Differential functional organization of amygdala-medial prefrontal cortex networks in macaque and human.

Over the course of evolution, the amygdala (AMG) and medial frontal cortex (mPFC) network, involved in behavioral adaptation, underwent structural changes in the old-world monkey and human lineages. Yet, whether and how the functional organization of this network differs remains poorly understood. Using resting-state functional magnetic resonance imagery, we show that the functional connectivity (FC) between AMG nuclei and mPFC regions differs between humans and awake macaques. In humans, the AMG-mPFC FC displays U-shaped pattern along the corpus callosum: a positive FC with the ventromedial prefrontal (vmPFC) and anterior cingulate cortex (ACC), a negative FC with the anterior mid-cingulate cortex (MCC), and a positive FC with the posterior MCC. Conversely, in macaques, the negative FC shifted more ventrally at the junction between the vmPFC and the ACC. The functional organization divergence of AMG-mPFC network between humans and macaques might help understanding behavioral adaptation abilities differences in their respective socio-ecological niches.

The relevance of the unique anatomy of the human prefrontal operculum to the emergence of speech.

Identifying the evolutionary origins of human speech remains a topic of intense scientific interest. Here we describe a unique feature of adult human neuroanatomy compared to chimpanzees and other primates that may provide an explanation of changes that occurred to enable the capacity for speech. That feature is the Prefrontal extent of the Frontal Operculum (PFOp) region, which is located in the ventrolateral prefrontal cortex, adjacent and ventromedial to the classical Broca's area. We also show that, in chimpanzees, individuals with the most human-like PFOp, particularly in the left hemisphere, have greater oro-facial and vocal motor control abilities. This critical discovery, when combined with recent paleontological evidence, suggests that the PFOp is a recently evolved feature of human cortical structure (perhaps limited to the genus Homo) that emerged in response to increasing selection for cognitive and motor functions evident in modern speech abilities.

A revised perspective on the evolution of the lateral frontal cortex in primates.

Detailed neuroscientific data from macaque monkeys have been essential in advancing understanding of human frontal cortex function, particularly for regions of frontal cortex without homologs in other model species. However, precise transfer of this knowledge for direct use in human applications requires an understanding of monkey to hominid homologies, particularly whether and how sulci and cytoarchitectonic regions in the frontal cortex of macaques relate to those in hominids. We combine sulcal pattern analysis with resting-state functional magnetic resonance imaging and cytoarchitectonic analysis to show that old-world monkey brains have the same principles of organization as hominid brains, with the notable exception of sulci in the frontopolar cortex. This essential comparative framework provides insights into primate brain evolution and a key tool to drive translation from invasive research in monkeys to human applications.

Frontal cortical functional connectivity is impacted by anaesthesia in macaques.

A critical aspect of neuroscience is to establish whether and how brain networks evolved across primates. To date, most comparative studies have used resting-state functional magnetic resonance imaging (rs-fMRI) in anaesthetized nonhuman primates and in awake humans. However, anaesthesia strongly affects rs-fMRI signals. The present study investigated the impact of the awareness state (anaesthesia vs. awake) within the same group of macaque monkeys on the rs-fMRI functional connectivity organization of a well-characterized network in the human brain, the cingulo-frontal lateral network. Results in awake macaques show that rostral seeds in the cingulate sulcus exhibited stronger correlation strength with rostral compared to caudal lateral frontal cortical areas, while more caudal seeds displayed stronger correlation strength with caudal compared to anterior lateral frontal cortical areas. Critically, this inverse rostro-caudal functional gradient was abolished under anaesthesia. This study demonstrated a similar functional connectivity (FC) organization of the cingulo-frontal cortical network in awake macaque to that previously uncovered in the human brain pointing toward a preserved FC organization from macaque to human. However, it can only be observed in awake state suggesting that this network is sensitive to anaesthesia and warranting significant caution when comparing FC patterns across species under different states.

The midcingulate cortex and temporal integration.

The ability to integrate information across time at multiple timescales is a vital element of adaptive behavior, because it provides the capacity to link events separated in time, extract useful information from previous events and actions, and to construct plans for behavior over time. Here we make the argument that this information integration capacity is a central function of the midcingulate cortex (MCC), by reviewing the anatomical, intrinsic network, neurophysiological, and behavioral properties of MCC. The MCC is the region of the medial wall situated dorsal to the corpus callosum and sometimes referred to as dACC. It is positioned within the densely connected core network of the primate brain, with a rich diversity of cognitive, somatomotor and autonomic connections. Furthermore, the MCC shows strong local network inhibition which appears to control the metastability of the region-an established feature of many cortical networks in which the neural dynamics move through a series of quasi-stationary states. We propose that the strong local inhibition in MCC leads to particularly long dynamic state durations, and so less frequent transitions. Apparently as a result of these anatomical features and synaptic and ionic determinants, the MCC cells display the longest neuronal timescales among a range of recorded cortical areas. We conclude that the anatomical position, intrinsic properties, and local network interactions of MCC make it a uniquely positioned cortical area to perform the integration of diverse information over time that is necessary for behavioral adaptation.

Imaging evolution of the primate brain: the next frontier?

Evolution, as we currently understand it, strikes a delicate balance between animals' ancestral history and adaptations to their current niche. Similarities between species are generally considered inherited from a common ancestor whereas observed differences are considered as more recent evolution. Hence comparing species can provide insights into the evolutionary history. Comparative neuroimaging has recently emerged as a novel subdiscipline, which uses magnetic resonance imaging (MRI) to identify similarities and differences in brain structure and function across species. Whereas invasive histological and molecular techniques are superior in spatial resolution, they are laborious, post-mortem, and oftentimes limited to specific species. Neuroimaging, by comparison, has the advantages of being applicable across species and allows for fast, whole-brain, repeatable, and multi-modal measurements of the structure and function in living brains and post-mortem tissue. In this review, we summarise the current state of the art in comparative anatomy and function of the brain and gather together the main scientific questions to be explored in the future of the fascinating new field of brain evolution derived from comparative neuroimaging.

Author Correction: Sulcal organization in the medial frontal cortex provides insights into primate brain evolution.

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

Sulcal organization in the medial frontal cortex provides insights into primate brain evolution.

Although the relative expansion of the frontal cortex in primate evolution is generally accepted, the nature of the human uniqueness, if any, and between-species anatomo-functional comparisons of the frontal areas remain controversial. To provide a novel interpretation of the evolution of primate brains, sulcal morphological variability of the medial frontal cortex was assessed in Old World monkeys (macaque/baboon) and Hominoidea (chimpanzee/human). We show that both Hominoidea possess a paracingulate sulcus, which was previously thought to be unique to the human brain and linked to higher cognitive functions, such as mentalizing. Also, we show systematic sulcal morphological organization of the medial frontal cortex that can be traced from Old World monkeys to Hominoidea species, demonstrating an evolutionarily conserved organizational principle. These data provide a new framework to compare sulcal morphology, cytoarchitectonic areal distribution, connectivity, and function across the primate order, leading to clear predictions about how other primate brains might be anatomo-functionally organized.

Variations of cingulate sulcal organization and link with cognitive performance.

The sulcal morphology of the human medial frontal cortex has received marked interest because of (1) its remarkable link with the functional organization of this region, and (2) observations that deviations from 'normal' sulcal morphological variability correlate with the prevalence of some psychiatric disorders, cognitive abilities, or personality traits. Unfortunately, background studies on environmental or genetic factors influencing the ontogenesis of the sulcal organization in this region are critically lacking. We analysed the sulcal morphological organization in this region in twins and non-twin siblings, as well as in control subjects for a total of 599 subjects from the Human Connectome Project. The data first confirm significant biases in the presence of paracingulate sulci in left vs right hemispheres in the whole population (twin: p < 2.4.10-9; non-twin: p < 2.10-6) demonstrating a clear general laterality in human subjects. Second, measures of similarity between siblings and estimations of heritability suggest significant environmental factors, in particular in-womb environment, and weak additive genetic factors influencing the presence of a paracingulate sulcus. Finally, we found that relationships between sulcal organization and performance in cognitive, motor, and affective tests depend on the twin status (Twins versus Non-twins). These results provide important new insights to the issue of the significance of sulcal organization in the human medial frontal cortex.

The Rhesus Monkey Hippocampus Critically Contributes to Scene Memory Retrieval, But Not New Learning.

Humans can recall a large number of memories years after the initial events. Patients with amnesia often have lesions to the hippocampus, but human lesions are imprecise, making it difficult to identify the anatomy underlying memory impairments. Rodent studies enable great precision in hippocampal manipulations, but not investigation of many interleaved memories. Thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. Furthermore, disagreement exists as to whether hippocampal inactivations lead to temporally graded or ungraded amnesia, which could be a consequence of differences between rodent and human studies. In the current study, rhesus monkeys of both sexes received either bilateral neurotoxic hippocampal lesions or remained unoperated controls and were tested on recognition and new learning of visual object-in-place scenes. Monkeys with hippocampal lesions were significantly impaired at remembering scenes that were encoded before the lesion. We did not observe any temporal gradient effect of the lesion on memory recognition, with recent and remote memories being equally affected by the lesion. Monkeys with hippocampal lesions showed no deficits in learning new scenes. Thus, the hippocampus, like other cortical regions, may be engaged in the acquisition and storage of new memories, but the role of the damaged hippocampus can be taken over by spared hippocampal tissue or extra-hippocampal regions following a lesion. These findings illustrate the utility of experimental paradigms for studying retrograde and anterograde amnesia that make use of the capacity of nonhuman primates to rapidly acquire many distinct visual memories.SIGNIFICANCE STATEMENT Recalling old memories, creating new memories, and the process by which memories transition from temporary to permanent storage all may rely on the hippocampus. Whether the hippocampus is necessary for encoding and retrieval of multiple related visual memories in primates is not known. Monkeys that learned many visual memory problems before precise lesions of the hippocampus were impaired at recalling those memories after hippocampal damage regardless of when the memories were formed, but could learn new memory problems at a normal rate. This suggests the hippocampus is normally vital for retrieval of complex visual memories regardless of their age, and also points to the importance of investigating mechanisms by which memories may be acquired in the presence of hippocampal damage.

Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss.

Learning to learn about uncertain feedback.

Unexpected outcomes can reflect noise in the environment or a change in the current rules. We should ignore noise but shift strategy after rule changes. How we learn to do this is unclear, but one possibility is that it relies on learning to learn in uncertain environments. We propose that acquisition of latent task structure during learning to learn, even when not necessary, is crucial. We report results consistent with this hypothesis. Macaque monkeys acquired adaptive responses to feedback while learning to learn serial stimulus-response associations with probabilistic feedback. Monkeys learned well, decreasing their errors to criterion, but they also developed an apparently nonadaptive reactivity to unexpected stochastic feedback, even though that unexpected feedback never predicted problem switch. This surprising learning trajectory permitted the same monkeys, naïve to relearning about previously learned stimuli, to transfer to a task of stimulus-response remapping at immediately asymptotic levels. Our results suggest that learning new problems in a stochastic environment promotes the acquisition of performance rules from latent task structure, providing behavioral flexibility. Learning to learn in a probabilistic and volatile environment thus appears to induce latent learning that may be beneficial to flexible cognition.

The Effects of Cognitive Control and Time on Frontal Beta Oscillations.

Frontal beta oscillations are associated with top-down control mechanisms but also change over time during a task. It is unclear whether change over time represents another control function or a neural instantiation of vigilance decrements over time, the time-on-task effect. We investigated how frontal beta oscillations are modulated by cognitive control and time. We used frontal chronic electrocorticography in monkeys performing a trial-and-error task, comprising search and repetition phases. Specific beta oscillations in the delay period of each trial were modulated by task phase and adaptation to feedback. Beta oscillations in this same period showed a significant within-session change. These separate modulations of beta oscillations did not interact. Crucially, and in contrast to previous investigations, we examined modulations of beta around spontaneous pauses in work. After pauses, the beta power modulation was reset and the cognitive control effect was maintained. Cognitive performance was also maintained whereas behavioral signs of fatigue continued to increase. We propose that these beta oscillations reflect multiple factors contributing to the regulation of cognitive control. Due to the effect of pauses, the time-sensitive factor cannot be a neural correlate of time-on-task but may reflect attentional effort.

Midcingulate Motor Map and Feedback Detection: Converging Data from Humans and Monkeys.

The functional and anatomical organization of the cingulate cortex across primate species is the subject of considerable and often confusing debate. The functions attributed to the midcingulate cortex (MCC) embrace, among others, feedback processing, pain, salience, action-reward association, premotor functions, and conflict monitoring. This multiplicity of functional concepts suggests either unresolved separation of functional contributions or integration and convergence. We here provide evidence from recent experiments in humans and from a meta-analysis of monkey data that MCC feedback-related activity is generated in the rostral cingulate premotor area by specific body maps directly related to the modality of feedback. As such, we argue for an embodied mechanism for adaptation and exploration in MCC. We propose arguments and precise tools to resolve the origins of performance monitoring signals in the medial frontal cortex, and to progress on issues regarding homology between human and nonhuman primate cingulate cortex.

A unilateral medial frontal cortical lesion impairs trial and error learning without visual control.

There is considerable debate regarding the involvement of the medial frontal cortex in motor and cognitive functions. Recent neuroimaging data suggest a fundamental underlying process that links the motor and cognitive roles of the mid-cingulate cortex (MCC), namely the processing of feedback during trial and error learning in the cingulate motor region that is related to the modality of the feedback. These data suggest that the specific motor context of a task may be a critical determinant of how its outcome is processed in the MCC. We assessed a patient before and after surgery for brain tumour removal in the medial frontal cortex, and a group of matched control subjects. Subjects had to find by trial and error the stimulus associated with the correct feedback amongst four or five similar stimuli. Subjects performed the task in two different visuo-motor contexts: with the response pad and hand visible and with no sight of either pad or hand. The patient showed a selective impairment in this task relative to control subjects in the hardest conditions and the impairment was most marked when the response pad and the hand were not visible. The results support a specific role of the medial frontal cortex in the construction of a sensorimotor representation of choices and related feedback by encoding the contingency between an efference copy of the action and its outcome.

Increased DAT binding in the early stage of the dopaminergic lesion: a longitudinal [11C]PE2I binding study in the MPTP-monkey.

The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BP(ND) during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanisms. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.

Causal effect of disconnection lesions on interhemispheric functional connectivity in rhesus monkeys.

In the absence of external stimuli or task demands, correlations in spontaneous brain activity (functional connectivity) reflect patterns of anatomical connectivity. Hence, resting-state functional connectivity has been used as a proxy measure for structural connectivity and as a biomarker for brain changes in disease. To relate changes in functional connectivity to physiological changes in the brain, it is important to understand how correlations in functional connectivity depend on the physical integrity of brain tissue. The causal nature of this relationship has been called into question by patient data suggesting that decreased structural connectivity does not necessarily lead to decreased functional connectivity. Here we provide evidence for a causal but complex relationship between structural connectivity and functional connectivity: we tested interhemispheric functional connectivity before and after corpus callosum section in rhesus monkeys. We found that forebrain commissurotomy severely reduced interhemispheric functional connectivity, but surprisingly, this effect was greatly mitigated if the anterior commissure was left intact. Furthermore, intact structural connections increased their functional connectivity in line with the hypothesis that the inputs to each node are normalized. We conclude that functional connectivity is likely driven by corticocortical white matter connections but with complex network interactions such that a near-normal pattern of functional connectivity can be maintained by just a few indirect structural connections. These surprising results highlight the importance of network-level interactions in functional connectivity and may cast light on various paradoxical findings concerning changes in functional connectivity in disease states.

Functional localization within the prefrontal cortex: missing the forest for the trees?

Anatomical and functional studies of the prefrontal cortex (PFC) have identified multiple PFC subregions. We argue that the PFC is involved in cognitive functions exceeding the sum of specific functions attributed to its subregions. These can be revealed either by lesions of the whole PFC, or more specifically by selective disconnection of the PFC from certain types of information (for example, visual) allowing the investigation of PFC function in toto. Recent studies in macaque monkeys using the latter approach lead to a second conclusion: that the PFC, as a whole, could be fundamentally specialized for representing events that are extended in time. The representation of temporally complex events might underlie PFC involvement in general intelligence, decision-making, and executive function.

Degraded transfer of memories between the visual hemifields in normal macaques revealed by a novel infrared eyetracking method without head fixation.

Electrophysiological evidence in macaque monkeys indicates that when the monkey views a visual scene with objects present in both visual hemifields, the cells of the temporal lobe respond to objects in the contralateral field, but are hardly affected by objects in the ipsilateral field. If visual memories are stored in the temporal lobes, as is generally believed, then this implies that the transfer of visual object memories from one hemifield to the other should either fail or at least suffer decrement. Building on a previous study in human subjects, we tested this prediction in rhesus monkeys (Macaca mulatta). We developed a method for tracking the eye movements of the awake, behaving monkey, which does not require the monkey to be restrained or surgically prepared. We optimised the system to provide reliable feedback of eye position in real time, and so provide hemifield-specific presentation of visual objects. In each acquisition phase the monkeys learned several object discriminations concurrently, each object only ever being presented to one hemifield, and with an object present in each hemifield on every trial. In subsequent transfer tests with the same objects, the monkeys performed significantly worse when the objects were shifted to the opposite hemifield than if shifted the same distance within one hemifield. Thus, in monkeys as well as in humans, and in association learning as well as in recognition memory, visual memories can be to a large extent hemifield-specific. This result shows that, like perceptual systems, mnemonic systems of the temporal lobe are largely hemifield-specific, and this has clear implications for studies of the temporal lobes. Further, the validation of our method will allow us to use it, in future experiments, to investigate in monkeys the effects of specific unilateral lesions on visual perception and memory for objects that are presented in known positions in the visual field.