Frontal Lobe and Posterior Parietal Contributions to the Cortico-cerebellar System

Our growing understanding of how cerebral cortical areas communicate with the cerebellum in primates has enriched our understanding of the data that cerebellar circuits can access, and the neocortical areas that cerebellar activity can influence. The cerebellum is part of some large-scale networks involving several parts of the neocortex including association areas in the frontal lobe and the posterior parietal cortex that are known for their contributions to higher cognitive function. Understanding their connections with the cerebellum informs the debates around the role of the cerebellum in higher cognitive functions because they provide mechanisms through which association areas and the cerebellum can influence each others' operations. In recent years, evidence from connectional anatomy and human neuroimaging have comprehensively overturned the view that the cerebellum contributes only to motor control. The aim of this review is to examine our changing perspectives on the nature of cortico-cerebellar anatomy and the ways in which it continues to shape our views on its contributions to function. The review considers the anatomical connectivity of the cerebellar cortex with frontal lobe areas and the posterior parietal cortex. It will first focus on the anatomical organisation of these circuits in non-human primates before discussing new findings about this system in the human brain. It has been suggested that in non-human primates "although there is a modest input from medial prefrontal cortex, there is very little or none from the more lateral prefrontal areas" [33]. This review discusses anatomical investigations that challenge this claim. It also attempts to dispel the misconception that prefrontal projections to the cerebellum are from areas concerned only with the kinematic control of eye movements. Finally, I argue that our revised understanding of anatomy compels us to reconsider conventional views of how these systems operate in the human brain.     

Connectivity-based parcellation of the human orbitofrontal cortex

The primate orbitofrontal cortex (OFC) is involved in reward processing, learning, and decision making. Research in monkeys has shown that this region is densely connected with higher sensory, limbic, and subcortical regions. Moreover, a parcellation of the monkey OFC into two subdivisions has been suggested based on its intrinsic anatomical connections. However, in humans, little is known about any functional subdivisions of the OFC except for a rather coarse medial/lateral distinction. Here, we used resting-state fMRI in combination with unsupervised clustering techniques to investigate whether OFC subdivisions can be revealed based on their functional connectivity profiles with other brain regions. Examination of different cluster solutions provided support for a parcellation into two parts as observed in monkeys, but it also highlighted a much finer hierarchical clustering of the orbital surface. Specifically, we identified (1) a medial, (2) a posterior-central, (3) a central, and (4-6) three lateral clusters spanning the anterior-posterior gradient. Consistent with animal tracing studies, these OFC clusters were connected to other cortical regions such as prefrontal, temporal, and parietal cortices but also subcortical areas in the striatum and the midbrain. These connectivity patterns provide important implications for identifying specific functional roles of OFC subdivisions for reward processing, learning, and decision making. Moreover, this parcellation schema can provide guidance to report results in future studies.     

Visuo‐motor transformations for arm reaching

Visuomanual co-ordination requires the merging of ocular and arm information in a common frame of reference. Here we consider behavioural evidence in humans for the use of a viewer-centred frame in the specification of end point positions of reaching. We then review anatomical and neurophysiological data in the non-human primate that indicate a prominent role of the parietal cortex in the process of multisensory fusion that leads to egocentric representations of space. Finally, we discuss the functional anatomy of the human parietal cortex in visuomanual co-ordination as revealed by neuroimaging.     

Projections from orbitofrontal cortex to anterior piriform cortex in the rat suggest a role in olfactory information processing

The orbitofrontal cortex (OFC) has been characterized as a higher-order, multimodal sensory cortex. Evidence from electrophysiological and behavioral studies in the rat has suggested that OFC plays a role in modulating olfactory guided behavior, and a significant projection to OFC arises from piriform cortex, the traditional primary olfactory cortex. To discern how OFC interacts with primary olfactory structures, the anterograde tracer Phaseolus vulgaris leucoagglutinin was injected into orbitofrontal cortical areas in adult male rats. Labeled fibers were found in the piriform cortex and olfactory bulb on the side ipsilateral to the injection. Notably, the projection to piriform cortex was predominantly from ventrolateral orbital cortex, and was not uniform; rostrally, the projection to the ventral portion of the anterior piriform cortex (APC) was substantial, while the dorsal APC was virtually free of labeled fibers. Labeled fibers were found in both the dorsal and ventral portions in more caudal regions of APC. Most labeled fibers were found in layer III, although a substantial number of fibers were observed in layers Ib and II. Labeled fibers in posterior piriform cortex also were seen after injection into orbitofrontal areas. Taken together with previous reports, these findings suggest that piriform cortex includes multiple subdivisions, which may perform separate, parallel functions in olfactory information processing. Further, these results suggest that the OFC, in addition to its putative role in encoding information about the significance of olfactory stimuli, may play a role in modulating odor response properties of neurons in piriform cortex.     

Cortical association areas in the gustatory system

The existence, location and interrelationships of cortical gustatory association areas in primates and rodents are discussed. Based on previous proposals, and on anatomical, physiological and lesion data, we propose that in addition to primary gustatory cortex, located in primate opercular cortex and rodent granular insular cortex, three association areas exist. A secondary area is located in dysgranular insular cortex, a tertiary area in agranular insular cortex, and the terminus of the cortical gustatory analyzer is located in perirhinal cortex. We propose that the subjective awareness of flavor is most probably due to neuronal activities in agranular insular cortex.     

The prefrontal cortex: comparative architectonic organization in the human and the macaque monkey brains

Detailed cytoarchitectonic studies of the human cerebral cortex appeared during the first quarter of the 20th century. The incorporation of the cytoarchitectonic map by Brodmann (1909) in the Talairach proportional stereotaxic space (Talairach and Tournoux, 1988) has established the Brodmann numerical nomenclature as the basis for describing the cortical location of structural and functional findings obtained with modern neuroimaging. In experimental anatomical and physiological investigations of the macaque monkey performed during the last 50 years, the numerical architectonic nomenclature used to describe findings in the prefrontal cortex has been largely based on the map by Walker (1940). Unfortunately, the map by Walker was not based on a comparative investigation of the cytoarchitecture of the human and macaque monkey prefrontal cortex and, as a result, the nomenclature and the criteria for demarcating areas in the two primate species are not always consistent. These discrepancies are a major obstacle in the ability to compare experimental findings from nonhuman primates with results obtained in functional and structural neuroimaging of the human brain. The present article outlines these discrepancies in the classical maps and describes comparative investigations of the cytoarchitecture of the prefrontal cortex of the macaque monkey and human (Petrides and Pandya, 1994, Petrides and Pandya, 1999, Petrides and Pandya, 2002a) in order to resolve these discrepancies and enable easy translation of experimental research in the monkey to findings in the human brain obtained with modern neuroimaging.     

The Functional Organization of Working Memory Processes Within Human Lateral Frontal Cortex: The Contribution of Functional Neuroimaging

Recent functional neuroimaging studies have provided a wealth of new information about the likely organization of working memory processes within the human lateral frontal cprtex. This article seeks to evaluate the results of these studies in the context of two contrasting theoretical models of lateral frontal-lobe function, developed through lesion and electrophysiological recording work in non-human primates (Goldman-Rakic, 1994, 1995; Petrides, 1994, 1995). Both models focus on a broadly similar distinction between anatomically and cytoarchitectonically distinct dorsolateral and ventrolateral frontal cortical areas, but differ in the precise functions ascribed to those regions. Following a review of the relevant anatomical data, the origins of these two theoretical positions are considered in some detail and the main predictions arising from each are identified. Recent functional neuroimaging studies of working memory processes are then critically reviewed in order to assess the extent to which they support either, or both, sets of predictions. The results of this meta-analysis suggest that lateral regions of the frontal lobe are not functionally organized according to stimulus modality, as has been widely assumed, but that specific regions within the dorsolateral or ventrolateral frontal cortex make identical functional contributions to both spatial and non-spatial working memory.     

Do rats have a prefrontal cortex?

The lack of a single anatomical or functional definition of 'prefrontal cortex' has led to different and, in some respects, controversial views on the existence of a prefrontal cortex in non-primate mammals, in particular in rats. Until the classic paper by Rose and Woolsey [Res. Publ. Assoc. Nerv. Ment. Dis. 27 (1948) 210], the general idea was that a prefrontal cortex is unique to primate species. Rose and Woolsey's 'prefrontal cortex' definition was based upon a single anatomical criterion, i.e. the cortical projection area of the mediodorsal thalamic nucleus. Single criteria, however, do not appear to be sufficient for defining the prefrontal cortex. Therefore, other anatomical and functional characteristics are currently used to identify the prefrontal cortex in different species. Yet, recently the debate about the nature of the prefrontal cortex in non-primate species has been resumed. In the present paper we will compare the structural and functional characteristics of the prefrontal cortex of nonhuman primates and rats. We will argue that rats have a functionally divided prefrontal cortex that includes not only features of the medial and orbital areas in primates, but also some features of the primate dorsolateral prefrontal cortex.     

Localization of human intraparietal areas AIP, CIP, and LIP using surface orientation and saccadic eye movement tasks

In monkeys, areas in the intraparietal sulcus (IPS) play a crucial role in visuospatial information processing. Despite many human neuroimaging studies, the location of the human functional homologs of some IPS areas is still a matter of debate. The aim of the present functional magnetic resonance imaging (fMRI) study was to identify the distinct locations of specific human IPS areas based on their functional properties using stimuli adapted from nonhuman primate experiments, in particular, surface orientation discrimination and memory guided saccadic eye movements (SEM). Intersubject anatomical variability likely accounts for much of the debate. By applying subject by subject analysis, we can demonstrate that sufficient intersubject anatomical and functional commonalities exist. Both the lateral bank of the anterior part of IPS, the putative human homolog of the area AIP, and the caudal part of the IPS (putative CIP) showed activation related to spatial discrimination of surface orientation. Eye tracking conducted during fMRI data acquisition allowed us to show that both areas were separated by an area related to SEM. This area was located in the middle region of the IPS (most probably including LIP), i.e., similar to the location observed in nonhuman primates. In 10 of 11 subjects our putative CIP activation was located in a medial side branch of the posterior part of the IPS, on the opposite side as described in nonhuman primates, making this landmark a useful anatomical marker for the location of CIP.     

Mapping the functional neuroanatomy of the intact human brain with brain work imaging

The recent development of noninvasive methods for measuring local rates of energy metabolism or blood flow in the brain has made it possible to investigate functional neuroanatomy in healthy human subjects. The best of these methods, high resolution measurement of regional cerebral blood flow (rCBF) with positron emission tomography (PET), provides a precision of anatomical localization that far exceeds that attainable with human brain lesion studies. Moreover, the study of healthy subjects avoids possible confounding effects of brain lesions, such as compensatory reorganization of brain function. PET-rCBF studies have already identified several cortical areas involved in higher-order visual processing, indicating that functional neuroimaging may yield a map of human visual cortex analogous to maps that have been developed by vision research in nonhuman primates. PET-rCBF studies of imagery and language demonstrate the potential of functional neuroimaging to map regions of human cortex that perform functions that cannot be studied so easily in nonhuman primates or perform functions that humans do not share with other species.     

Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat

We utilised retrograde and anterograde tracing procedures to study the origin and termination of prefrontal cortical (PFC) projections to the periaqueductal gray (PAG) in the rat. A previous study, in the primate, had demonstrated that distinct subgroups of PFC areas project to specific PAG columns. Retrograde tracing experiments revealed that projections to dorsolateral (dlPAG) and ventrolateral (vlPAG) periaqueductal gray columns arose from medial PFC, specifically prelimbic, infralimbic, and anterior cingulate cortices. Injections made in the vlPAG also labeled cells in medial, ventral, and dorsolateral orbital cortex and dorsal and posterior agranular insular cortex. Other orbital and insular regions, including lateral and ventrolateral orbital, ventral agranular insular, and dysgranular and granular insular cortex did not give rise to appreciable projections to the PAG. Anterograde tracing experiments revealed that the projections to different PAG columns arose from specific PFC areas. Projections from the caudodorsal medial PFC (caudal prelimbic and anterior cingulate cortices) terminated predominantly in dlPAG, whereas projections from the rostroventral medial PFC (rostral prelimbic cortex) innervated predominantly the vlPAG. As well, consistent with the retrograde data, projections arising from select orbital and agranular insular cortical areas terminated selectively in the vlPAG. The results indicate: (1) that rat orbital and medial PFC possesses an organisation broadly similar to that of the primate; and (2) that subdivisions within the rat orbital and medial PFC can be recognised on the basis of projections to distinct PAG columns.     

Medial orbitofrontal cortex codes relative rather than absolute value of financial rewards in humans

Functional imaging studies in recent years have confirmed the involvement of orbitofrontal cortex (OFC) in human reward processing and have suggested that OFC responses are context-dependent. A seminal electrophysiological experiment in primates taught animals to associate abstract visual stimuli with differently valuable food rewards. Subsequently, pairs of these learned abstract stimuli were presented and firing of OFC neurons to the medium-value stimulus was measured. OFC firing was shown to depend on the relative value context. In this study, we developed a human analogue of this paradigm and scanned subjects using functional magnetic resonance imaging. The analysis compared neuronal responses to two superficially identical events, which differed only in terms of the preceding context. Medial OFC response to the same perceptual stimulus was greater when the stimulus predicted the more valuable of two rewards than when it predicted the less valuable. Additional responses were observed in other components of reward circuitry, the amygdala and ventral striatum. The central finding is consistent with the primate results and suggests that OFC neurons code relative rather than absolute reward value. Amygdala and striatal involvement in coding reward value is also consistent with recent functional imaging data. By using a simpler and less confounded paradigm than many functional imaging studies, we are able to demonstrate that relative financial reward value per se is coded in distinct subregions of an extended reward and decision-making network.     

Cortical plasticity after stroke: implications for rehabilitation.

While adaptive processes in the cerebral cortex have long been thought to contribute to functional recovery after stroke, the precise neuronal structures and mechanisms underlying these processes have been difficult to identify. Over the past 15 years, a large number of studies conducted in human stroke patients and in experimental animal models have contributed to a more coherent picture of the brain's adaptive capacity after injury. These studies suggest that the cerebral cortex undergoes significant and functional structural plasticity for at least several weeks to months following injury. Adaptive changes have been demonstrated in the intact tissue surrounding the lesion, as well as in other cortical motor areas remote from the site of injury. Recent results from non-human primate studies of cortical reorganization after stroke demonstrate marked functional changes in the intact cortical tissue adjacent to the infarct in the weeks following an ischemic lesion. Further, intensive task-specific practice with the impaired limb has a modulatory effect on the inevitable cortical plasticity. Taken together with parallel studies of forced use in human stroke patients, it is likely that use of the impaired limb can influence adaptive reorganizational mechanisms in the intact cerebral cortex, and thus, promote functional recovery.     

Sexual dimorphism and laterality in the evolution of the primate prefrontal cortex

Social selective pressures are commonly considered as the main driving force of primate brain evolution. Primate social behaviour is, however, known to be sexually dimorphic, and no previous study has made a direct comparison between male and female brain structures across species. We quantify sex-specific evolutionary trends in the prefrontal cortex of anthropoid primates (including humans) to investigate how sexual selection has shaped brain evolution in primates. The prefrontal cortex is of particular importance to the investigation of sexual dimorphism in primate brain evolution because of its association to those cognitive capacities central to primate (and human) evolution: sociality and higher-order cognitive processing. Our results demonstrate sex-by-hemisphere differences in the evolution of the prefrontal cortex in humans and non-human anthropoid primates congruent with the principal selective pressures considered to underlie anthropoid behavioural evolution. Our findings further show how sexual selection can shape brain adaptation in primates and provide an evolutionary framework for interpreting sex and sex-by-hemisphere differences in cortical organization in humans and non-human primates.     

Direct comparison of visual cortex activation in human and non-human primates using functional magnetic resonance imaging

We report a technique for functional magnetic resonance imaging (fMRI) in an awake, co-operative, rhesus macaque (Macaca mulatta) in a conventional 1.5T clinical MR scanner, thus accomplishing the first direct comparison of activation in visual cortex between humans and non-human primates with fMRI. Activation was seen in multiple areas of striate and extra-striate visual cortex and in areas for motion, object and face recognition in the monkey and in homologous visual areas in a human volunteer. This article describes T1, T2 and T2* values for macaque cortex, suitable MR imaging sequences, a training schedule, stimulus delivery apparatus and restraining hardware for monkey fMRI using a conventional 19 cm knee coil. Much of our understanding of the functional organization of the primate brain comes from physiological studies in monkeys. Direct comparison between species using fMRI such as those described here will help us to relate the wealth of existing knowledge on the functional organization of the non-human primate brain to human fMRI.     

Social attachment in juvenile monkeys with neonatal lesion of the hippocampus, amygdala and orbital frontal cortex

Non-human primates, like humans, develop and maintain social relationships and attachments throughout their life. The first and most crucial relationship in a primate life is that with its mother. Yet, in absence of their biological mother, infant primates form attachment to surrogate mothers. Although, this early attachment is critical for the development of normal species-typical social and emotional skills, the neural substrates underlying the formation of social relationships in primates are still unclear. The present study assessed, in infant rhesus monkeys (Macaca mulatta) reared by human caregivers and social interactions with peers, the effects of bilateral neonatal (1-2 weeks of age) ibotenic acid lesions of the amygdala and hippocampus (N=6 in each group), aspiration lesions of the orbital frontal cortex (N=6) or sham lesions (N=5) on the development of a social attachment with the principal human caregiver. A specific preference for the later was assessed at 11 months of age, in a two-choice discrimination task, opposing the principal human caregiver to another familiar human, in a familiar environment. None of the lesions impaired the expression of preferential responses toward the principal human caregiver. Nevertheless, lesions of the orbital frontal cortex led to a weaker preference, suggesting that this structure may play a role in the quality and/or strength of the infant/mother relationships. The present non-human primate findings are discussed in terms of their relevance for autism.     

Taste-olfactory convergence, and the representation of the pleasantness of flavour, in the human brain

The functional architecture of the central taste and olfactory systems in primates provides evidence that the convergence of taste and smell information onto single neurons is realized in the caudal orbitofrontal cortex (and immediately adjacent agranular insula). These higher-order association cortical areas thus support flavour processing. Much less is known, however, about homologous regions in the human cortex, or how taste-odour interactions, and thus flavour perception, are implemented in the human brain. We performed an event-related fMRI study to investigate where in the human brain these interactions between taste and odour stimuli (administered retronasally) may be realized. The brain regions that were activated by both taste and smell included parts of the caudal orbitofrontal cortex, amygdala, insular cortex and adjoining areas, and anterior cingulate cortex. It was shown that a small part of the anterior (putatively agranular) insula responds to unimodal taste and to unimodal olfactory stimuli, and that a part of the anterior frontal operculum is a unimodal taste area (putatively primary taste cortex) not activated by olfactory stimuli. Activations to combined olfactory and taste stimuli where there was little or no activation to either alone (providing positive evidence for interactions between the olfactory and taste inputs) were found in a lateral anterior part of the orbitofrontal cortex. Correlations with consonance ratings for the smell and taste combinations, and for their pleasantness, were found in a medial anterior part of the orbitofrontal cortex. These results provide evidence on the neural substrate for the convergence of taste and olfactory stimuli to produce flavour in humans, and where the pleasantness of flavour is represented in the human brain.     

Somatotopic organization of the medial wall of the cerebral hemispheres: a 3 Tesla fMRI study.

Somatotopic organization of the human medial wall of the cerebral hemispheres was studied using functional MRI conducted at high field strength (3 T) with fine spatial resolution ( approximately 2 mm). Healthy subjects performed paced, repetitive movements of the fingers and toes. Within the supplementary motor area (SMA), two regions were identified: finger movements activated a region rostral and superior to that for toe movements. Two activation foci were also identified in the cingulate motor area: toe movements activated a region rostral and ventral to that activated by finger movements. All foci were located between the anterior and posterior commissures. Our results confirm previous human and non-human primate studies regarding the rostral-caudal organization of the SMA and CMA. The dorsal-ventral organization of the CMA, however, appears to be divergent from results derived from cortical stimulation studies conducted in non-human primates.     

Large-scale cortical networks and cognition

The well-known parcellation of the mammalian cerebral cortex into a large number of functionally distinct cytoarchitectonic areas presents a problem for understanding the complex cortical integrative functions that underlie cognition. How do cortical areas having unique individual functional properties cooperate to accomplish these complex operations? Do neurons distributed throughout the cerebral cortex act together in large-scale functional assemblages? This review examines the substantial body of evidence supporting the view that complex integrative functions are carried out by large-scale networks of cortical areas. Pathway tracing studies in non-human primates have revealed widely distributed networks of interconnected cortical areas, providing an anatomical substrate for large-scale parallel processing of information in the cerebral cortex. Functional coactivation of multiple cortical areas has been demonstrated by neurophysiological studies in non-human primates and several different cognitive functions have been shown to depend on multiple distributed areas by human neuropsychological studies. Electriphysiological studies on interareal synchronization have provided evidence that active neurons in different cortical areas may become not only coactive, but also functionally interdependent. The computational advantages of synchronization between cortical areas in large-scale networks have been elucidated by studies using artificial neural network models. Recent observations of time-varying multi-areal cortical synchronization suggest that the functional topology of a large-scale cortical network is dynamically reorganized during visuomotor behavior.     

Social modulation of cognition: Lessons from rhesus macaques relevant to education

Any animal, human or non-human, lives in a world where there are others like itself. Individuals’ behaviors are thus inevitably influenced by others, and cognition is no exception. Long acknowledged in psychology, social modulations of cognition have been neglected in cognitive neuroscience. Yet, infusing this classic topic in psychology with brain science methodologies could yield valuable educational insights. In recent studies, we used a non-human primate model, the rhesus macaque, to identify social influences representing ancient biases rooted in evolution, and neuroimaging to shed light on underlying mechanisms. The behavioral and neural data garnered in humans and macaques are summarized, with a focus on two findings relevant to human education. First, peers’ mistakes stand out as exceptional professors and seem to have devoted areas and neurons in the primates’ brain. Second, peers’ mere presence suffices to enhance performance in well-learned tasks, possibly by boosting activity in the brain network involved in the task at hand. These findings could be translated into concrete pedagogical interventions in the classroom.