Anatomo-functional correspondence in the voice-selective regions of human prefrontal cortex.

Group level analyses of functional regions involved in voice perception show evidence of 3 sets of bilateral voice-sensitive activations in the human prefrontal cortex, named the anterior, middle and posterior Frontal Voice Areas (FVAs). However, the relationship with the underlying sulcal anatomy, highly variable in this region, is still unknown. We examined the inter-individual variability of the FVAs in conjunction with the sulcal anatomy. To do so, anatomical and functional MRI scans from 74 subjects were analyzed to generate individual contrast maps of the FVAs and relate them to each subject's manually labeled prefrontal sulci. We report two major results. First, the frontal activations for the voice are significantly associated with the sulcal anatomy. Second, this correspondence with the sulcal anatomy at the individual level is a better predictor than coordinates in the MNI space. These findings offer new perspectives for the understanding of anatomical-functional correspondences in this complex cortical region. They also shed light on the importance of considering individual-specific variations in subject's anatomy.

A small, but vocal, brain.

In the May issue of Cell Reports, Jafari et al.1 used ultra-high-field fMRI to show that marmosets, like humans and macaques, possess an extensive network of voice-selective areas.

The path of voices in our brain.

Categorising voices is crucial for auditory-based social interactions. A recent study by Rupp and colleagues in PLOS Biology capitalises on human intracranial recordings to describe the spatiotemporal pattern of neural activity leading to voice-selective responses in associative auditory cortex.

Categorization of vocal and nonvocal stimuli in Guinea baboons (Papio papio).

Categorization of vocal sounds apart from other sounds is one of the key abilities in human voice processing, but whether this ability is present in other animals, particularly nonhuman primates, remains unclear. In the present study, 25 socially housed Guinea baboons (Papio papio) were tested on a vocal/nonvocal categorization task using Go/Nogo paradigm implemented on freely accessible automated learning devices. Three individuals from the group successfully learned to sort Grunt vocalizations from nonvocal sounds, and they generalized to new stimuli from the two categories, indicating that some baboons have the ability to develop open-ended categories in the auditory domain. Contrary to our hypothesis based on the human literature, these monkeys learned the nonvocal category faster than the Grunt category. Moreover, they failed to generalize their classification to new classes of conspecific vocalizations (wahoo, bark, yak, and copulation calls), and they categorized human vocalizations in the nonvocal category, suggesting that they had failed to represent the task as a vocal versus nonvocal categorization problem. Thus, our results do not confirm the existence of a separate perceptual category for conspecific vocalizations in baboons. Interestingly, the three successful baboons are the youngest of the group, with less training in visual tasks, which supports previous reports of age and learning history as crucial factors in auditory laboratory experiments.

The Temporal Voice Areas are not "just" Speech Areas.

The Temporal Voice Areas (TVAs) respond more strongly to speech sounds than to non-speech vocal sounds, but does this make them Temporal "Speech" Areas? We provide a perspective on this issue by combining univariate, multivariate, and representational similarity analyses of fMRI activations to a balanced set of speech and non-speech vocal sounds. We find that while speech sounds activate the TVAs more than non-speech vocal sounds, which is likely related to their larger temporal modulations in syllabic rate, they do not appear to activate additional areas nor are they segregated from the non-speech vocal sounds when their higher activation is controlled. It seems safe, then, to continue calling these regions the Temporal Voice Areas.

Functionally homologous representation of vocalizations in the auditory cortex of humans and macaques.

How the evolution of speech has transformed the human auditory cortex compared to other primates remains largely unknown. While primary auditory cortex is organized largely similarly in humans and macaques,1 the picture is much less clear at higher levels of the anterior auditory pathway,2 particularly regarding the processing of conspecific vocalizations (CVs). A "voice region" similar to the human voice-selective areas3,4 has been identified in the macaque right anterior temporal lobe with functional MRI;5 however, its anatomical localization, seemingly inconsistent with that of the human temporal voice areas (TVAs), has suggested a "repositioning of the voice area" in recent human evolution.6 Here we report a functional homology in the cerebral processing of vocalizations by macaques and humans, using comparative fMRI and a condition-rich auditory stimulation paradigm. We find that the anterior temporal lobe of both species possesses cortical voice areas that are bilateral and not only prefer conspecific vocalizations but also implement a representational geometry categorizing them apart from all other sounds in a species-specific but homologous manner. These results reveal a more similar functional organization of higher-level auditory cortex in macaques and humans than currently known.

Cerebellar and Cortical Correlates of Internal and External Speech Error Monitoring.

An event-related functional magnetic resonance imaging study examined how speakers inspect their own speech for errors. Concretely, we sought to assess 1) the role of the temporal cortex in monitoring speech errors, linked with comprehension-based monitoring; 2) the involvement of the cerebellum in internal and external monitoring, linked with forward modeling; and 3) the role of the medial frontal cortex for internal monitoring, linked with conflict-based monitoring. In a word production task priming speech errors, we observed enhanced involvement of the right posterior cerebellum for trials that were correct, but on which participants were more likely to make a word as compared with a nonword error (contrast of internal monitoring). Furthermore, comparing errors to correct utterances (contrast of external monitoring), we observed increased activation of the same cerebellar region, of the superior medial cerebellum, and of regions in temporal and medial frontal cortex. The presence of the cerebellum for both internal and external monitoring indicates the use of forward modeling across the planning and articulation of speech. Dissociations across internal and external monitoring in temporal and medial frontal cortex indicate that monitoring of overt errors is more reliant on vocal feedback control.

Common functional localizers to enhance NHP & cross-species neuroscience imaging research.

Functional localizers are invaluable as they can help define regions of interest, provide cross-study comparisons, and most importantly, allow for the aggregation and meta-analyses of data across studies and laboratories. To achieve these goals within the non-human primate (NHP) imaging community, there is a pressing need for the use of standardized and validated localizers that can be readily implemented across different groups. The goal of this paper is to provide an overview of the value of localizer protocols to imaging research and we describe a number of commonly used or novel localizers within NHPs, and keys to implement them across studies. As has been shown with the aggregation of resting-state imaging data in the original PRIME-DE submissions, we believe that the field is ready to apply the same initiative for task-based functional localizers in NHP imaging. By coming together to collect large datasets across research group, implementing the same functional localizers, and sharing the localizers and data via PRIME-DE, it is now possible to fully test their robustness, selectivity and specificity. To do this, we reviewed a number of common localizers and we created a repository of well-established localizer that are easily accessible and implemented through the PRIME-RE platform.

The representational dynamics of perceived voice emotions evolve from categories to dimensions.

Long-standing affective science theories conceive the perception of emotional stimuli either as discrete categories (for example, an angry voice) or continuous dimensional attributes (for example, an intense and negative vocal emotion). Which position provides a better account is still widely debated. Here we contrast the positions to account for acoustics-independent perceptual and cerebral representational geometry of perceived voice emotions. We combined multimodal imaging of the cerebral response to heard vocal stimuli (using functional magnetic resonance imaging and magneto-encephalography) with post-scanning behavioural assessment of voice emotion perception. By using representational similarity analysis, we find that categories prevail in perceptual and early (less than 200 ms) frontotemporal cerebral representational geometries and that dimensions impinge predominantly on a later limbic-temporal network (at 240 ms and after 500 ms). These results reconcile the two opposing views by reframing the perception of emotions as the interplay of cerebral networks with different representational dynamics that emphasize either categories or dimensions.

FMRI-based identity classification accuracy in left temporal and frontal regions predicts speaker recognition performance.

Speaker recognition is characterized by considerable inter-individual variability with poorly understood neural bases. This study was aimed at (1) clarifying the cerebral correlates of speaker recognition in humans, in particular the involvement of prefrontal areas, using multi voxel pattern analysis (MVPA) applied to fMRI data from a relatively large group of participants, and (2) at investigating the relationship across participants between fMRI-based classification and the group's variable behavioural performance at the speaker recognition task. A cohort of subjects (N = 40, 28 females) selected to present a wide distribution of voice recognition abilities underwent an fMRI speaker identification task during which they were asked to recognize three previously learned speakers with finger button presses. The results showed that speaker identity could be significantly decoded based on fMRI patterns in voice-sensitive regions including bilateral temporal voice areas (TVAs) along the superior temporal sulcus/gyrus but also in bilateral parietal and left inferior frontal regions. Furthermore, fMRI-based classification accuracy showed a significant correlation with individual behavioural performance in left anterior STG/STS and left inferior frontal gyrus. These results highlight the role of both temporal and extra-temporal regions in performing a speaker identity recognition task with motor responses.

Flexizyme-aminoacylated shortened tRNAs demonstrate that only the aminoacylated acceptor arms of the two tRNA substrates are required for cyclodipeptide synthase activity.

Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs (AA-tRNAs) to catalyse cyclodipeptide formation in a ping-pong mechanism. Despite intense studies of these enzymes in past years, the tRNA regions of the two substrates required for CDPS activity are poorly documented, mainly because of two limitations. First, previously studied CDPSs use two identical AA-tRNAs to produce homocyclodipeptides, thus preventing the discriminative study of the binding of the two substrates. Second, the range of tRNA analogues that can be aminoacylated by aminoacyl-tRNA synthetases is limited. To overcome the limitations, we studied a new model CDPS that uses two different AA-tRNAs to produce an heterocyclodipeptide. We also developed a production pipeline for the production of purified shortened AA-tRNA analogues (AA-minitRNAs). This method combines the use of flexizymes to aminoacylate a diversity of minitRNAs and their subsequent purifications by anion-exchange chromatography. Finally, we were able to show that aminoacylated molecules mimicking the entire acceptor arms of tRNAs were as effective a substrate as entire AA-tRNAs, thereby demonstrating that the acceptor arms of the two substrates are the only parts of the tRNAs required for CDPS activity. The method developed in this study should greatly facilitate future investigations of the specificity of CDPSs and of other AA-tRNAs-utilizing enzymes.

Progressive phonagnosia in a telephone operator carrying a C9orf72 expansion.

Selectivity is the rule, rather than the exception, in neurodegenerative disease. A retired telephone operator carrying a C9orf72 expansion developed phonagnosia, a selective impairment of voice recognition, contrasting with intact person knowledge and recognition of faces, as a presenting sign of genetically confirmed fronto-temporal dementia. Since the dysfunction in this patient fell into his area of professional expertise, we discuss if overload in voice related neural networks might have caused failure propagating to connected nodes. The interaction with downstream molecular events, triggered by the C9orf72 expansion, may have led to breakdown at the network level, leading to this specific phenotype.

In vivo characterization of the activities of novel cyclodipeptide oxidases: new tools for increasing chemical diversity of bioproduced 2,5-diketopiperazines in Escherichia coli.

BACKGROUND: Cyclodipeptide oxidases (CDOs) are enzymes involved in the biosynthesis of 2,5-diketopiperazines, a class of naturally occurring compounds with a large range of pharmaceutical activities. CDOs belong to cyclodipeptide synthase (CDPS)-dependent pathways, in which they play an early role in the chemical diversification of cyclodipeptides by introducing Cα-Cß dehydrogenations. Although the activities of more than 100 CDPSs have been determined, the activities of only a few CDOs have been characterized. Furthermore, the assessment of the CDO activities on chemically-synthesized cyclodipeptides has shown these enzymes to be relatively promiscuous, making them interesting tools for cyclodipeptide chemical diversification. The purpose of this study is to provide the first completely microbial toolkit for the efficient bioproduction of a variety of dehydrogenated 2,5-diketopiperazines. RESULTS: We mined genomes for CDOs encoded in biosynthetic gene clusters of CDPS-dependent pathways and selected several for characterization. We co-expressed each with their associated CDPS in the pathway using Escherichia coli as a chassis and showed that the cyclodipeptides and the dehydrogenated derivatives were produced in the culture supernatants. We determined the biological activities of the six novel CDOs by solving the chemical structures of the biologically produced dehydrogenated cyclodipeptides. Then, we assessed the six novel CDOs plus two previously characterized CDOs in combinatorial engineering experiments in E. coli. We co-expressed each of the eight CDOs with each of 18 CDPSs selected for the diversity of cyclodipeptides they synthesize. We detected more than 50 dehydrogenated cyclodipeptides and determined the best CDPS/CDO combinations to optimize the production of 23. CONCLUSIONS: Our study establishes the usefulness of CDPS and CDO for the bioproduction of dehydrogenated cyclodipeptides. It constitutes the first step toward the bioproduction of more complex and diverse 2,5-diketopiperazines.

The perception of caricatured emotion in voice.

Affective vocalisations such as screams and laughs can convey strong emotional content without verbal information. Previous research using morphed vocalisations (e.g. 25% fear/75% anger) has revealed categorical perception of emotion in voices, showing sudden shifts at emotion category boundaries. However, it is currently unknown how further modulation of vocalisations beyond the veridical emotion (e.g. 125% fear) affects perception. Caricatured facial expressions produce emotions that are perceived as more intense and distinctive, with faster recognition relative to the original and anti-caricatured (e.g. 75% fear) emotions, but a similar effect using vocal caricatures has not been previously examined. Furthermore, caricatures can play a key role in assessing how distinctiveness is identified, in particular by evaluating accounts of emotion perception with reference to prototypes (distance from the central stimulus) and exemplars (density of the stimulus space). Stimuli consisted of four emotions (anger, disgust, fear, and pleasure) morphed at 25% intervals between a neutral expression and each emotion from 25% to 125%, and between each pair of emotions. Emotion perception was assessed using emotion intensity ratings, valence and arousal ratings, speeded categorisation and paired similarity ratings. We report two key findings: 1) across tasks, there was a strongly linear effect of caricaturing, with caricatured emotions (125%) perceived as higher in emotion intensity and arousal, and recognised faster compared to the original emotion (100%) and anti-caricatures (25%-75%); 2) our results reveal evidence for a unique contribution of a prototype-based account in emotion recognition. We show for the first time that vocal caricature effects are comparable to those found previously with facial caricatures. The set of caricatured vocalisations provided open a promising line of research for investigating vocal affect perception and emotion processing deficits in clinical populations.

Single-trial fMRI activation maps measured during the InterTVA event-related voice localizer. A data set ready for inter-subject pattern analysis.

Multivariate pattern analysis (MVPA) of functional neuroimaging data has emerged as a key tool for studying the cognitive architecture of the human brain. At the group level, we have recently demonstrated the advantages of an under-exploited scheme that consists in training a machine learning model on data from a set of subjects and evaluating its generalization ability on data from unseen subjects (see Inter-subject pattern analysis: A straightforward and powerful scheme for group-level MVPA [1]). We here provide a data set that is fully ready to perform inter-subject pattern analysis, which includes 5616 single-trial brain activation maps recorded in 39 participants who were scanned using functional magnetic resonance imaging (fMRI) with a voice localizer paradigm. This data set should therefore reveal valuable for data scientists developing brain decoding algorithms as well as cognitive neuroscientists interested in voice perception.

Cyclodipeptide synthases: a promising biotechnological tool for the synthesis of diverse 2,5-diketopiperazines.

Covering: Up to mid-2019 Cyclodipeptide synthases (CDPSs) catalyse the formation of cyclodipeptides using aminoacylated-tRNA as substrates. The recent characterization of large sets of CDPSs has revealed that they can produce highly diverse products, and therefore have great potential for use in the production of different 2,5-diketopiperazines (2,5-DKPs). Sequence similarity networks (SSNs) are presented as a new, efficient way of classifying CDPSs by specificity and identifying new CDPS likely to display novel specificities. Several strategies for further increasing the diversity accessible with these enzymes are discussed here, including the incorporation of non-canonical amino acids by CDPSs and use of the remarkable diversity of 2,5-DKP-tailoring enzymes discovered in recent years.

Exploring the cerebral substrate of voice perception in primate brains.

One can consider human language to be the Swiss army knife of the vast domain of animal communication. There is now growing evidence suggesting that this technology may have emerged from already operational material instead of being a sudden innovation. Sharing ideas and thoughts with conspecifics via language constitutes an amazing ability, but what value would it hold if our conspecifics were not first detected and recognized? Conspecific voice (CV) perception is fundamental to communication and widely shared across the animal kingdom. Two questions that arise then are: is this apparently shared ability reflected in common cerebral substrate? And, how has this substrate evolved? The paper addresses these questions by examining studies on the cerebral basis of CV perception in humans' closest relatives, non-human primates. Neuroimaging studies, in particular, suggest the existence of a 'voice patch system', a network of interconnected cortical areas that can provide a common template for the cerebral processing of CV in primates. This article is part of the theme issue 'What can animal communication teach us about human language?'

Neural oscillations in human auditory cortex revealed by fast fMRI during auditory perception.

Previous work pointed to the neural and functional significance of infraslow neural oscillations below 1 â€‹Hz that can be detected and precisely located with fast functional magnetic resonance imaging (fMRI). While previous work demonstrated this significance for brain dynamics during very low-level sensory stimulation, we here provide the first evidence for the detectability and functional significance of infraslow oscillatory blood oxygenation level-dependent (BOLD) responses to auditory stimulation by the sociobiological relevant and more complex category of voices. Previous work pointed to a specific area of the mammalian auditory cortex (AC) that is sensitive to vocal signals as quantified by activation levels. Here we show, by using fast fMRI, that the human voice-sensitive AC prioritizes vocal signals not only in terms of activity level but also in terms of specific infraslow BOLD oscillations. We found unique sustained and transient oscillatory BOLD patterns in the AC for vocal signals. For transient oscillatory patterns, vocal signals showed faster peak oscillatory responses across all AC regions. Furthermore, we identified an exclusive sustained oscillatory component for vocal signals in the primary AC. Fast fMRI thus demonstrates the significance and richness of infraslow BOLD oscillations for neurocognitive mechanisms in social cognition as demonstrated here for the sociobiological relevance of voice processing.

Study of bicyclomycin biosynthesis in Streptomyces cinnamoneus by genetic and biochemical approaches.

The 2,5-Diketopiperazines (DKPs) constitute a large family of natural products with important biological activities. Bicyclomycin is a clinically-relevant DKP antibiotic that is the first and only member in a class known to target the bacterial transcription termination factor Rho. It derives from cyclo-(L-isoleucyl-L-leucyl) and has an unusual and highly oxidized bicyclic structure that is formed by an ether bridge between the hydroxylated terminal carbon atom of the isoleucine lateral chain and the alpha carbon of the leucine in the diketopiperazine ring. Here, we paired in vivo and in vitro studies to complete the characterization of the bicyclomycin biosynthetic gene cluster. The construction of in-frame deletion mutants in the biosynthetic gene cluster allowed for the accumulation and identification of biosynthetic intermediates. The identity of the intermediates, which were reproduced in vitro using purified enzymes, allowed us to characterize the pathway and corroborate previous reports. Finally, we show that the putative antibiotic transporter was dispensable for the producing strain.

Author Correction: Reprogramming Escherichia coli for the production of prenylated indole diketopiperazine alkaloids.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.