Medial to lateral frontal functional connectivity mapping reveals the organization of cingulate cortex.

The functional organization of the frontal lobe is a source of debate, focusing on broad functional subdivisions, large-scale networks, or local refined specificities. Multiple neurocognitive models have tried to explain how functional interactions between cingulate and lateral frontal regions contribute to decision making and cognitive control, but their neuroanatomical bases remain unclear. We provide a detailed description of the functional connectivity between cingulate and lateral frontal regions using resting-state functional MRI in rhesus macaques. The analysis focuses on the functional connectivity of the rostral part of the cingulate sulcus with the lateral frontal cortex. Data-driven and seed-based analysis revealed three clusters within the cingulate sulcus organized along the rostro-caudal axis: the anterior, mid, and posterior clusters display increased functional connectivity with, respectively, the anterior lateral prefrontal regions, face-eye lateral frontal motor cortical areas, and hand lateral frontal motor cortex. The location of these clusters can be predicted in individual subjects based on morphological landmarks. These results suggest that the anterior cluster corresponds to the anterior cingulate cortex, whereas the posterior clusters correspond to the face-eye and hand cingulate motor areas within the anterior midcingulate cortex. These data provide a comprehensive framework to identify cingulate subregions based on functional connectivity and local organization.

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.

Sulcal Morphology in Cingulate Cortex is Associated with Voluntary Oro-Facial Motor Control and Gestural Communication in Chimpanzees (Pan troglodytes).

Individual differences in sulcal variation within the anterior and mid-cingulate cortex of the human brain, particularly the presence or absence of a paracingulate sulcus (PCGS), are associated with various motor and cognitive processes. Recently, it has been reported that chimpanzees possess a PCGS, previously thought to be a unique feature of the human brain. Here, we examined whether individual variation in the presence or absence of a PCGS as well as the variability in the intralimbic sulcus (ILS) are associated with oro-facial motor control, handedness for manual gestures, and sex in a sample of MRI scans obtained in 225 chimpanzees. Additionally, we quantified the depth of the cingulate sulcus (CGS) along the anterior-posterior axis and tested for association with oro-facial motor control, handedness, and sex. Chimpanzees with better oro-facial motor control were more likely to have a PCGS, particularly in the left hemisphere compared to those with poorer control. Male chimpanzees with better oro-facial motor control showed increased leftward asymmetries in the depth of the anterior CGS, whereas female chimpanzees showed the opposite pattern. Significantly, more chimpanzees had an ILS in the left compared to the right hemisphere, but variability in this fold was not associated with sex, handedness, or oro-facial motor control. Finally, significant population-level leftward asymmetries were found in the anterior portion of the CGS, whereas significant rightward biases were evident in the posterior regions. The collective results suggest that the emergence of a PCGS and enhanced gyrification within the anterior and mid-cingulate gyrus may have directly or indirectly evolved in response to selection for increasing oro-facial motor control in primates.

Chimpanzee histology and functional brain imaging show that the paracingulate sulcus is not human-specific.

The paracingulate sulcus -PCGS- has been considered for a long time to be specific to the human brain. Its presence/absence has been discussed in relation to interindividual variability of personality traits and cognitive abilities. Recently, a putative PCGS has been observed in chimpanzee brains. To demonstrate that this newly discovered sulcus is the homologue of the PCGS in the human brain, we analyzed cytoarchitectonic and resting-state functional magnetic resonance imaging data in chimpanzee brains which did or did not display a PCGS. The results show that the organization of the mid-cingulate cortex of the chimpanzee brain is comparable to that of the human brain, both cytoarchitectonically and in terms of functional connectivity with the lateral frontal cortex. These results demonstrate that the PCGS is not human-specific but is a shared feature of the primate brain since at least the last common ancestor to humans and great apes ~6 mya.

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.

Cognitive control of orofacial motor and vocal responses in the ventrolateral and dorsomedial human frontal cortex.

In the primate brain, a set of areas in the ventrolateral frontal (VLF) cortex and the dorsomedial frontal (DMF) cortex appear to control vocalizations. The basic role of this network in the human brain and how it may have evolved to enable complex speech remain unknown. In the present functional neuroimaging study of the human brain, a multidomain protocol was utilized to investigate the roles of the various areas that comprise the VLF-DMF network in learning rule-based cognitive selections between different types of motor actions: manual, orofacial, nonspeech vocal, and speech vocal actions. Ventrolateral area 44 (a key component of the Broca's language production region in the human brain) is involved in the cognitive selection of orofacial, as well as, speech and nonspeech vocal responses; and the midcingulate cortex is involved in the analysis of speech and nonspeech vocal feedback driving adaptation of these responses. By contrast, the cognitive selection of speech vocal information requires this former network and the additional recruitment of area 45 and the presupplementary motor area. We propose that the basic function expressed by the VLF-DMF network is to exert cognitive control of orofacial and vocal acts and, in the language dominant hemisphere of the human brain, has been adapted to serve higher speech function. These results pave the way to understand the potential changes that could have occurred in this network across primate evolution to enable speech production.

Midcingulate somatomotor and autonomic functions.

The midcingulate cortex (MCC) is viewed as a central node within a large-scale system devoted to adjusting behavior in the face of changing environments. Whereas the role of the MCC in interfacing action and cognition is well established, its role in regulating the autonomic nervous system is poorly understood. Yet, adaptive reactions to novel or threatening situations induce coordinated changes in the sympathetic and the parasympathetic systems. The somatomotor maps in the MCC are organized dorsoventrally. A meta-analysis of the literature reveals that the dorsoventral organization might also concern connections with the autonomic nervous system. Activation of the dorsal and ventral parts of the MCC correlate with recruitments of the sympathetic and the parasympathetic systems, respectively. Data also suggest that, in the MCC, projections toward the sympathetic system are mapped along the sensory-motor system following the same cervico-sacral organization as projections on the spinal cord for skeletal motor control.

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.

The Human Ventromedial Prefrontal Cortex: Sulcal Morphology and Its Influence on Functional Organization.

The ventromedial prefrontal cortex (vmPFC), which comprises several distinct cytoarchitectonic areas, is a key brain region supporting decision-making processes, and it has been shown to be one of the main hubs of the Default Mode Network, a network classically activated during resting state. We here examined the interindividual variability in the vmPFC sulcal morphology in 57 humans (37 females) and demonstrated that the presence/absence of the inferior rostral sulcus and the subgenual intralimbic sulcus influences significantly the sulcal organization of this region. Furthermore, the sulcal organization influences the location of the vmPFC peak of the Default Mode Network, demonstrating that the location of functional activity can be affected by local sulcal patterns. These results are critical for the investigation of the function of the vmPFC and show that taking into account the sulcal variability might be essential to guide the interpretation of neuroimaging studies.SIGNIFICANCE STATEMENT The ventromedial prefrontal cortex (vmPFC) is one of the main hubs of the Default Mode Network and plays a central role in value coding and decision-making. The present study provides a complete description of the interindividual variability of anatomical morphology of this large portion of prefrontal cortex and its relation to functional organization. We have shown that two supplementary medial sulci predominantly determine the organization of the vmPFC, which in turn affects the location of the functional peak of activity in this region. Those results show that taking into account the variability in sulcal patterns might be essential to guide the interpretation of neuroimaging studies of the human brain and of the vmPFC in particular.

An Open Resource for Non-human Primate Imaging.

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

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.

Functional rostro-caudal gradient in the human posterior lateral frontal cortex.

The present study examined the hypothesis that the posterior motor/premotor region of the lateral frontal cortex is functionally organized along a rostro-caudal axis. During functional magnetic resonance imaging scanning, the subjects performed various tasks assessing basic saccadic eye or hand actions and also tasks requiring the cognitive selection between competing hand or eye movements based on previously learned conditional relations (if A, select movement X, but if B select movement Y). Subject-by-subject analysis demonstrated precise relationships between the foci of functional activity and specific sulci. In agreement with previous reports, basic eye movements activated the Frontal Eye Field (FEF) in the ventral branch of the superior precentral sulcus, but the high-level selection of saccadic eye movements was localized systematically anterior to this region in the superior frontal sulcus. Similarly, basic performance of hand movements activated the primary motor cortex, but the region involved in the high-level selection between competing hand movements was systematically localized within the dorsal branch of the superior precentral sulcus, anterior to the primary motor region. Importantly, there was no overlap between the anterior cognitive selection regions, suggesting an effector specific organization. These results demonstrate a functional rostro-caudal gradient within the posterior lateral frontal cortex reflecting a hierarchical organization of action control.

Reward activations and face fields in monkey cingulate motor areas.

Several premotor areas have been identified within primate cingulate cortex; however their function is yet to be uncovered. Recent brain imaging work in humans revealed a topographic anatomofunctional overlap between feedback processing during exploratory behaviors and the corresponding body fields in the rostral cingulate motor area (RCZa), suggesting an embodied representation of feedback. In particular, a face field in RCZa processes juice feedback. Here we tested an extension of the embodied principle in which unexpected or relevant information obtained through the eye or the face would be processed by face fields in cingulate motor areas, and whether this applied to monkey cingulate cortex. We show that activations for juice reward, eye movement, eye blink, and tactile stimulation on the face overlap over two subfields within the cingulate sulcus likely corresponding to the rostral and caudal cingulate motor areas. This suggests that in monkeys as is the case in humans, behaviorally relevant information is processed through multiple cingulate body/effector maps. NEW & NOTEWORTHY What is the role of cingulate motor areas? In this study we observed in monkeys that, as in humans, neural responses to face-related events, juice reward, eye movement, eye blink, and tactile stimulations, clustered redundantly in two separate cingulate subfields. This suggests that behaviorally relevant information is processed by multiple cingulate effector maps. Importantly, this overlap supports the principle that the cingulate cortex processes feedback based on where it is experienced on the body.

Cognitive control of vocalizations in the primate ventrolateral-dorsomedial frontal (VLF-DMF) brain network.

This review centers on the neural mechanisms underlying the primate cognitive control of vocalizations, i.e. the capacity to regulate vocal productions in a goal-directed manner. In both human and non-human primates (NHPs), two main frontal brain regions are associated with top-down vocal control: a ventrolateral frontal region (VLF), comprising the ventrolateral prefrontal cortex and ventral premotor region; and a dorsomedial frontal region (DMF), comprising the mid-cingulate cortex, pre-supplementary and supplementary motor areas. These regions are cytoarchitectonically comparable across humans and NHPs and could serve generic functions in primate vocal control. Here, we first summarize the key anatomical properties of VLF and DMF regions as well as their involvements in the motor and cognitive control of vocalizations in both humans and NHPs. Finally, in light of the reviewed evidence, we discuss the existence of a primate VLF-DMF network and its generic functions in the cognitive control of vocalizations. We further suggest how this network and its functions may have changed across primate evolution to enable modern human speech.

Rostro-Caudal Organization of Connectivity between Cingulate Motor Areas and Lateral Frontal Regions.

According to contemporary views, the lateral frontal cortex is organized along a rostro-caudal functional axis with increasingly complex cognitive/behavioral control implemented rostrally, and increasingly detailed motor control implemented caudally. Whether the medial frontal cortex follows the same organization remains to be elucidated. To address this issue, the functional connectivity of the 3 cingulate motor areas (CMAs) in the human brain with the lateral frontal cortex was investigated. First, the CMAs and their representations of hand, tongue, and eye movements were mapped via task-related functional magnetic resonance imaging (fMRI). Second, using resting-state fMRI, their functional connectivity with lateral prefrontal and lateral motor cortical regions of interest (ROIs) were examined. Importantly, the above analyses were conducted at the single-subject level to account for variability in individual cingulate morphology. The results demonstrated a rostro-caudal functional organization of the CMAs in the human brain that parallels that in the lateral frontal cortex: the rostral CMA has stronger functional connectivity with prefrontal regions and weaker connectivity with motor regions; conversely, the more caudal CMAs have weaker prefrontal and stronger motor connectivity. Connectivity patterns of the hand, tongue and eye representations within the CMAs are consistent with that of their parent CMAs. The parallel rostral-to-caudal functional organization observed in the medial and lateral frontal cortex could likely contribute to different hierarchies of cognitive-motor control.

Single subject analyses reveal consistent recruitment of frontal operculum in performance monitoring.

There are continuing uncertainties regarding whether performance monitoring recruits the anterior insula (aI) and/or the frontal operculum (fO). The proximity and morphological complexity of these two regions make proper identification and isolation of the loci of activation extremely difficult. The use of group averaging methods in human neuroimaging might contribute to this problem. The result has been heterogeneous labeling of this region as aI, fO, or aI/fO, and a discussion of results oriented towards either cognitive or interoceptive functions depending on labeling. In the present article, we adapted the spatial preprocessing of functional magnetic resonance imaging data to account for group averaging artifacts and performed a subject-by-subject analysis in three performance monitoring tasks. Results show that functional activity related to feedback or action monitoring consistently follows local morphology in this region and demonstrate that the activity is located predominantly in the fO rather than in the aI. From these results, we propose that a full understanding of the respective role of aI and fO would benefit from increased spatial resolution and subject-by-subject analysis.