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•Combined brain perturbation and neuroimaging can reveal causal brain mechanisms.•Overview of perturbation methods used with non-human primate neuroimaging.•Methodological considerations of the different techniques are discussed.•Translational potential and future directions are laid out and critically assessed. 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.

Environmental contexts serve as powerful cues for episodic memory, allowing humans to recall events tied to specific settings. While rats can learn context-specific associations and temporal order, their ability to manage multiple contexts and rapidly adapt to changes in context remains unclear. This study investigated whether rats could order objects across two distinct contexts. Eight Lister Hooded rats were trained in a dual-context maze, where each context contained a pair of objects. In each trial, rats entered the maze, selected an object, and then re-entered either the same or a different context to complete the trial in the correct temporal order. Six rats successfully learned object order within a single context, but only two reached criterion in the more complex two-context condition. Group error analyses revealed a partial reliance on a procedural learning strategy and a tendency to favour one context, where prior location influenced object selection in subsequent trials. While two rats successfully adapted to the two-context condition beyond these simple strategies, most struggled with context switching, exhibiting perseveration difficulties—a trait also observed in some humans. These findings highlight the evolutionary foundations of context-guided memory and reveal remarkable individual variability in the ability to flexibly navigate multiple contexts.

An evolutionary account of human language as a neurobiological system must distinguish between human-unique neurocognitive processes supporting language and evolutionarily conserved, domain-general processes that can be traced back to our primate ancestors. Neuroimaging studies across species may determine whether candidate neural processes are supported by homologous, functionally conserved brain areas or by different neurobiological substrates. Here we use functional magnetic resonance imaging in Rhesus macaques and humans to examine the brain regions involved in processing the ordering relationships between auditory nonsense words in rule-based sequences. We find that key regions in the human ventral frontal and opercular cortex have functional counterparts in the monkey brain. These regions are also known to be associated with initial stages of human syntactic processing. This study raises the possibility that certain ventral frontal neural systems, which play a significant role in language function in modern humans, originally evolved to support domain-general abilities involved in sequence processing. This study uses functional magnetic resonance imaging in humans and monkeys to show similar ventral frontal and opercular cortical responses when processing sequences of auditory nonsense words. The study indicates that this frontal region is involved in evaluating the order of incoming sounds in a sequence, a process that may be conserved in primates.

Bayesian models describe precision (inverse variance) as a key determinant of perception. However, there is limited evidence on the behavioural effects of precision. The default assumption is that higher precision leads to greater surprise (or perceived change) from otherwise equivalent sensory changes. Four human experiments investigated the influence of precision on perceived salience of systematic changes in auditory stimulus streams. Participants reported Perceived Salience of Change (PSC) in the mean value of Gaussian sequences of pure tones varying in either frequency or intensity, with sequences differing in precision. We hypothesised that PSC, for a particular absolute mean change, would positively correlate with stimulus precision. Surprisingly, we observed multiple instances of the opposite effect, where PSC was rated as higher in low-precision conditions. The conditions under which we found evidence for a counter-Bayesian strategy was under extreme values of individual stimuli within sequences, and mostly in experiments where frequency rather than intensity was the varied parameter. Further scrutiny of the specific conditions for these surprising results showed that low precision could be associated with worsened, unaffected or improved correct reporting of the direction of sound frequency change. These results raise the intriguing possibility that certain circumstances, particularly those characterised by low signal-to-noise, human perception may adopt a counter-Bayesian strategy, and we discuss the potential mechanisms, evolutionary benefits, and clinical implications for future work to further test this falsifiable hypothesis.

•Value of fMRI localizer protocols to NHP & cross-species neuroscience research.•Commonly used or novel localizers within NHPs, & keys implementation criteria.•Open access repository of well-established localizer on PRIME-RE platform. 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.

Learning complex ordering relationships between sensory events in a sequence is fundamental for animal perception and human communication. While it is known that rhythmic sensory events can entrain brain oscillations at different frequencies, how learning and prior experience with sequencing relationships affect neocortical oscillations and neuronal responses is poorly understood. We used an implicit sequence learning paradigm (an \"artificial grammar\") in which humans and monkeys were exposed to sequences of nonsense words with regularities in the ordering relationships between the words. We then recorded neural responses directly from the auditory cortex in both species in response to novel legal sequences or ones violating specific ordering relationships. Neural oscillations in both monkeys and humans in response to the nonsense word sequences show strikingly similar hierarchically nested low-frequency phase and high-gamma amplitude coupling, establishing this form of oscillatory coupling-previously associated with speech processing in the human auditory cortex-as an evolutionarily conserved biological process. Moreover, learned ordering relationships modulate the observed form of neural oscillatory coupling in both species, with temporally distinct neural oscillatory effects that appear to coordinate neuronal responses in the monkeys. This study identifies the conserved auditory cortical neural signatures involved in monitoring learned sequencing operations, evident as modulations of transient coupling and neuronal responses to temporally structured sensory input.

The cerebral cortex displays a bewildering diversity of shapes and sizes across and within species. Despite this diversity, we present a universal multi-scale description of primate cortices. We show that all cortical shapes can be described as a set of nested folds of different sizes. As neighbouring folds are gradually merged, the cortices of 11 primate species follow a common scale-free morphometric trajectory, that also overlaps with over 70 other mammalian species. Our results indicate that all cerebral cortices are approximations of the same archetypal fractal shape with a fractal dimension of d f = 2.5. Importantly, this new understanding enables a more precise quantification of brain morphology as a function of scale. To demonstrate the importance of this new understanding, we show a scale-dependent effect of ageing on brain morphology. We observe a more than fourfold increase in effect size (from two standard deviations to eight standard deviations) at a spatial scale of approximately 2 mm compared to standard morphological analyses. Our new understanding may, therefore, generate superior biomarkers for a range of conditions in the future. Many of the brain’s essential functions – from decision-making to movement – take place in its outer layer known as the cerebral cortex. The shape of the cerebral cortex varies significantly between species. For instance, in humans, it is folded in to grooves and ridges, whereas in other animals, including mice, it is completely smooth. The structure of the cortex can also differ within a species, and be altered by aging and certain diseases. This vast variation can make it difficult it to characterize and compare the structure of the cortex between different species, ages and diseases. To address this, Wang et al. developed a new mathematical model for describing the shape of the cortex. The model uses a method known as coarse graining to erase, or ‘melt away’, any cortical folds or structures smaller than a given threshold size. As this threshold increases, the cortex becomes progressively smoother. The relationship between surface areas and threshold sizes indicates the fractal dimension – that is, how fragmented the cortex is across different scales. Wang et al. applied their model to the brain scans of eleven primates, including humans, and found the fractal dimension of the cortex was almost exactly 2.5 for all eleven species . This suggests that the cortices of the different primates follow a single fractal shape, which means the folds of each cortex have a similar branching pattern. Although there were distinctions between the species, they were mainly due to the different ranges of fold sizes in each cortex. The model revealed that the broader the range of fold sizes, the more folded the brain – but the fractal pattern remains the same. The brain melting method created by Wang et al. provides a new way to characterise cortical shape. Besides revealing a hitherto hidden regularity of nature, they hope that in the future their new method will be useful in assessing brain changes during human development and ageing, and in diseases like Alzheimer’s and epilepsy.

Significance Social animals often combine vocal and facial signals into a coherent percept, despite variable misalignment in the onset of informative audiovisual content. However, whether and how natural misalignments in communication signals affect integrative neuronal responses is unclear, especially for neurons in recently identified temporal voice-sensitive cortex in nonhuman primates, which has been suggested as an animal model for human voice areas. We show striking effects on the excitability of voice-sensitive neurons by the variable misalignment in the onset of audiovisual communication signals. Our results allow us to predict the state of neuronal excitability from the cross-sensory asynchrony in natural communication signals and suggest that the general pattern that we observed would generalize to face-sensitive cortex and certain other brain areas. When social animals communicate, the onset of informative content in one modality varies considerably relative to the other, such as when visual orofacial movements precede a vocalization. These naturally occurring asynchronies do not disrupt intelligibility or perceptual coherence. However, they occur on time scales where they likely affect integrative neuronal activity in ways that have remained unclear, especially for hierarchically downstream regions in which neurons exhibit temporally imprecise but highly selective responses to communication signals. To address this, we exploited naturally occurring face- and voice-onset asynchronies in primate vocalizations. Using these as stimuli we recorded cortical oscillations and neuronal spiking responses from functional MRI (fMRI)-localized voice-sensitive cortex in the anterior temporal lobe of macaques. We show that the onset of the visual face stimulus resets the phase of low-frequency oscillations, and that the face–voice asynchrony affects the prominence of two key types of neuronal multisensory responses: enhancement or suppression. Our findings show a three-way association between temporal delays in audiovisual communication signals, phase-resetting of ongoing oscillations, and the sign of multisensory responses. The results reveal how natural onset asynchronies in cross-sensory inputs regulate network oscillations and neuronal excitability in the voice-sensitive cortex of macaques, a suggested animal model for human voice areas. These findings also advance predictions on the impact of multisensory input on neuronal processes in face areas and other brain regions.

Using high-resolution fMRI in macaque monkeys, the authors demonstrate the existence of a topographic representation for temporal sound properties, which runs from dorsomedial to the ventralateral in the inferior colliculus. This is in addition to a previously reported representation of sound spectral properties (also found here), running approximately perpendicular to the temporal map. 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.

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. The human brain is a distributed system composed of highly interconnected hubs. Here, patients undergoing a rare operation reveal the immediate impact and compensatory brain network changes that occur when a key hub is removed.