Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

The Representation of Time Windows in Primate Auditory Cortex.

Whether human and nonhuman primates process the temporal dimension of sound similarly remains an open question. We examined the brain basis for the processing of acoustic time windows in rhesus macaques using stimuli simulating the spectrotemporal complexity of vocalizations. We conducted functional magnetic resonance imaging in awake macaques to identify the functional anatomy of response patterns to different time windows. We then contrasted it against the responses to identical stimuli used previously in humans. Despite a similar overall pattern, ranging from the processing of shorter time windows in core areas to longer time windows in lateral belt and parabelt areas, monkeys exhibited lower sensitivity to longer time windows than humans. This difference in neuronal sensitivity might be explained by a specialization of the human brain for processing longer time windows in speech.

Neuronal figure-ground responses in primate primary auditory cortex.

Figure-ground segregation, the brain's ability to group related features into stable perceptual entities, is crucial for auditory perception in noisy environments. The neuronal mechanisms for this process are poorly understood in the auditory system. Here, we report figure-ground modulation of multi-unit activity (MUA) in the primary and non-primary auditory cortex of rhesus macaques. Across both regions, MUA increases upon presentation of auditory figures, which consist of coherent chord sequences. We show increased activity even in the absence of any perceptual decision, suggesting that neural mechanisms for perceptual grouping are, to some extent, independent of behavioral demands. Furthermore, we demonstrate differences in figure encoding between more anterior and more posterior regions; perceptual saliency is represented in anterior cortical fields only. Our results suggest an encoding of auditory figures from the earliest cortical stages by a rate code.

Reward cues readily direct monkeys' auditory performance resulting in broad auditory cortex modulation and interaction with sites along cholinergic and dopaminergic pathways.

In natural settings, the prospect of reward often influences the focus of our attention, but how cognitive and motivational systems influence sensory cortex is not well understood. Also, challenges in training nonhuman animals on cognitive tasks complicate cross-species comparisons and interpreting results on the neurobiological bases of cognition. Incentivized attention tasks could expedite training and evaluate the impact of attention on sensory cortex. Here we develop an Incentivized Attention Paradigm (IAP) and use it to show that macaque monkeys readily learn to use auditory or visual reward cues, drastically influencing their performance within a simple auditory task. Next, this paradigm was used with functional neuroimaging to measure activation modulation in the monkey auditory cortex. The results show modulation of extensive auditory cortical regions throughout primary and non-primary regions, which although a hallmark of attentional modulation in human auditory cortex, has not been studied or observed as broadly in prior data from nonhuman animals. Psycho-physiological interactions were identified between the observed auditory cortex effects and regions including basal forebrain sites along acetylcholinergic and dopaminergic pathways. The findings reveal the impact and regional interactions in the primate brain during an incentivized attention engaging auditory task.

Auditory figure-ground analysis in rostral belt and parabelt of the macaque monkey.

Segregating the key features of the natural world within crowded visual or sound scenes is a critical aspect of everyday perception. The neurobiological bases for auditory figure-ground segregation are poorly understood. We demonstrate that macaques perceive an acoustic figure-ground stimulus with comparable performance to humans using a neural system that involves high-level auditory cortex, localised to the rostral belt and parabelt.

Auditory and Visual Sequence Learning in Humans and Monkeys using an Artificial Grammar Learning Paradigm.

Language flexibly supports the human ability to communicate using different sensory modalities, such as writing and reading in the visual modality and speaking and listening in the auditory domain. Although it has been argued that nonhuman primate communication abilities are inherently multisensory, direct behavioural comparisons between human and nonhuman primates are scant. Artificial grammar learning (AGL) tasks and statistical learning experiments can be used to emulate ordering relationships between words in a sentence. However, previous comparative work using such paradigms has primarily investigated sequence learning within a single sensory modality. We used an AGL paradigm to evaluate how humans and macaque monkeys learn and respond to identically structured sequences of either auditory or visual stimuli. In the auditory and visual experiments, we found that both species were sensitive to the ordering relationships between elements in the sequences. Moreover, the humans and monkeys produced largely similar response patterns to the visual and auditory sequences, indicating that the sequences are processed in comparable ways across the sensory modalities. These results provide evidence that human sequence processing abilities stem from an evolutionarily conserved capacity that appears to operate comparably across the sensory modalities in both human and nonhuman primates. The findings set the stage for future neurobiological studies to investigate the multisensory nature of these sequencing operations in nonhuman primates and how they compare to related processes in humans.

Artificial grammar learning in vascular and progressive non-fluent aphasias.

Patients with non-fluent aphasias display impairments of expressive and receptive grammar. This has been attributed to deficits in processing configurational and hierarchical sequencing relationships. This hypothesis had not been formally tested. It was also controversial whether impairments are specific to language, or reflect domain general deficits in processing structured auditory sequences. Here we used an artificial grammar learning paradigm to compare the abilities of controls to participants with agrammatic aphasia of two different aetiologies: stroke and frontotemporal dementia. Ten patients with non-fluent variant primary progressive aphasia (nfvPPA), 12 with non-fluent aphasia due to stroke, and 11 controls implicitly learned a novel mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships. We compared response profiles for otherwise identical sequences of speech tokens (nonsense words) and tone sweeps. In all three groups the ability to detect grammatical violations varied with sequence complexity, with performance improving over time and being better for adjacent than non-adjacent relationships. Patients performed less well than controls overall, and this was related more strongly to aphasia severity than to aetiology. All groups improved with practice and performed well at a control task of detecting oddball nonwords. Crucially, group differences did not interact with sequence complexity, demonstrating that aphasic patients were not disproportionately impaired on complex structures. Hierarchical cluster analysis revealed that response patterns were very similar across all three groups, but very different between the nonsense word and tone tasks, despite identical artificial grammar structures. Overall, we demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently. The similarity of profiles of discriminatory abilities and rule learning across groups suggests that insights from previous studies of implicit sequence learning in vascular aphasia are likely to prove applicable in nfvPPA.

Functional Imaging of Audio-Visual Selective Attention in Monkeys and Humans: How do Lapses in Monkey Performance Affect Cross-Species Correspondences?

The cross-species correspondences and differences in how attention modulates brain responses in humans and animal models are poorly understood. We trained 2 monkeys to perform an audio-visual selective attention task during functional magnetic resonance imaging (fMRI), rewarding them to attend to stimuli in one modality while ignoring those in the other. Monkey fMRI identified regions strongly modulated by auditory or visual attention. Surprisingly, auditory attention-related modulations were much more restricted in monkeys than humans performing the same tasks during fMRI. Further analyses ruled out trivial explanations, suggesting that labile selective-attention performance was associated with inhomogeneous modulations in wide cortical regions in the monkeys. The findings provide initial insights into how audio-visual selective attention modulates the primate brain, identify sources for "lost" attention effects in monkeys, and carry implications for modeling the neurobiology of human cognition with nonhuman animals.

Evolutionary origins of non-adjacent sequence processing in primate brain potentials.

There is considerable interest in understanding the ontogeny and phylogeny of the human language system, yet, neurobiological work at the interface of both fields is absent. Syntactic processes in language build on sensory processing and sequencing capabilities on the side of the receiver. While we better understand language-related ontogenetic changes in the human brain, it remains a mystery how neurobiological processes at specific human development stages compare with those in phylogenetically closely related species. To address this knowledge gap, we measured EEG event-related potentials (ERPs) in two macaque monkeys using a paradigm developed to evaluate human infant and adult brain potentials associated with the processing of non-adjacent ordering relationships in sequences of syllable triplets. Frequent standard triplet sequences were interspersed with infrequent voice pitch or non-adjacent rule deviants. Monkey ERPs show early pitch and rule deviant mismatch responses that are strikingly similar to those previously reported in human infants. This stands in contrast to adults' later ERP responses for rule deviants. The results reveal how non-adjacent sequence ordering relationships are processed in the primate brain and provide evidence for evolutionarily conserved neurophysiological effects, some of which are remarkably like those seen at an early human developmental stage.

Individually customisable non-invasive head immobilisation system for non-human primates with an option for voluntary engagement.

BACKGROUND: Head immobilisation is often necessary for neuroscientific procedures. A number of Non-invasive Head Immobilisation Systems (NHIS) for monkeys are available, but the need remains for a feasible integrated system combining a broad range of essential features. NEW METHOD: We developed an individualised macaque NHIS addressing several animal welfare and scientific needs. The system comprises a customised-to-fit facemask that can be used separately or combined with a back piece to form a full-head helmet. The system permits presentation of visual and auditory stimuli during immobilisation and provides mouth access for reward. RESULTS: The facemask was incorporated into an automated voluntary training system, allowing the animals to engage with it for increasing periods leading to full head immobilisation. We evaluated the system during performance on several auditory or visual behavioural tasks with testing sessions lasting 1.5-2h, used thermal imaging to monitor for and prevent pressure points, and measured head movement using MRI. COMPARISON WITH EXISTING METHODS: A comprehensive evaluation of the system is provided in relation to several scientific and animal welfare requirements. Behavioural results were often comparable to those obtained with surgical implants. Cost-benefit analyses were conducted comparing the system with surgical options, highlighting the benefits of implementing the non-invasive option. CONCLUSIONS: The system has a number of potential applications and could be an important tool in neuroscientific research, when direct access to the brain for neuronal recordings is not required, offering the opportunity to conduct non-invasive experiments while improving animal welfare and reducing reliance on surgically implanted head posts.

Who is That? Brain Networks and Mechanisms for Identifying Individuals.

Social animals can identify conspecifics by many forms of sensory input. However, whether the neuronal computations that support this ability to identify individuals rely on modality-independent convergence or involve ongoing synergistic interactions along the multiple sensory streams remains controversial. Direct neuronal measurements at relevant brain sites could address such questions, but this requires better bridging the work in humans and animal models. Here, we overview recent studies in nonhuman primates on voice and face identity-sensitive pathways and evaluate the correspondences to relevant findings in humans. This synthesis provides insights into converging sensory streams in the primate anterior temporal lobe (ATL) for identity processing. Furthermore, we advance a model and suggest how alternative neuronal mechanisms could be tested.

EEG potentials associated with artificial grammar learning in the primate brain.

Electroencephalography (EEG) has identified human brain potentials elicited by Artificial Grammar (AG) learning paradigms, which present participants with rule-based sequences of stimuli. Nonhuman animals are sensitive to certain AGs; therefore, evaluating which EEG Event Related Potentials (ERPs) are associated with AG learning in nonhuman animals could identify evolutionarily conserved processes. We recorded EEG potentials during an auditory AG learning experiment in two Rhesus macaques. The animals were first exposed to sequences of nonsense words generated by the AG. Then surface-based ERPs were recorded in response to sequences that were 'consistent' with the AG and 'violation' sequences containing illegal transitions. The AG violations strongly modulated an early component, potentially homologous to the Mismatch Negativity (mMMN), a P200 and a late frontal positivity (P500). The macaque P500 is similar in polarity and time of occurrence to a late EEG positivity reported in human AG learning studies but might differ in functional role.

Parcellation of Human and Monkey Core Auditory Cortex with fMRI Pattern Classification and Objective Detection of Tonotopic Gradient Reversals.

Auditory cortex (AC) contains several primary-like, or "core," fields, which receive thalamic input and project to non-primary "belt" fields. In humans, the organization and layout of core and belt auditory fields are still poorly understood, and most auditory neuroimaging studies rely on macroanatomical criteria, rather than functional localization of distinct fields. A myeloarchitectonic method has been suggested recently for distinguishing between core and belt fields in humans (Dick F, Tierney AT, Lutti A, Josephs O, Sereno MI, Weiskopf N. 2012. In vivo functional and myeloarchitectonic mapping of human primary auditory areas. J Neurosci. 32:16095-16105). We propose a marker for core AC based directly on functional magnetic resonance imaging (fMRI) data and pattern classification. We show that a portion of AC in Heschl's gyrus classifies sound frequency more accurately than other regions in AC. Using fMRI data from macaques, we validate that the region where frequency classification performance is significantly above chance overlaps core auditory fields, predominantly A1. Within this region, we measure tonotopic gradients and estimate the locations of the human homologues of the core auditory subfields A1 and R. Our results provide a functional rather than anatomical localizer for core AC. We posit that inter-individual variability in the layout of core AC might explain disagreements between results from previous neuroimaging and cytological studies.

Auditory and visual modulation of temporal lobe neurons in voice-sensitive and association cortices.

Effective interactions between conspecific individuals can depend upon the receiver forming a coherent multisensory representation of communication signals, such as merging voice and face content. Neuroimaging studies have identified face- or voice-sensitive areas (Belin et al., 2000; Petkov et al., 2008; Tsao et al., 2008), some of which have been proposed as candidate regions for face and voice integration (von Kriegstein et al., 2005). However, it was unclear how multisensory influences occur at the neuronal level within voice- or face-sensitive regions, especially compared with classically defined multisensory regions in temporal association cortex (Stein and Stanford, 2008). Here, we characterize auditory (voice) and visual (face) influences on neuronal responses in a right-hemisphere voice-sensitive region in the anterior supratemporal plane (STP) of Rhesus macaques. These results were compared with those in the neighboring superior temporal sulcus (STS). Within the STP, our results show auditory sensitivity to several vocal features, which was not evident in STS units. We also newly identify a functionally distinct neuronal subpopulation in the STP that appears to carry the area's sensitivity to voice identity related features. Audiovisual interactions were prominent in both the STP and STS. However, visual influences modulated the responses of STS neurons with greater specificity and were more often associated with congruent voice-face stimulus pairings than STP neurons. Together, the results reveal the neuronal processes subserving voice-sensitive fMRI activity patterns in primates, generate hypotheses for testing in the visual modality, and clarify the position of voice-sensitive areas within the unisensory and multisensory processing hierarchies.

Auditory artificial grammar learning in macaque and marmoset monkeys.

Artificial grammars (AG) are designed to emulate aspects of the structure of language, and AG learning (AGL) paradigms can be used to study the extent of nonhuman animals' structure-learning capabilities. However, different AG structures have been used with nonhuman animals and are difficult to compare across studies and species. We developed a simple quantitative parameter space, which we used to summarize previous nonhuman animal AGL results. This was used to highlight an under-studied AG with a forward-branching structure, designed to model certain aspects of the nondeterministic nature of word transitions in natural language and animal song. We tested whether two monkey species could learn aspects of this auditory AG. After habituating the monkeys to the AG, analysis of video recordings showed that common marmosets (New World monkeys) differentiated between well formed, correct testing sequences and those violating the AG structure based primarily on simple learning strategies. By comparison, Rhesus macaques (Old World monkeys) showed evidence for deeper levels of AGL. A novel eye-tracking approach confirmed this result in the macaques and demonstrated evidence for more complex AGL. This study provides evidence for a previously unknown level of AGL complexity in Old World monkeys that seems less evident in New World monkeys, which are more distant evolutionary relatives to humans. The findings allow for the development of both marmosets and macaques as neurobiological model systems to study different aspects of AGL at the neuronal level.

Voice cells in the primate temporal lobe.

Communication signals are important for social interactions and survival and are thought to receive specialized processing in the visual and auditory systems. Whereas the neural processing of faces by face clusters and face cells has been repeatedly studied [1-5], less is known about the neural representation of voice content. Recent functional magnetic resonance imaging (fMRI) studies have localized voice-preferring regions in the primate temporal lobe [6, 7], but the hemodynamic response cannot directly assess neurophysiological properties. We investigated the responses of neurons in an fMRI-identified voice cluster in awake monkeys, and here we provide the first systematic evidence for voice cells. "Voice cells" were identified, in analogy to "face cells," as neurons responding at least 2-fold stronger to conspecific voices than to "nonvoice" sounds or heterospecific voices. Importantly, whereas face clusters are thought to contain high proportions of face cells [4] responding broadly to many faces [1, 2, 4, 5, 8-10], we found that voice clusters contain moderate proportions of voice cells. Furthermore, individual voice cells exhibit high stimulus selectivity. The results reveal the neurophysiological bases for fMRI-defined voice clusters in the primate brain and highlight potential differences in how the auditory and visual systems generate selective representations of communication signals.

Orthogonal representation of sound dimensions in the primate midbrain.

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.

Evolutionary conservation and neuronal mechanisms of auditory perceptual restoration.

Auditory perceptual 'restoration' occurs when the auditory system restores an occluded or masked sound of interest. Behavioral work on auditory restoration in humans began over 50 years ago using it to model a noisy environmental scene with competing sounds. It has become clear that not only humans experience auditory restoration: restoration has been broadly conserved in many species. Behavioral studies in humans and animals provide a necessary foundation to link the insights being obtained from human EEG and fMRI to those from animal neurophysiology. The aggregate of data resulting from multiple approaches across species has begun to clarify the neuronal bases of auditory restoration. Different types of neural responses supporting restoration have been found, supportive of multiple mechanisms working within a species. Yet a general principle has emerged that responses correlated with restoration mimic the response that would have been given to the uninterrupted sound of interest. Using the same technology to study different species will help us to better harness animal models of 'auditory scene analysis' to clarify the conserved neural mechanisms shaping the perceptual organization of sound and to advance strategies to improve hearing in natural environmental settings.

Multisensory interactions in primate auditory cortex: fMRI and electrophysiology.

Recent studies suggest that multisensory integration does not only occur in higher association cortices but also at early stages of auditory processing, possibly in primary or secondary auditory cortex. Support for such early multisensory influences comes from functional magnetic resonance imaging experiments in humans and monkeys. However we argue that the current understanding of neurovascular coupling and of the neuronal basis underlying the imaging signal does not permit the direct extrapolation from imaging data to properties of neurons in the same region. While imaging can guide subsequent electrophysiological studies, only these can determine whether and how neurons in auditory cortices combine information from multiple modalities. Indeed, electrophysiological studies only partly confirm the findings from imaging studies. While recordings of field potentials reveal strong influences of visual or somatosensory stimulation on synaptic activity even in primary auditory cortex, single unit studies find only a small minority of neurons as being influenced by non-acoustic stimuli. We propose the analysis of the information coding properties of individual neurons as one way to quantitatively determine whether the representation of our acoustic environment in (primary) auditory cortex indeed benefits from multisensory input.

A voice region in the monkey brain.

For vocal animals, recognizing species-specific vocalizations is important for survival and social interactions. In humans, a voice region has been identified that is sensitive to human voices and vocalizations. As this region also strongly responds to speech, it is unclear whether it is tightly associated with linguistic processing and is thus unique to humans. Using functional magnetic resonance imaging of macaque monkeys (Old World primates, Macaca mulatta) we discovered a high-level auditory region that prefers species-specific vocalizations over other vocalizations and sounds. This region not only showed sensitivity to the 'voice' of the species, but also to the vocal identify of conspecific individuals. The monkey voice region is located on the superior-temporal plane and belongs to an anterior auditory 'what' pathway. These results establish functional relationships with the human voice region and support the notion that, for different primate species, the anterior temporal regions of the brain are adapted for recognizing communication signals from conspecifics.