Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

Activity-induced gene expression in the human brain.

Activity-induced gene expression underlies synaptic plasticity and brain function. Here, using molecular sequencing techniques, we define activity-dependent transcriptomic and epigenomic changes at the tissue and single-cell level in the human brain following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Genes related to transcriptional regulation and microglia-specific cytokine activity displayed the greatest induction pattern, revealing a precise molecular signature of neuronal activation in the human brain.

A framework and resource for global collaboration in non-human primate neuroscience.

As science and technology evolve, there is an increasing need for promotion of international scientific exchange. Collaborations, while offering substantial opportunities for scientists and benefit to society, also present challenges for those working with animal models, such as non-human primates (NHPs). Diversity in regulation of animal research is sometimes mistaken for the absence of common international welfare standards. Here, the ethical and regulatory protocols for 13 countries that have guidelines in place for biomedical research involving NHPs were assessed with a focus on neuroscience. Review of the variability and similarity in trans-national NHP welfare regulations extended to countries in Asia, Europe and North America. A tabulated resource was established to advance solution-oriented discussions and scientific collaborations across borders. Our aim is to better inform the public and other stakeholders. Through cooperative efforts to identify and analyze information with reference to evidence-based discussion, the proposed key ingredients may help to shape and support a more informed, open framework. This framework and resource can be expanded further for biomedical research in other countries.

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.

Unified ethical principles and an animal research 'Helsinki' declaration as foundations for international collaboration.

Ethical frameworks are the foundation for any research with humans or nonhuman animals. Human research is guided by overarching international ethical principles, such as those defined in the Helsinki Declaration by the World Medical Association. However, for nonhuman animal research, because there are several sets of ethical principles and national frameworks, it is commonly thought that there is substantial variability in animal research approaches internationally and a lack of an animal research 'Helsinki Declaration', or the basis for one. We first overview several prominent sets of ethical principles, including the 3Rs, 3Ss, 3Vs, 4Fs and 6Ps. Then using the 3Rs principles, originally proposed by Russell & Burch, we critically assess them, asking if they can be Replaced, Reduced or Refined. We find that the 3Rs principles have survived several replacement challenges, and the different sets of principles (3Ss, 3Vs, 4Fs and 6Ps) are complementary, a natural refinement of the 3Rs and are ripe for integration into a unified set of principles, as proposed here. We also overview international frameworks and documents, many of which incorporate the 3Rs, including the Basel Declaration on animal research. Finally, we propose that the available animal research guidance documents across countries can be consolidated, to provide a similar structure as seen in the Helsinki Declaration, potentially as part of an amended Basel Declaration on animal research. In summary, we observe substantially greater agreement on and the possibility for unification of the sets of ethical principles and documents that can guide animal research internationally.

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.

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.

Combining brain perturbation and neuroimaging in non-human primates.

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods.

MRI monitoring of macaque monkeys in neuroscience: Case studies, resource and normative data comparisons.

Information from Magnetic Resonance Imaging (MRI) is useful for diagnosis and treatment management of human neurological patients. MRI monitoring might also prove useful for non-human animals involved in neuroscience research provided that MRI is available and feasible and that there are no MRI contra-indications precluding scanning. However, MRI monitoring is not established in macaques and a resource is urgently needed that could grow with scientific community contributions. Here we show the utility and potential benefits of MRI-based monitoring in a few diverse cases with macaque monkeys. We also establish a PRIMatE MRI Monitoring (PRIME-MRM) resource within the PRIMatE Data Exchange (PRIME-DE) and quantitatively compare the cases to normative information drawn from MRI data from typical macaques in PRIME-DE. In the cases, the monkeys presented with no or mild/moderate clinical signs, were well otherwise and MRI scanning did not present a significant increase in welfare impact. Therefore, they were identified as suitable candidates for clinical investigation, MRI-based monitoring and treatment. For each case, we show MRI quantification of internal controls in relation to treatment steps and comparisons with normative data in typical monkeys drawn from PRIME-DE. We found that MRI assists in precise and early diagnosis of cerebral events and can be useful for visualising, treating and quantifying treatment response. The scientific community could now grow the PRIME-MRM resource with other cases and larger samples to further assess and increase the evidence base on the benefits of MRI monitoring of primates, complementing the animals' clinical monitoring and treatment regime.

Common fronto-temporal effective connectivity in humans and monkeys.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

Current Research in Neurobiology, an experimental platform for innovation.

Welcome to Current Research in Neurobiology (CRNEUR), the gold open access, sibling journal to Current Opinion in Neurobiology, a journal for timely original research in neuroscience. At its very core, CRNEUR is a journal for creativity and innovation in science and publishing. As a journal, we ambitiously aim for CRNEUR to be a vehicle for what many of us envisioned an academic journal could be. Empowered by our commitment to fairness and transparency-to hold ourselves and others to a higher standard-here we describe our ambitions for innovation going forward. We need your help in this process and welcome your views via this survey (https://www.surveymonkey.co.uk/r/5LHWTML) and on social media (to start or join a discussion please use the hashtag #CRNEUR).

Protective cranial implant caps for macaques.

BACKGROUND: Neuroscience studies with macaque monkeys may require cranial implants to stabilize the head or gain access to the brain for scientific purposes. Wound management that promotes healing after the cranial implant surgery in non-human primates can be difficult as it is not necessarily possible to cover the wound margins. NEW METHOD: Here, we developed an easily modifiable head cap that protects the sutured skin margins after cranial implant surgery and contributes to wound healing. The protective head cap was developed in response to monkeys picking at sutured skin margins around an implant, complicating healing. The user-friendly protective cap, made from Klarity- R™ Sheet (3.2 mm thick with 36 % or 42 % perforation) is affixed to the implant post-surgically. Once secured and while the monkey is still anesthetized, the plastic sheeting is molded around the implant. The protective head cap restricts the monkey's finger access to its' wound margins while allowing air to circulate to promote wound healing. RESULTS AND COMPARISON WITH EXISTING METHODS: Across two UK primate facilities, the protective head cap promoted wound healing. In monkeys that did not wear the head cap, re-suturing was necessary in ∼30 % of cases. In contrast, none of the monkeys that wore the head cap required re-suturing. The monkeys wearing the head cap also had reduced numbers of days of prescribed antibiotics and analgesia. CONCLUSION: This bespoken, easily adaptable, protective head cap supports postoperative wound healing, and enhances the welfare of monkeys involved in neuroscience research.

Primate auditory prototype in the evolution of the arcuate fasciculus.

The human arcuate fasciculus pathway is crucial for language, interconnecting posterior temporal and inferior frontal areas. Whether a monkey homolog exists is controversial and the nature of human-specific specialization unclear. Using monkey, ape and human auditory functional fields and diffusion-weighted MRI, we identified homologous pathways originating from the auditory cortex. This discovery establishes a primate auditory prototype for the arcuate fasciculus, reveals an earlier phylogenetic origin and illuminates its remarkable transformation.

Editors' Review and Introduction: Learning Grammatical Structures: Developmental, Cross-Species, and Computational Approaches.

Human languages all have a grammar, that is, rules that determine how symbols in a language can be combined to create complex meaningful expressions. Despite decades of research, the evolutionary, developmental, cognitive, and computational bases of grammatical abilities are still not fully understood. "Artificial Grammar Learning" (AGL) studies provide important insights into how rules and structured sequences are learned, the relevance of these processes to language in humans, and whether the cognitive systems involved are shared with other animals. AGL tasks can be used to study how human adults, infants, animals, or machines learn artificial grammars of various sorts, consisting of rules defined typically over syllables, sounds, or visual items. In this introduction, we distill some lessons from the nine other papers in this special issue, which review the advances made from this growing body of literature. We provide a critical synthesis, identify the questions that remain open, and recognize the challenges that lie ahead. A key observation across the disciplines is that the limits of human, animal, and machine capabilities have yet to be found. Thus, this interdisciplinary area of research firmly rooted in the cognitive sciences has unearthed exciting new questions and venues for research, along the way fostering impactful collaborations between traditionally disconnected disciplines that are breaking scientific ground.

Structured Sequence Learning: Animal Abilities, Cognitive Operations, and Language Evolution.

Human language is a salient example of a neurocognitive system that is specialized to process complex dependencies between sensory events distributed in time, yet how this system evolved and specialized remains unclear. Artificial Grammar Learning (AGL) studies have generated a wealth of insights into how human adults and infants process different types of sequencing dependencies of varying complexity. The AGL paradigm has also been adopted to examine the sequence processing abilities of nonhuman animals. We critically evaluate this growing literature in species ranging from mammals (primates and rats) to birds (pigeons, songbirds, and parrots) considering also cross-species comparisons. The findings are contrasted with seminal studies in human infants that motivated the work in nonhuman animals. This synopsis identifies advances in knowledge and where uncertainty remains regarding the various strategies that nonhuman animals can adopt for processing sequencing dependencies. The paucity of evidence in the few species studied to date and the need for follow-up experiments indicate that we do not yet understand the limits of animal sequence processing capacities and thereby the evolutionary pattern. This vibrant, yet still budding, field of research carries substantial promise for advancing knowledge on animal abilities, cognitive substrates, and language evolution.

Structured sequence processing and combinatorial binding: neurobiologically and computationally informed hypotheses.

Understanding how the brain forms representations of structured information distributed in time is a challenging endeavour for the neuroscientific community, requiring computationally and neurobiologically informed approaches. The neural mechanisms for segmenting continuous streams of sensory input and establishing representations of dependencies remain largely unknown, as do the transformations and computations occurring between the brain regions involved in these aspects of sequence processing. We propose a blueprint for a neurobiologically informed and informing computational model of sequence processing (entitled: Vector-symbolic Sequencing of Binding INstantiating Dependencies, or VS-BIND). This model is designed to support the transformation of serially ordered elements in sensory sequences into structured representations of bound dependencies, readily operates on multiple timescales, and encodes or decodes sequences with respect to chunked items wherever dependencies occur in time. The model integrates established vector symbolic additive and conjunctive binding operators with neurobiologically plausible oscillatory dynamics, and is compatible with modern spiking neural network simulation methods. We show that the model is capable of simulating previous findings from structured sequence processing tasks that engage fronto-temporal regions, specifying mechanistic roles for regions such as prefrontal areas 44/45 and the frontal operculum during interactions with sensory representations in temporal cortex. Finally, we are able to make predictions based on the configuration of the model alone that underscore the importance of serial position information, which requires input from time-sensitive cells, known to reside in the hippocampus and dorsolateral prefrontal cortex. This article is part of the theme issue 'Towards mechanistic models of meaning composition'.

The distribution and nature of responses to broadband sounds associated with pitch in the macaque auditory cortex.

The organisation of pitch-perception mechanisms in the primate cortex is controversial, in that divergent results have been obtained, ranging from a single circumscribed 'pitch centre' to systems widely distributed across auditory cortex. Possible reasons for such discrepancies include different species, recording techniques, pitch stimuli, sampling of auditory fields, and the neural metrics recorded. In the present study, we sought to bridge some of these divisions by examining activity related to pitch in both neurons and neuronal ensembles within the auditory cortex of the rhesus macaque, a primate species with similar pitch perception and auditory cortical organisation to humans. We demonstrate similar responses, in primary and non-primary auditory cortex, to two different types of broadband pitch above the macaque lower limit in both neurons and local field potential (LFP) gamma oscillations. The majority of broadband pitch responses in neurons and LFP sites did not show equivalent tuning for sine tones.

Interactions between Conscious and Subconscious Signals: Selective Attention under Feature-Based Competition Increases Neural Selectivity during Brain Adaptation.

Efficient perception in natural environments depends on neural interactions between voluntary processes within cognitive control, such as attention, and those that are automatic and subconscious, such as brain adaptation to predictable input (also called repetition suppression). Although both attention and adaptation have been studied separately and there is considerable knowledge of the neurobiology involved in each of these processes, how attention interacts with adaptation remains equivocal. We examined how attention interacts with visual and auditory adaptation by measuring neuroimaging effects consistent with changes in either neural gain or selectivity. Male and female human participants were scanned with functional magnetic resonance imaging (fMRI) first while they discriminated repetition of morphed faces or voices and either directed their attention to stimulus identity or spatial location. Attention to face or voice identity, while ignoring stimulus location, solely increased the gain of respectively face- or voice-sensitive cortex. The results were strikingly different in an experiment when participants attended to voice identity versus stimulus loudness. In this case, attention to voice while ignoring sound loudness increased neural selectivity. The combined results show that how attention affects adaptation depends on the level of feature-based competition, reconciling prior conflicting observations. The findings are theoretically important and are discussed in relation to neurobiological interactions between attention and different types of predictive signals.SIGNIFICANCE STATEMENT Adaptation to repeated environmental events is ubiquitous in the animal brain, an automatic typically subconscious, predictive signal. Cognitive influences, such as by attention, powerfully affect sensory processing and can overcome brain adaptation. However, how neural interactions occur between adaptation and attention remains controversial. We conducted fMRI experiments regulating the focus of attention during adaptation to repeated stimuli with perceptually balanced stimulus expectancy. We observed an interaction between attention and adaptation consistent with increased neural selectivity, but only under conditions of feature-based competition, challenging the notion that attention interacts with brain adaptation by only affecting response gain. This demonstrates that attention retains its full complement of mechanistic influences on sensory cortex even as it interacts with more automatic or subconscious predictive processes.