceptor cells is a prerequisite for their survival, as they depend on the RPE to remove the outer segments and are also influenced by RPE cell paracrine factors. RPE cell death can cause a progressive loss of photoreceptor function, which can diminish vision and, over time, blindness ensues. Degeneration of the retina has been shown to induce a variety of retinopathies, such as Stargardt's disease, Cone-Rod Dystrophy (CRD), Retinitis Pigmentosa (RP), Fundus Flavimaculatus (FFM), Best's disease and Age-related Macular Degeneration (AMD). We have cultured primary bovine RPE cells to gain a further understanding of the mechanisms of RPE cell death. One of the cultures, named tRPE, surpassed senescence and was further characterized to determine its viability as a model for retinal diseases., Results: The tRPE cell line has been passaged up to 150 population doublings and was shown to be morphologically similar to primary cells. They have been characterized to be of RPE origin by reverse transcriptase PCR and immunocytochemistry using the RPE-specific genes RPE65 and CRALBP and RPE-specific proteins RPE65 and Bestrophin. The tRPE cells are also immunoreactive to vimentin, cytokeratin and zonula occludens-1 antibodies. Chromosome analysis indicates a normal diploid number. The tRPE cells do not grow in suspension or in soft agar. After 3H thymidine incorporation, the cells do not appear to divide appreciably after confluency., Conclusion: The tRPE cells are immortal, but still exhibit contact inhibition, serum dependence, monolayer growth and secrete an extra-cellular matrix. They retain the in-vivo morphology, gene expression and cell polarity. Additionally, the cells endocytose exogenous melanin, A2E and purified lipofuscin granules. This cell line may be a useful in-vitro research model for retinal maculopathies.

Feeling the beat of a musical piece is easier for some pieces than others, depending on the underlying metrical structure. The present study sought to determine whether increasing metricality, meaning the amount of information supporting an intended meter, would elicit a corresponding increase in the precision of the temporal encoding of rhythmic sequences. Metricality was varied i) by using the Povel and Essens (1985) model of temporal accent induction to create a strong or weak sense of meter and ii) by including metrically plausible (compact) or implausible (open) endings. Precision of temporal encoding as a function of degree of metricality was assessed in an adaptively controlled change detection task. The change to be detected was a perturbation of relative interval timing that affected sequences as a whole rather than at specific points only. Change detection thresholds were significantly lower for sequences featuring a strong compared to a weak meter, and a compact compared to an open ending. Subjective ratings of rhythmicality of sequences also yielded main effects of strength of meter and ending. The data support an increase in the precision of temporal pattern encoding for sequences with a higher-order metrical time framework.

Recent work has shown that responses in first-order sensory thalamic nuclei are modulated by cortical areas. However, the functional role of such corticothalamic modulation and its relevance for human perception is still unclear. Here, we show in two functional magnetic resonance imaging (fMRI) studies that the neuronal response in the first-order auditory thalamus, the medial geniculate body (MGB), is increased when rapidly varying spectrotemporal features of speech sounds are processed, as compared to processing slowly varying spectrotemporal features of the same sounds. The strength of this task-dependent modulation is positively correlated with the speech recognition scores of individual subjects. These results show that task-dependent modulation of the MGB serves the processing of specific features of speech sounds and is behaviorally relevant for speech recognition. Our findings suggest that the first-order auditory thalamus is not simply a nonspecific gatekeeper controlled by attention. Together with studies in nonhuman mammals, our findings imply a mechanism in which the first-order auditory thalamus, possibly by corticothalamic modulation, reacts adaptively to features of sensory input.

Natural sounds contain multiple spectral components that vary over time. The degree of variation can be characterized in terms of correlation between successive time frames of the spectrum, or as a time window within which any two frames show a minimum degree of correlation: the greater the correlation of the spectrum between successive time frames, the longer the time window. Recent studies suggest differences in the encoding of shorter and longer time windows in left and right auditory cortex, respectively. The present functional magnetic resonance imaging study assessed brain activation in response to the systematic variation of the time window in complex spectra that are more similar to natural sounds than in previous studies. The data show bilateral activity in the planum temporale and anterior superior temporal gyrus as a function of increasing time windows, as well as activity in the superior temporal sulcus that was significantly lateralized to the right. The results suggest a coexistence of hierarchical and lateralization schemes for representing increasing time windows in auditory association cortex.

We all know people with tone deafness: these are the people who get thrown out of the choir at school. Although tone deafness is recognised as an output disorder, recent studies have characterised it as one of music perception in the absence of deafness or any associated cognitive disorder. The disorder can therefore be characterised as a form of auditory agnosia. This article considers how the phenotype might be deconstructed to the level of a causal deficit in the perception of pitch pattern. Based on our evolving understanding of the normal brain bases for this process a cortical deficit beyond primary cortex would be predicted. In tone deafness, structural cortical variations have been demonstrated by recent studies that detect subtle changes in the cortical mantle and underlying white matter: these changes are within a right hemisphere network for pitch pattern analysis and working memory for pitch. Studies of multiply affected families are underway to see if the disruption of this network can be caused by single genes. This disorder therefore offers the opportunity to study how a complex phenotype can be characterised as a cortical perceptual disorder potentially explained by a single gene or molecule. Although tone deafness is not pernicious, the underlying abnormality may prove to be a disorder of cortical connectivity that provides a model for disorders that are more so, such as schizophrenia.

Certain sounds, for example, the squeal of chalk on a blackboard, are typically perceived as highly unpleasant. This study addressed the question of what aspects of the auditory representation of such sounds are associated with judgments of unpleasantness. Participants rated the perceived unpleasantness of a large number of sounds that included "griding" and other unpleasant sounds. A multivariate partial least-squares (PLS) model was then built to relate the ratings of unpleasantness with an auditory representation derived from a model of processing in the auditory pathway. The "existence region" of unpleasantness in the auditory space of frequency-temporal modulation was determined after the PLS model had been validated by predicting the unpleasantness of novel sounds from the auditory representation. It was observed that the existence region corresponded to spectral frequencies between 2500 and 5500 Hz, and temporal modulations in the range 1-16 Hz.

Humans use differences in the timing of sounds at the two ears to determine the location of a sound source. Various models have been posited for the neural representation of these interaural time differences (ITDs). These models make opposing predictions about the lateralization of ITD processing in the human brain. The weighted-image model predicts that sounds leading in time at one ear activate maximally the opposite brain hemisphere for all values of ITD. In contrast, the pi-limit model assumes that ITDs beyond half the period of the stimulus center frequency are not explicitly encoded in the brain and that such "long" ITDs activate maximally the side of the brain to which the sound is heard. A previous neuroimaging study revealed activity in the human inferior colliculus consistent with the pi-limit. Here we show that cortical responses to sounds with ITDs within the pi-limit are in line with the predictions of both models. However, contrary to the immediate predictions of both models, neural activation is bilateral for "long" ITDs, despite these being perceived as clearly lateralized. Furthermore, processing of long ITDs leads to higher activation in cortex than processing of short ITDs. These data show that coding of ITD in cortex is fundamentally different from coding of ITD in the brain stem. We discuss these results in the context of the two models.

The visual system is suggested to have two main processing streams, dorsal and ventral, the former being an 'action stream' concerned with motor responses, as opposed to perception. Two recent studies suggest the existence of a comparable mechanism in the auditory system.

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., (Copyright 2007 Wiley-Liss, Inc.)

Pitch patterns, such as melodies, consist of two levels of structure: a global level, comprising the pattern of ups and downs, or contour; and a local level, comprising the precise intervals that make up this contour. An influential neuropsychological model suggests that these two levels of processing are hierarchically linked, with processing of the global structure occurring within the right hemisphere in advance of local processing within the left. However, the predictions of this model and its anatomical basis have not been tested in neurologically normal individuals. The present study used fMRI and required participants to listen to consecutive pitch sequences while performing a same/different one-back task. Sequences, when different, either preserved (local) or violated (global) the contour of the sequence preceding them. When the activations for the local and global conditions were contrasted directly, additional activation was seen for local processing in right planum temporale and posterior superior temporal sulcus (pSTS). The presence of additional activation for local over global processing supports the hierarchical view that the global structure of a pitch sequence acts as a "framework" on which the local detail is subsequently hung. However, the lateralisation of activation seen in the present study, with global processing occurring in left pSTS and local processing occurring bilaterally, differed from that predicted by the neuroanatomical model. A re-examination of the individual lesion data on which the neuroanatomical model is based revealed that the lesion data equally well support the laterality scheme suggested by our data. While the present study supports the hierarchical view of local and global processing, there is an evident need for further research, both in patients and neurologically normal individuals, before an understanding of the functional lateralisation of local and global processing can be considered established.

Speech analysis is a prototypical categorical mechanism that has been examined behaviorally in work going back to Haskins Laboratory studies in the 1950s: such work examined the perception of continua between phonemes and demonstrated sharp discontinuities consistent with categorical perception. In this issue of Neuron, Raizada and Poldrack examine analysis mechanisms for such processing by measurement of the fMRI BOLD response in the boundary region between different phonemes and argue for a specific amplification mechanism for this type of categorical perception.

Congenital amusia (or tone deafness) is a lifelong disorder characterized by impairments in the perception and production of music. A previous voxel-based morphometry (VBM) study revealed that amusic individuals had reduced white matter in the right inferior frontal gyrus (IFG) relative to musically intact controls (Hyde et al., 2006). However, this VBM study also revealed associated increases in gray matter in the same right IFG region of amusics. The objective of the present study was to better understand this morphological brain anomaly by way of cortical thickness measures that provide a more specific measure of cortical morphology relative to VBM. We found that amusic subjects (n = 21) have thicker cortex in the right IFG and the right auditory cortex relative to musically intact controls (n = 26). These cortical thickness differences suggest the presence of cortical malformations in the amusic brain, such as abnormal neuronal migration, that may have compromised the normal development of a right frontotemporal pathway.

The entropy metric derived from information theory provides a means to quantify the amount of information transmitted in acoustic streams like speech or music. By systematically varying the entropy of pitch sequences, we sought brain areas where neural activity and energetic demands increase as a function of entropy. Such a relationship is predicted to occur in an efficient encoding mechanism that uses less computational resource when less information is present in the signal: we specifically tested the hypothesis that such a relationship is present in the planum temporale (PT). In two convergent functional MRI studies, we demonstrated this relationship in PT for encoding, while furthermore showing that a distributed fronto-parietal network for retrieval of acoustic information is independent of entropy. The results establish PT as an efficient neural engine that demands less computational resource to encode redundant signals than those with high information content.

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.

The size of a resonant source can be estimated by the acoustic-scale information in the sound [1-3]. Previous studies revealed that posterior superior temporal gyrus (STG) responds to acoustic scale in human speech when it is controlled for spectral-envelope change (unpublished data). Here we investigate whether the STG activity is specific to the processing of acoustic scale in human voice or whether it reflects a generic mechanism for the analysis of acoustic scale in resonant sources. In two functional magnetic resonance imaging (fMRI) experiments, we measured brain activity in response to changes in acoustic scale in different categories of resonant sound (human voice, animal call, and musical instrument). We show that STG is activated bilaterally for spectral-envelope changes in general; it responds to changes in category as well as acoustic scale. Activity in left posterior STG is specific to acoustic scale in human voices and not responsive to acoustic scale in other resonant sources. In contrast, the anterior temporal lobe and intraparietal sulcus are activated by changes in acoustic scale across categories. The results imply that the human voice requires special processing of acoustic scale, whereas the anterior temporal lobe and intraparietal sulcus process auditory size information independent of source category.

We describe work that addresses the cortical basis for the analysis of auditory objects using 'generic' sounds that do not correspond to any particular events or sources (like vowels or voices) that have semantic association. The experiments involve the manipulation of synthetic sounds to produce systematic changes of stimulus features, such as spectral envelope. Conventional analyses of normal functional imaging data demonstrate that the analysis of spectral envelope and perceived timbral change involves a network consisting of planum temporale (PT) bilaterally and the right superior temporal sulcus (STS). Further analysis of imaging data using dynamic causal modelling (DCM) and Bayesian model selection was carried out in the right hemisphere areas to determine the effective connectivity between these auditory areas. Specifically, the objective was to determine if the analysis of spectral envelope in the network is done in a serial fashion (that is from HG to PT to STS) or parallel fashion (that is PT and STS receives input from HG simultaneously). Two families of models, serial and parallel (16 in total) that represent different hypotheses about the connectivity between HG, PT and STS were selected. The models within a family differ with respect to the pathway that is modulated by the analysis of spectral envelope. After the models are identified, Bayesian model selection procedure is then used to select the 'optimal' model from the specified models. The data strongly support a particular serial model containing modulation of the HG to PT effective connectivity during spectral envelope variation. Parallel work in neurological subjects addresses the effect of lesions to different parts of this network. We have recently studied in detail subjects with 'dystimbria': an alteration in the perceived quality of auditory objects distinct from pitch or loudness change. The subjects have lesions of the normal network described above with normal perception of pitch strength but abnormal perception of the analysis of spectral envelope change.

This work examines the computational architecture used by the brain during the analysis of the spectral envelope of sounds, an important acoustic feature for defining auditory objects. Dynamic causal modelling and Bayesian model selection were used to evaluate a family of 16 network models explaining functional magnetic resonance imaging responses in the right temporal lobe during spectral envelope analysis. The models encode different hypotheses about the effective connectivity between Heschl's Gyrus (HG), containing the primary auditory cortex, planum temporale (PT), and superior temporal sulcus (STS), and the modulation of that coupling during spectral envelope analysis. In particular, we aimed to determine whether information processing during spectral envelope analysis takes place in a serial or parallel fashion. The analysis provides strong support for a serial architecture with connections from HG to PT and from PT to STS and an increase of the HG to PT connection during spectral envelope analysis. The work supports a computational model of auditory object processing, based on the abstraction of spectro-temporal "templates" in the PT before further analysis of the abstracted form in anterior temporal lobe areas.

The study of the brain bases for normal musical listening has advanced greatly in the last 30 years. The evidence from basic and clinical neuroscience suggests that listening to music involves many cognitive components with distinct brain substrates. Using patient cases reported in the literature, we develop an approach for understanding disordered musical listening that is based on the systematic assessment of the perceptual and cognitive analysis of music and its emotional effect. This approach can be applied both to acquired and congenital deficits of musical listening, and to aberrant listening in patients with musical hallucinations. Both the bases for normal musical listening and the clinical assessment of disorders now have a solid grounding in systems neuroscience.

Congenital amusia (or tone deafness) is a lifelong disability that prevents otherwise normal-functioning individuals from developing basic musical skills. Behavioural evidence indicates that congenital amusia is due to a severe deficit in pitch processing, but very little is known about the neural correlates of this condition. The objective of the present study was to investigate the structural neural correlates of congenital amusia. To this aim, voxel-based morphometry was used to detect brain anatomical differences in amusic individuals relative to musically intact controls, by analysing T1-weighted magnetic resonance images from two independent samples of subjects. The results were consistent across samples in highlighting a reduction in white matter concentration in the right inferior frontal gyrus of amusic individuals. This anatomical anomaly was correlated with performance on pitch-based musical tasks. The results are consistent with neuroimaging findings implicating right inferior frontal regions in musical pitch encoding and melodic pitch memory. We conceive the present results as a consequence of an impoverished communication in a right-hemisphere-based network involving the inferior frontal cortex and the right auditory cortex. Moreover, the data point to the integrity of white matter tracts in right frontal brain areas as being key in acquiring normal musical competence.

Interaural time difference (ITD) is a critical cue to sound-source localization. Traditional models assume that sounds leading at one ear, and perceived on that side, are processed in the opposite midbrain. Using functional magnetic resonance imaging we demonstrate that as the ITDs of sounds increase, midbrain activity can switch sides, even though perceived location remains on the same side. The data require a new model for human ITD processing.

The length of a vocal tract is reflected in the sound it is producing. The length of the vocal tract is correlated with body size and humans are very good at making size judgments based on the acoustic effect of vocal tract length only. Here we investigate the underlying mechanism for processing this main auditory cue to size information in the human brain. Sensory encoding of the acoustic effect of vocal tract length (VTL) depends on a time-stabilized spectral scaling mechanism that is independent of glottal pulse rate (GPR, or voice pitch); we provide evidence that a potential neural correlate for such a mechanism exists in the medial geniculate body (MGB). The perception of the acoustic effect of speaker size is influenced by GPR suggesting an interaction between VTL and GPR processing; such an interaction occurs only at the level of non-primary auditory cortex in planum temporale and anterior superior temporal gyrus. Our findings support a two-stage model for the processing of size information in speech based on an initial stage of sensory analysis as early as MGB, and a neural correlate of the perception of source size in non-primary auditory cortex.

In this functional magnetic resonance imaging study, we investigated human brain mechanisms that are involved in the analysis of voices as sound sources and in the pre-semantic analysis of voice information. The source of the voice was altered by changing the speaker, and the salience of the voice was altered by changing the amount of spectrotemporal detail. We identified a mechanism for detecting a change in the source of the voice in the posterior superior temporal lobe and anatomically distinct mechanisms for the detailed analysis of voice information in a bilateral network extending from the posterior to the anterior superior temporal lobe surrounding the superior temporal sulcus. The findings are consistent with a processing hierarchy in which general source attributes are analyzed in the posterior superior temporal lobe, abstraction of voice identity features occurs in posterior superior temporal sulcus, and further analysis of voice information occurs in anterior superior temporal sulcus and higher order cortices in the middle and anterior temporal lobe.

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.

Musically tone-deaf individuals have psychophysical deficits in detecting pitch changes, yet their discrimination of intonation contours in speech appears to be normal. One hypothesis for this dissociation is that intonation contours use coarse pitch contrasts which exceed the pitch-change detection thresholds of tone-deaf individuals (). We test this idea by presenting intonation contours for discrimination, both in the context of the original sentences in which they occur and in a "pure" form dissociated from any phonetic context. The pure form consists of gliding-pitch analogs of the original intonation contours which exactly follow their pattern of pitch and timing. If the spared intonation perception of tone-deaf individuals is due to the coarse pitch contrasts of intonation, then such individuals should discriminate the original sentences and the gliding-pitch analogs equally well. In contrast, we find that discrimination of the gliding-pitch analogs is severely degraded. Thus it appears that the dissociation between spoken and musical pitch perception in tone-deaf individuals is due to a deficit at a higher level than simple pitch-change detection.

Spectral envelope is the shape of the power spectrum of sound. It is an important cue for the identification of sound sources such as voices or instruments, and particular classes of sounds such as vowels. In everyday life, sounds with similar spectral envelopes are perceived as similar: we recognize a voice or a vowel regardless of pitch and intensity variations, and we recognize the same vowel regardless of whether it is voiced (a spectral envelope applied to a harmonic series) or whispered (a spectral envelope applied to noise). In this functional magnetic resonance imaging (fMRI) experiment, we investigated the basis for analysis of spectral envelope by the human brain. Changing either the pitch or the spectral envelope of harmonic sounds produced similar activation within a bilateral network including Heschl's gyrus and adjacent cortical areas in the superior temporal lobe. Changing the spectral envelope of continuously alternating noise and harmonic sounds produced additional right-lateralized activation in superior temporal sulcus (STS). Our findings show that spectral shape is abstracted in superior temporal sulcus, suggesting that this region may have a generic role in the spectral analysis of sounds. These distinct levels of spectral analysis may represent early computational stages in a putative anteriorly directed stream for the categorization of sound.

Objects are the building blocks of experience, but what do we mean by an object? Increasingly, neuroscientists refer to 'auditory objects', yet it is not clear what properties these should possess, how they might be represented in the brain, or how they might relate to the more familiar objects of vision. The concept of an auditory object challenges our understanding of object perception. Here, we offer a critical perspective on the concept and its basis in the brain.

The organization of the cortical auditory system remains controversial. In particular, the extent to which there is regional specialization in the cortical processing of complex sound is unclear. Here, we ask whether we are currently asking the right questions of auditory cortex, or using the appropriate techniques to do so. A key factor that will promote such understanding in the future will be increasing dialogue between workers using electrophysiological recording methods to assess the response properties of single neurons and those using imaging techniques to map regional organization. In the future, further insights will be obtained by efforts to test hypotheses developed on the basis of one approach by the use of the other. Imaging can tell the neurophysiologists where to look, and work on single neurons can constrain network models based on imaging. There is a crucial need for better understanding of the anatomy of the auditory cortex in different species and for comparative studies that will underpin both approaches.

Pitch changes that occur in speech and melodies can be described in terms of contour patterns of rises and falls in pitch and the actual pitches at each point in time. This study investigates whether training can improve the perception of these different features. One group of ten adults trained on a pitch-contour discrimination task, a second group trained on an actual-pitch discrimination task, and a third group trained on a contour comparison task between pitch sequences and their visual analogs. A fourth group did not undergo training. It was found that training on pitch sequence comparison tasks gave rise to improvements in pitch-contour perception. This occurred irrespective of whether the training task required the discrimination of contour patterns or the actual pitch details. In contrast, none of the training tasks were found to improve the perception of the actual pitches in a sequence. The results support psychological models of pitch processing where contour processing is an initial step before actual pitch details are analyzed. Further studies are required to determine whether pitch-contour training is effective in improving speech and melody perception.