Primate Frontal Lobe Research Articles

Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe.

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas, including novel subdivisions of Walker's areas 10, 9, 8B, and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Indeed, structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains and revealed 5 clusters encompassing frontal lobe areas. We used the MRI datasets from the non-human primate data sharing consortium PRIME-DE to perform functional connectivity analyses using the resulting frontal maps as seed regions. In general, rostrally located frontal areas were characterized by bigger fingerprints, that is, higher receptor densities, and stronger regional interconnections. Whereas more caudal areas had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, this study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile the discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.

Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging

The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using physiologically aged non-human primates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling encompassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro-inflammatory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons ofaged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging invitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating eventof the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons invitro or oral administration to aged mice.

Brain-wide and cell-specific transcriptomic insights into MRI-derived cortical morphology in macaque monkeys

Integrative analyses of transcriptomic and neuroimaging data have generated a wealth of information about biological pathways underlying regional variability in imaging-derived brain phenotypes in humans, but rarely in nonhuman primates due to the lack of a comprehensive anatomically-defined atlas of brain transcriptomics. Here we generate complementary bulk RNA-sequencing dataset of 819 samples from 110 brain regions and single-nucleus RNA-sequencing dataset, and neuroimaging data from 162 cynomolgus macaques, to examine the link between brain-wide gene expression and regional variation in morphometry. We not only observe global/regional expression profiles of macaque brain comparable to human but unravel a dorsolateral-ventromedial gradient of gene assemblies within the primate frontal lobe. Furthermore, we identify a set of 971 protein-coding and 34 non-coding genes consistently associated with cortical thickness, specially enriched for neurons and oligodendrocytes. These data provide a unique resource to investigate nonhuman primate models of human diseases and probe cross-species evolutionary mechanisms.

From affective to cognitive processing: Functional organization of the medial frontal cortex.

The medial wall of the primate frontal lobe encompasses multiple anatomical subregions. Based on distinct neurophysiological correlates and effects of lesions, individual areas are thought to play unique roles in behavior. Further, evidence suggests that dysfunction localized to specific subregions is commonly found in different neuropsychiatric disorders. The neurobiological underpinnings of these disorders, however, remain far from clear. Here, to better understand the functions of medial frontal cortex (MFC) and its role in psychiatric disease, we focus on its functional organization. We describe the emerging pattern in which more dorsal regions subserve temporally extended cognitive functions and more ventral regions predominantly subserve affective functions. We focus on two specific domains, decision-making and social cognition, that require integration across emotion and cognition. In each case, we discuss the current understanding of the functions believed to depend on subregions of MFC as a stepping-stone to speculate on how they might work in unison. We conclude with an overview of how symptoms of certain psychiatric disorders relate to our understanding of MFC functional organization and how further discovery could fuel advances in circuit-based therapies.

Layer specificity of inputs from supplementary motor area and dorsal premotor cortex to primary motor cortex in macaque monkeys

The primate frontal lobe processes diverse motor information in parallel through multiple motor-related areas. For example, the supplementary motor area (SMA) is mainly involved in internally-triggered movements, whereas the premotor cortex (PM) is highly responsible for externally-guided movements. The primary motor cortex (M1) deals with both aspects of movements to execute a single motor behavior. To elucidate how the cortical motor system is structured to process a variety of information, the laminar distribution patterns of signals were examined between SMA and M1, or PM and M1 in macaque monkeys by using dual anterograde tract-tracing. Dense terminal labeling was observed in layers 1 and upper 2/3 of M1 after one tracer injection into SMA, another tracer injection into the dorsal division of PM resulted in prominent labeling in the deeper portion of layer 2/3. Weaker labeling was also visible in layer 5 in both cases. On the other hand, inputs from M1 terminated in both the superficial and the deep layers of SMA and PM. The present data indicate that distinct types of motor information are arranged in M1 in a layer-specific fashion to be orchestrated through a microcircuit within M1.

Functional Specialization of the Primate Frontal Lobe during Cognitive Control of Vocalizations

Cognitive vocal control is indispensable for human language. Frontal lobe areas are involved in initiating purposeful vocalizations, but their functions remain elusive. We explored the respective roles of frontal lobe areas in initiating volitional vocalizations. Macaques were trained to vocalize in response to visual cues. Recordings from the ventrolateral prefrontal cortex (vlPFC), the anterior cingulate cortex (ACC), and the pre-supplementary motor area (preSMA) revealed single-neuron and population activity differences. Pre-vocal activity appeared first after the go cue in vlPFC, showing onset activity that was tightly linked to vocal reaction times. However, pre-vocal ACC onset activity was not indicative of call timing; instead, ramping activity reaching threshold values betrayed call onset. Neurons in preSMA showed weakest correlation with volitional call initiation and timing. These results suggest that vlPFC encodes the decision to produce volitional calls, whereas downstream ACC represents a motivational preparatory signal, followed by a general motor priming signal in preSMA.

How humans stand out in frontal lobe scaling

All studies from the last 15 y of collecting data on primate frontal lobe volumes share one central result: allometric scaling of the human frontal lobe is not larger than expected. Recent studies collecting data on the prefrontal cortex confirm this result, but additionally indicate human prefrontal white matter specialization.

Cyto-, myelo- and chemoarchitecture of the prefrontal cortex of the Cebus monkey

BackgroundAccording to several lines of evidence, the great expansion observed in the primate prefrontal cortex (PfC) was accompanied by the emergence of new cortical areas during phylogenetic development. As a consequence, the structural heterogeneity noted in this region of the primate frontal lobe has been associated with diverse behavioral and cognitive functions described in human and non-human primates. A substantial part of this evidence was obtained using Old World monkeys as experimental model; while the PfC of New World monkeys has been poorly studied.In this study, the architecture of the PfC in five capuchin monkeys (Cebus apella) was analyzed based on four different architectonic tools, Nissl and myelin staining, histochemistry using the lectin Wisteria floribunda agglutinin and immunohistochemistry using SMI-32 antibody.ResultsTwenty-two architectonic areas in the Cebus PfC were distinguished: areas 8v, 8d, 9d, 12l, 45, 46v, 46d, 46vr and 46dr in the lateral PfC; areas 11l, 11m, 12o, 13l, 13m, 13i, 14r and 14c in the orbitofrontal cortex, with areas 14r and 14c occupying the ventromedial corner; areas 32r, 32c, 25 and 9m in the medial PfC, and area 10 in the frontal pole. This number is significantly higher than the four cytoarchitectonic areas previously recognized in the same species. However, the number and distribution of these areas in Cebus were to a large extent similar to those described in Old World monkeys PfC in more recent studies.ConclusionsThe present parcellation of the Cebus PfC considerably modifies the scheme initially proposed for this species but is in line with previous studies on Old World monkeys. Thus, it was observed that the remarkable anatomical similarity between the brains of genera Macaca and Cebus may extend to architectonic aspects. Since monkeys of both genera evolved independently over a long period of time facing different environmental pressures, the similarities in the architectonic maps of PfC in both genera are issues of interest. However, additional data about the connectivity and function of the Cebus PfC are necessary to evaluate the possibility of potential homologies or parallelisms.

Action recognition in the premotor cortex. By Vittorio Gallese, Luciano Fadiga, Leonardo Fogassi and Giacomo Rizzolatti. Brain 1996: 119; 593-609.

Dogma—following Karl Brodmann's studies from the early 1900s—teaches that the agranular cortex of the primate frontal lobe consists of area 4 containing giant pyramidal neurons and area 6 which does not; to which can be added a functional classification of primary (area 4 and the lateral part of area 6) and supplementary motor cortex (the medial component of area 6). But this is overly simplified and a variety of anatomical methodologies (immunohistochemistry, neurochemistry and hodology, inter alia ) have revealed a mosaic of structures in the agranular frontal region to which distinct functional properties can be assigned. The classical view of the premotor cortex as the orchestrator strictly of motor control is now supplemented by evidence for its role in cognitive and behavioural functions—coding space, decoding the intrinsic properties of objects and contributing to associative learning. But special attention should be paid to F5, lying immediately caudal to the inferior arm of the arcuate sulcus, and concerned with hand and mouth movements in its dorsal and ventral portions, respectively. The hand neurons discharge during goal-directed movements, such as specific types of grasping, tearing, manipulating and holding; and they become active when 3D objects that are the same size as those activating that neuron during grip, are seen but not moved. Now the Italian team describe simian neurons that discharge not only with movement but also when the monkey observes meaningful movements made by the experimenter. They also provide a detailed description of the properties of these cells—designated ‘mirror neurons’—and some clinical implications arising from their discovery. Their method is to record from the rostral inferior part of area 6 in one or both hemispheres of two monkeys trained to observe and then reach for food and other objects of differing sizes and shapes—movements that require precision grip (index finger and thumb), …

Beautiful Minds—For How Long?

Beautiful Minds—For How Long?

A Frontal Lobe Refresher

The Frontal Lobes: Development, Function and Pathology. Jarl Risberg and Jordan Grafman (Eds.). 2006. New York: Cambridge University Press. 240 pp., $70.00 (PB)The Frontal Lobes: Development, Function and Pathology is an edited volume comprised of chapters that are the result of presentations at the annual Advanced Studies Institute sponsored by the International Neuropsychological Society (INS) and by the Vivian Smith Foundation. The eight chapters represent multiple approaches to studying or understanding the frontal lobes, including: evolution and genetics, primate frontal lobe neuroanatomy, cognitive neuroscience models of frontal lobe functioning, microcircuit models based on single neuron recording, developmental models of frontal lobe functioning, case studies of frontal lobe lesion patients, functional neuroimaging of frontal lobe activity, and postmortem neuropathological findings in demented patients. This is a solid but not comprehensive list of approaches to understanding frontal lobe functioning, but the editors clearly state that this volume is not designed to be an exhaustive review. Rather, it is a volume that is better viewed as the state of the art of selected approaches to frontal lobe research as of about 2004, when most of the authors presented a variation of the chapter to the INS Summer Institute. With these qualifications in mind, I can say that the volume is a useful overview that will inform the reader of current and future directions in frontal lobe research.

Frontal cortical areas of the monkey brain engaged in reaching behavior: A 14C-deoxyglucose imaging study

The ( 14C)-deoxyglucose method was employed to study whether different areas of the primate frontal lobe are involved in different aspects of reaching behavior. To this end, we mapped the functional activity of the frontal motor cortical areas in three monkeys performing reaching movements with one forelimb. The first monkey had to capture a peripheral visual target with a saccade and a forelimb-reach together, the second monkey had to reach a peripheral visual target with one forelimb while fixating a central target, and the third one had to reach a peripheral memorized target with one forelimb in complete darkness while the eyes maintained a straight ahead direction. The extent and intensity of activations were compared to those of three respective control monkeys: a saccade-control, a fixation-control, and a dark-control. The primary somatosensory (S1) and motor (F1) forelimb representation, the S1- and F1-trunk representation, the F2-dimple region, areas F3-forelimb, F4, F5-bank of arcuate sulcus, F7-ridge, the dorsal bank of cingulate sulcus, and 24c were activated in all reaching monkeys regardless of accompanying visual stimulation and oculomotor behavior. Interestingly, the S1-forelimb activation in the monkey reaching to memorized targets in complete darkness was more pronounced than that in the monkeys reaching to visual targets in the light, indicating that increased somatosensory processing compensates for the absence of visual feedback. On the other hand, areas F2-periarcuate, F5-convexity, F6, and 23 were preferentially activated by reaching to visual targets and remained unaffected during reaching to memorized targets when no visual feedback was available.

Oculomotor areas of the primate frontal lobes: a transneuronal transfer of rabies virus and [14C]-2-deoxyglucose functional imaging study.

We used the [14C]-2-deoxyglucose method to study the location and extent of primate frontal lobe areas activated for saccades and fixation and the retrograde transneuronal transfer of rabies virus to determine whether these regions are oligosynaptically connected with extraocular motoneurons. Fixation-related increases of local cerebral glucose utilization (LCGU) values were found around the fundus of the inferior limb of the arcuate sulcus (AS) just ventral to its genu, in the dorsomedial frontal cortex (DMFC), cingulate cortex, and orbitofrontal cortex. Significant increases of LCGU values were found in and around both banks of the AS, DMFC, and caudal principal, cingulate, and orbitofrontal cortices of monkeys executing visually guided saccades. All of these areas are oligosynaptically connected to extraocular motoneurons, as shown by the presence of retrogradely transneuronally labeled cells after injection of rabies virus in the lateral rectus muscle. Our data demonstrate that the arcuate oculomotor cortex occupies a region considerably larger than the classic, electrical stimulation-defined, frontal eye field. Besides a large part of the anterior bank of the AS, it includes the caudal prearcuate convexity and part of the premotor cortex in the posterior bank of the AS. They also demonstrate that the oculomotor DMFC occupies a small area straddling the ridge of the brain medial to the superior ramus of the AS. Our results support the notion that a network of several interconnected frontal lobe regions is activated during rapid, visually guided eye movements and that their output is conveyed in parallel to subcortical structures projecting to extraocular motoneurons.

Electrical stimulation of the frontal eye field in a monkey produces combined eye and head movements.

The frontal eye field (FEF), an area in the primate frontal lobe, has long been considered important for the production of eye movements. Past studies have evoked saccade-like movements from the FEF using electrical stimulation in animals that were not allowed to move their heads. Using electrical stimulation in two monkeys that were free to move their heads, we have found that the FEF produces gaze shifts that are composed of both eye and head movements. Repeated stimulation at a site evoked gaze shifts of roughly constant amplitude. However, that gaze shift could be accomplished with varied amounts of head and eye movements, depending on their (head and eye) respective starting positions. This evidence suggests that the FEF controls visually orienting movements using both eye and head rotations rather than just shifting the eyes as previously thought.

Neurosurgery for mental disorder: past and present

Carlyle Jacobsen and John Fulton, at Yale in the early and mid-1930s, investigated primate frontal lobe function. Following bilateral frontal lobecotomy, monkeys and chimpanzees developed a delayed-response deficit, being unable to perform tasks when there was a significant delay between the stimulus and the required response. There were accompanying behavioural changes, with the animals becoming more placid and lethargic and losing their characteristic inquisitive initiative. They became distractible, with difficulty in maintaining an attention set. They had great difficulty in adapting to changes in the directions of an already learned task, tending to perseverate.

On the relationship between synaptic input and spike output jitter in individual neurons.

What is the relationship between the temporal jitter in the arrival times of individual synaptic inputs to a neuron and the resultant jitter in its output spike? We report that the rise time of firing rates of cells in striate and extrastriate visual cortex in the macaque monkey remain equally sharp at different stages of processing. Furthermore, as observed by others, multiunit recordings from single units in the primate frontal lobe reveal a strong peak in their cross-correlation in the 10-150 msec range with very small temporal jitter (on the order of 1 msec). We explain these results using numerical models to study the relationship between the temporal jitter in excitatory and inhibitory synaptic input and the variability in the spike output timing in integrate-and-fire units and in a biophysically and anatomically detailed model of a cortical pyramidal cell. We conclude that under physiological circumstances, the standard deviation in the output jitter is linearly related to the standard deviation in the input jitter, with a constant of less than one. Thus, the timing jitter in successive layers of such neurons will converge to a small value dictated by the jitter in axonal propagation times.

Representation of object-centered space in the primate frontal lobe

Object-centered spatial awareness – awareness of locations of parts relative to an object – plays an important role in perception and action. Indirect evidence from psychological and neuropsychological studies has indicated that this form of spatial awareness may be served by a cortical system in which neurons encode specific object-centered locations. We set out to obtain direct evidence for object-centered spatial selectivity by recording from single neurons in the frontal cortex of monkeys trained to make eye movements to particular locations on reference objects. We found that neurons in the supplementary eye field (SEF) fire differentially as a function of the location on an object to which an eye movement is directed.

The sources of visual information to the primate frontal lobe: a novel role for the superior parietal lobule.

Reaching movements are performed in order to bring the hand to targets of interest. It is widely believed that the distributed cortical network underlying visual reaching transforms the information concerning the spatial location of the target into an appropriate motor command. Modern views decompose this process into sequences of coordinate transformations between informational domains. The set of cortical areas and pathways by which the information on target location is relayed from the visual areas of the occipital lobe to the motor areas of the frontal lobe have, so far, been poorly understood. Recent data from different fields of neuroscience offer the basis for a new definition of the cortical system subserving reaching and, at the same time, for a reconsideration of the nature of the underlying visuo-to-motor transformation.

Myelo‐ and cytoarchitecture of the granular frontal cortex and surrounding regions in the strepsirhine primate Galago and the anthropoid primate Macaca

As the first part of a comparative investigation of primate frontal cortex, we compared the frontal architectonic organization of Galago, a small-brained, strepsirhine (or "prosimian") primate, to that of an anthropoid primate, Macaca, by using myelin- and Nissl-stained material. We were able to distinguish many more areas in both taxa than have been recognized in most previous studies of the primate frontal lobe. In particular, we were able to subdivide many of the areas shown in the commonly cited architectonic map of Walker (J. Comp. Neurol. 73:59-86, 1940). Delineation of areas was greatly facilitated by the use of the Gallyas technique for staining myelin. The areal organization of much of frontal cortex (specifically, the premotor, orbital, and medial regions) appears to be very similar in Galago and Macaca. In these regions, we were able to recognize the same complement of areas in both taxa, with few exceptions. In the granular frontal cortex (GFC), by contrast, we were able to distinguish about twice as many areas in Macaca as in Galago. For most of the GFC areas of Galago, there are architectonically similar areas in Macaca; the areas shared by both taxa correspond mainly to the arcuate and superior areas of Macaca (i.e., the region encompassed by Walker's areas 45, 8A, and 8B). However, there are many additional, more rostral, areas in Macaca for which there are no obvious homologues in Galago. In particular, Galago lacks cortex resembling the distinctive, lightly myelinated cortex of the Macaca principal sulcus (Walker's area 46 and its subdivisions). Our results are difficult to reconcile with the view that frontal lobe organization varies little across taxa. Rather, they suggest that granular frontal cortex underwent considerable change during primate evolution, including the addition of new areas in anthropoids.

The nature of the medial wall deficit in the rat

Spatial and temporal (go/no-go) alternation tasks were run in a computerized Y-maze apparatus in an attempt to characterize the behavioral deficit which results from frontopolar and medial cortical lesions in rats. The medial cortex lesions caused a severe behavioral impairment on both tasks. The deficit is characterized as an inability to temporally organize recent events. This interpretation is consistent with theories of primate frontal lobe function based on similar data obtained in non-human primates and man.