Frontal cortical areas of the monkey brain engaged in reaching behavior: a (14)C-deoxyglucose imaging study.

The ((14)C)-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 24 c 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.

Projections from the superior temporal sulcus to the agranular frontal cortex in the macaque.

The aim of this study was to investigate the organization of the projections from the superior temporal sulcus (STS) to the various areas forming the agranular frontal cortex. Injections of retrograde neuronal tracers were made in the various agranular areas, in nine macaque monkeys. The results showed that two rostral premotor areas, F6 (pre-SMA) and F7, and the ventrorostral part of area F2 (F2vr) are targets of projections from the upper bank of the STS (uSTS). F6 and the dorsorostral part of F7 (supplementary eye field, SEF) are targets of projections from the rostral part of the uSTS, corresponding to the so-called 'superior temporal polysensory area' (STP). In contrast, the ventral part of area F7 (not including the SEF) and F2vr are targets of afferents from the caudal part of the uSTS. Ventral F7 is the target of weak afferents from the caudalmost and dorsalmost part of the uSTS (area 7a), whilst F2vr is the target of projections from a relatively more rostral and ventral sector of the uSTS, close to the fundus of the sulcus. This sector should correspond to area MST. In conclusion, F6 and SEF receive high order information from STP, whereas ventral F7 and F2vr receive information from areas of the dorsal visual stream.

The cortical connections of area V6: an occipito-parietal network processing visual information.

The aim of this work was to study the cortical connections of area V6 by injecting neuronal tracers into different retinotopic representations of this area. To this purpose, we first functionally recognized V6 by recording from neurons of the parieto-occipital cortex in awake macaque monkeys. Penetrations with recording syringes were performed in the behaving animals in order to inject tracers exactly at the recording sites. The tracers were injected into the central or peripheral field representation of V6 in different hemispheres. Irrespective of whether injections were made in the centre or periphery, area V6 showed reciprocal connections with areas V1, V2, V3, V3A, V4T, the middle temporal area /V5 (MT/V5), the medial superior temporal area (MST), the medial intraparietal area (MIP), the ventral intraparietal area (VIP), the ventral part of the lateral intraparietal area and the ventral part of area V6A (V6AV). No labelled cells or terminals were found in the inferior temporal, mesial and frontal cortices. The connections of V6 with V1, and with all the retinotopically organized prestriate areas, were organized retinotopically. The connection of V6 with MIP suggests a visuotopic organization for this latter. Labelling in V6A and VIP after either central or peripheral V6 injections was very similar in location and extent, as expected on the basis of the nonretinotopic organization of these areas. We suggest that V6 plays a pivotal role in the dorsal visual stream, by distributing the visual information coming from the occipital lobe to the sensorimotor areas of the parietal cortex. Given the functional characteristics of the cells of this network, we suggest that it could perform the fast form and motion analyses needed for the visual guiding of arm movements as well as their coordination with the eyes and the head.

Parietofrontal circuits for action and space perception in the macaque monkey.

The classical view of the functional role of the posterior parietal cortex has been radically changed in recent years. The parietal lobe is formed by a multiplicity of functionally distinct areas strongly and reciprocally connected in a rather selective way with the various areas forming the agranular frontal cortex (motor cortex). These connections-parietofrontal circuits-mediate, in parallel, the sensorimotor transformation for the control of specific actions. According to this view, space coding is now believed to be the result of the construction of multiple space representations that may be related to a specific class of actions. Therefore, the concept of one single parietal master center for space perception is no more tenable.

Functional neuroanatomy of the primate isocortical motor system.

The concept of the primate motor cortex based on the cytoarchitectonic subdivision into areas 4 and 6 according to Brodmann or the functional subdivision into primary motor, supplementary motor, and lateral premotor cortex has changed in recent years. Instead, this cortical region is now regarded as a complex mosaic of different areas. This review article gives an overview of the structure and function of the isocortical part of the motor cortex in the macaque and human brain. In the macaque monkey, the primary motor cortex (Brodmann's area 4 or area F1) with its giant pyramidal or Betz cells lies immediately anterior to the central sulcus. The non-primary motor cortex (Brodmann's area 6) lies further rostrally and can be subdivided into three groups of areas: the supplementary motor areas "SMA proper" (area F3) and "pre-SMA" (area F6) on the mesial cortical surface, the dorsolateral premotor cortex (areas F2 and F7) on the dorsolateral convexity, and the ventrolateral premotor cortex (areas F4 and F5) on the ventrolateral convexity. The primary motor cortex is mainly involved in controlling kinematic and dynamic parameters of voluntary movements, whereas non-primary motor areas are more related to preparing voluntary movements in response to a variety of internal or external cues. Since a structural map of the human isocortical motor system as detailed as in the macaque is not yet available, homologies between the two species have not been firmly established. There is increasing evidence, however, that a similar organizational principle (i.e., primary motor cortex, supplementary motor areas, dorso- and ventrolateral premotor cortex) also exists in humans. Imaging studies have revealed that functional gradients can be discerned within the human non-primary motor cortex. More rostral cortical regions are active when a motor task is nonroutine, whereas more routine motor actions engage more caudal areas.

Neurofilament protein distribution in the macaque monkey dorsolateral premotor cortex.

Regional and laminar distribution patterns of neurofilament proteins in the dorsolateral premotor cortex (PMd) were studied with monoclonal antibody SMI-32 in five adult macaque monkeys and compared with the cytoarchitectonical features of the PMd. Our goal was to reveal whether the increasing functional diversity of the PMd which electrophysiological studies have unravelled over the last years is reflected on a structural level by differences in the neurochemical phenotype. Differences in size, shape and packing density of immunopositive layer III and V pyramidal cells define areas much more clearly than do differences in cytoarchitecture. The PMd can be subdivided into a rostral and a caudal part at a level slightly anterior to the genu of the arcuate sulcus. The extent of these two areas matches the two cytoarchitectonically defined areas F7 and F2, respectively. Within area F2, differences in layer V immunoreactive neurons define a dorsal (F2d) and a ventral (F2v) region. The border between areas F2d and F2v lies at the superior precentral dimple and cannot be detected cytoarchitectonically in Nissl-stained sections. Neurofilament proteins are involved in the stabilization of the cytoskeleton of the axon and have been correlated with axonal size and conduction velocity of nerve fibres. This regional variability in the neurochemical phenotype of layer V within the caudal PMd may reflect a differential organization of the descending output from this part of the premotor cortex. It might also be related to differences in the motor control of voluntary arm and leg movements.

Largely segregated parietofrontal connections linking rostral intraparietal cortex (areas AIP and VIP) and the ventral premotor cortex (areas F5 and F4).

Two functionally different cortical areas are located in the rostral part of the intraparietal sulcus (IP): the ventral intraparietal area (VIP), along the fundus of the sulcus, and the anterior intraparietal area (AIP), rostral in the lateral bank. VIP and AIP have functional properties comparable to those of the ventral premotor areas, F4 and F5, respectively. The aim of this study was to establish whether these intraparietal and premotor areas have direct and specific anatomical connections. Neural tracers were injected in F4, F5, and AIP in three macaque monkeys. The results showed that F4 and F5 are targets of strong projections from VIP and AIP, respectively, and that the linkage between F5 and AIP is highly selective. These data support the notion that parietofrontal connections selectively link areas displaying similar functional properties and form largely segregated anatomical circuits. Each of these circuits is possibly dedicated to specific aspects of sensorimotor transformations. In particular, the AIP-F5 circuit should play a crucial role in visuomotor transformation for grasping, the VIP-F4 circuit is possibly involved in peripersonal space coding for movement.

Visual responses in the dorsal premotor area F2 of the macaque monkey.

This study aimed to determine the presence of neurons responding to visual stimuli in area F2 of the dorsal premotor cortex of the macaque monkey. In order to delimit the sector in which visually responsive neurons are located, the somatotopic organization of area F2 was studied with intracortical microstimulation and single neuron recording. The results showed that: (1) in area F2 there is a significant percentage of visually responsive neurons (15.9% of all recorded neurons); (2) area F2 is excitable with a low-threshold current (average 28.1 microA) and has a somatotopic representation of the whole body, except the face; and (3) most visually driven neurons (n=130 out of 169) are concentrated within the rostrolateral sector of the forelimb representation of area F2, thus providing for the first time functional support for the neuroanatomical evidence that the visual input to area F2 is mostly restricted to this sector.

Superior area 6 afferents from the superior parietal lobule in the macaque monkey.

Superior area 6 of the macaque monkey frontal cortex is formed by two cytoarchitectonic areas: F2 and F7. In the present experiment, we studied the input from the superior parietal lobule (SPL) to these areas by injecting retrograde neural tracers into restricted parts of F2 and F7. Additional injections of retrograde tracers were made into the spinal cord to define the origin of corticospinal projections from the SPL. The results are as follows: 1) The part of F2 located around the superior precentral dimple (F2 dimple region) receives its main input from areas PEc and PEip (PE intraparietal, the rostral part of area PEa of Pandya and Seltzer, [1982] J. Comp. Neurol. 204:196-210). Area PEip was defined as that part of area PEa that is the source of corticospinal projections. 2) The ventrorostral part of F2 is the target of strong projections from the medial intraparietal area (area MIP) and from the dorsal part of the anterior wall of the parietooccipital sulcus (area V6A). 3) The ventral and caudal parts of F7 receive their main parietal input from the cytoarchitectonic area PGm of the SPL and from the posterior cingulate cortex. 4) The dorsorostral part of F7, which is also known as the supplementary eye field, is not a target of the SPL, but it receives mostly afferents from the inferior parietal lobule and from the temporal cortex. It is concluded that at least three separate parietofrontal circuits link the superior parietal lobule with the superior area 6. Considering the functional properties of the areas that form these circuits, it is proposed that the PEc/PEip-F2 dimple region circuit is involved in controlling movements on the basis of somatosensory information, which is the traditional role proposed for the whole dorsal premotor cortex. The two remaining circuits appear to be involved in different aspects of visuomotor transformations.

The organization of the cortical motor system: new concepts.

A series of recent anatomical and functional data has radically changed our view on the organization of the motor cortex in primates. In the present article we present this view and discuss its fundamental principles. The basic principles are the following: (a) the motor cortex, defined as the agranular frontal cortex, is formed by a mosaic of separate areas, each of which contains an independent body movement representation, (b) each motor area plays a specific role in motor control, based on the specificity of its cortical afferents and descending projections, (c) in analogy to the motor cortex, the posterior parietal cortex is formed by a multiplicity of areas, each of which is involved in the analysis of particular aspects of sensory information. There are no such things as multipurpose areas for space or body schema and (d) the parieto-frontal connections form a series of segregated anatomical circuits devoted to specific sensorimotor transformations. These circuits transform sensory information into action. They represent the basic functional units of the motor system. Although these conclusions mostly derive from monkey experiments, anatomical and brain-imaging evidence suggest that the organization of human motor cortex is based on the same principles. Possible homologies between the motor cortices of humans and non-human primates are discussed.

Parcellation of human mesial area 6: cytoarchitectonic evidence for three separate areas.

The mesial sector of primate area 6 is usually described as consisting of two distinct areas: the supplementary motor area (SMA or SMA proper) and the pre-SMA. Recent human brain imaging studies showed, however, that this subdivision is not completely satisfactory and that, most likely, SMA proper consists of two functionally distinct parts. In order to elucidate whether this hypothesis has an anatomical counterpart, we examined the cytoarchitectonic organization of human mesial area 6 in three brains of subjects deceased without any previous sign of neurological disorders. The data showed that human mesial area 6 consists of three separate cytoarchitectonic areas. Two of them are located mostly caudal to the vertical line transversing the anterior commissure (VCA line), the third one is located rostral to it. Given the location and some architectonic similarities between the two caudal areas, we named them caudal SMA (SMAc) and rostral SMA (SMAr). The area rostral to the VCA line is referred to as pre-SMA. The possible functional role of the three areas is discussed.

Receptor autoradiographic mapping of the mesial motor and premotor cortex of the macaque monkey.

This study analyzes regional and laminar distribution patterns of neurotransmitter binding sites in the motor areas of the macaque mesial frontal cortex. Differences in distribution patterns are compared with the cytoarchitectonic parcellation. Binding sites were analyzed with quantitative in vitro receptor autoradiography in unfixed brains of five macaque monkeys. Alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) binding sites were labeled with [3H]AMPA, [3H]kainate, and [3H]MK-801, respectively, muscarinic binding sites with [3H]pirenzepine or [3H]oxotremorine-M, noradrenergic binding sites with [3H]prazosin or [3H]UK-14304, gamma-aminobutyric acid (GABA)A binding sites with [3H]muscimol, and serotoninergic binding sites with [3H]ketanserine. Adjacent sections were stained with a modified Nissl method for cytoarchitectonic analysis. In the motor areas F1, F3, and F6, [3H]AMPA, [3H]pirenzepine, and [3H]oxotremorine-M binding was maximal in layers II, III, and V, and [3H]kainate binding was maximal in layers V and VI. Clear-cut changes in laminar distribution patterns of [3H]AMPA, [3H]kainate, and [3H]oxotremorine-M binding sites very closely matched corresponding cytoarchitectonic borders. Mean areal binding densities of all ligands to F1, F3, and F6 were plotted as polar plots for each area. A polygon was obtained for each area ("neurochemical fingerprint") when all the density values belonging to one area were connected with each other. The "neurochemical fingerprints" of F1, F3, and F6 were virtually identical in shape but increased in size from F1 to F6. This result reflects the functional similarity of these motor-related areas and possibly correlates with their differential involvement in motor control. Areas F1, F3, and F6 can thus be grouped into one "neurochemical family" of areas.

Localization of grasp representations in humans by PET: 1. Observation versus execution.

Positron emission tomography (PET) was used to localize brain regions that are active during the observation of grasping movements. Normal, right-handed subjects were tested under three conditions. In the first, they observed grasping movements of common objects performed by the experimenter. In the second, they reached and grasped the same objects. These two conditions were compared with a third condition consisting of object observation. On the basis of monkey data, it was hypothesized that during grasping observation, activations should be present in the region of the superior temporal sulcus (STS) and in inferior area 6. The findings in humans demonstrated that grasp observation significantly activates the cortex of the middle temporal gyrus including that of the adjacent superior temporal sulcus (Brodmann's area 21) and the caudal part of the left inferior frontal gyrus (Brodmann's area 45). The possible functional homologies between these areas and the monkey STS region and frontal area F5 are discussed.

Thalamic input to mesial and superior area 6 in the macaque monkey.

The aim of the present study was to define the origin of the thalamocortical projections to each of the mesial and superior area 6 areas. To this purpose, restricted injections of neuronal tracers were made into areas F3, F6, F2, and F7 after physiological identification of the injection sites. The results showed that each of these areas receives afferents from a set of thalamic nuclei and that this set differs, qualitatively and quantitatively, according to the injected area. The main inputs to F3 [supplementary motor area properly defined (SMA-proper)] originate in the nuclei ventral lateral, pars oralis (VLo), ventral posterior lateral, pars oralis (VPLo), and ventral lateral, pars caudalis (VLc) as well as in caudal parts of the VPLo and VLc (VPLo/VLc complex). F6 (pre-SMA) is mainly the target of nucleus ventral anterior, pars parvocellularis (VApc), and area X of Olszewski. The input to F2 originates mainly in the VPLo/VLc complex, in VLc, and in VLo. The dorsal part of F7 (supplementary eye field) mainly receives from area X, VApc, and nucleus ventral anterior, pars magnocellularis (VAmc), whereas the ventral F7 is connected with VApc, area X, VLc, and the VPLo/VLc complex. All of the injected areas receive a strong projection from the medial dorsal nucleus (MD). It is concluded that each cortical area is a target of both cerebellar and basal ganglia circuits. F3 and F2 are targets of the so-called "motor" basal ganglia circuit and a cerebellar circuit originating in dorsorostral sectors of dentate and interpositus nuclei. In contrast, F6 and ventral F7 receive a basal ganglia input mainly from the so-called "complex" circuit and a cerebellar input originating in the ventrocaudal sectors of dentate and interpositus nuclei. Finally, with respect to the rest of F7, dorsal F7 also receives a basal ganglia input from the "oculomotor circuit."

Coding of peripersonal space in inferior premotor cortex (area F4).

1. We studied the functional properties of neurons in the caudal part of inferior area 6 (area F4) in awake monkeys. In agreement with previous reports, we found that the large majority (87%) of neurons responded to sensory stimuli. The responsive neurons fell into three categories: somatosensory neurons (30%); visual neurons (14%); and bimodal, visual and somatosensory neurons (56%). Both somatosensory and bimodal neurons typically responded to light touch of the skin. Their RFs were located on the face, neck, trunk, and arms. Approaching objects were the most effective visual stimuli. Visual RFs were mostly located in the space near the monkey (peripersonal space). Typically they extended in the space adjacent to the tactile RFs. 2. The coordinate system in which visual RFs were coded was studied in 110 neurons. In 94 neurons the RF location was independent of eye position, remaining in the same position in the peripersonal space regardless of eye deviation. The RF location with respect to the monkey was not modified by changing monkey position in the recording room. In 10 neurons the RF's location followed the eye movements, remaining in the same retinal position (retinocentric RFs). For the remaining six neurons the RF organization was not clear. We will refer to F4 neurons with RF independent of eye position as somatocentered neurons. 3. In most somatocentered neurons (43 of 60 neurons) the background level of activity and the response to visual stimuli were not modified by changes in eye position, whereas they were modulated in the remaining 17. It is important to note that eye deviations were constantly accompanied by a synergic increase of the activity of the ipsilateral neck muscles. It is not clear, therefore, whether the modulation of neuron discharge depended on eye position or was a consequence of changes in neck muscle activity. 4. The effect of stimulus velocity (20-80 cm/s) on neuron response intensity and RF extent in depth was studied in 34 somatocentered neurons. The results showed that in most neurons the increase of stimulus velocity produced an expansion in depth of the RF. 5. We conclude that space is coded differently in areas that control somatic and eye movements. We suggest that space coding in different cortical areas depends on the computational necessity of the effectors they control.

Mapping of human and macaque sensorimotor areas by integrating architectonic, transmitter receptor, MRI and PET data.

The human and macaque sensorimotor cortex was subdivided into numerous areas by a correlative analysis based on cytoarchitectonics, myeloarchitecture and the distribution of transmitter receptors. Receptor densities and laminar distribution patterns differ not only between motor and somatosensory regions, but also between different areas within these regions of the cortex. Changes in receptor distribution often match architectonically defined borders. Receptor findings provide new criteria for a more detailed mapping in the human brain which cannot be achieved by cytoarchitectonic analysis alone. Morphological data on these areas were integrated with functional data from positron emission tomography (PET) on the basis of a recently developed computerised brain atlas. The central sulcus marks the border between (1) the agranular motor cortex with a generally low density of glutamatergic, muscarinic, GABAergic and serotoninergic receptors, and (2) the granular somatosensory cortex with higher densities of these receptors. Rostral to the primary motor cortex, 2 isocortical areas are found on the mesial cortex which probably represent the functionally defined supplementary motor areas (SMA) SMA-proper (caudally) and pre-SMA (rostrally). Below SMA-proper the areas 24d (macaque) and the caudal cingulate motor area cmc (human) are located in the cingulate sulcus. Both regions correspond to the 'posterior cingulate motor areas' of recent PET studies and to the posterior part of the agranular cingulate cortex of architectonic studies. Below pre-SMA the area 24c (macaque) and the rostral cingulate motor area cmr (human) are located in the cingulate sulcus; they correspond to the 'anterior cingulate motor areas' of recent PET observations and to the anterior part of the agranular cingulate cortex of architectonic studies. Homologous sensorimotor areas can be defined in both species on the basis of common architectonic features.

Convergence of pallidal and cerebellar outputs on the frontal motor areas.

The general pattern of the organization of the thalamo-cortical projections to the agranular frontal cortex of the monkey is still matter of debate. An important issue is whether each motor area is the target of a single thalamic nucleus or it receives afferences from multiple thalamic sources. In this light it is of interest to determine whether the basal ganglia and cerebellar outputs, which are segregated in the thalamus, remain segregated also at the cortical level or, on the contrary, both converge on the same cortical areas. In the present article we present data concerning the thalamic input to mesial area 6 obtained with cortical injections of retrograde neural tracers. This cortical sector, classically considered as coextensive with the so called supplementary motor area (SMA), was recently found to be formed by two independent anatomo-functional areas: F3 (SMA-proper) and F6 (pre-SMA). On the basis of the neurophysiological properties of the two areas we have proposed that F6 plays a hierarchically higher role in motor control than F3. The present results allow us the following main conclusions: a) Each motor area is the target of a distinct set of thalamic nuclei. b) Each area is the target of both basal ganglia and cerebellar outflows. c) As far as the basal ganglia input is concerned, F3 is a part of the so called "basal ganglia motor loop", whereas, F6 belongs to the "basal ganglia complex loop". This differential basal ganglia input provides further evidence in favor of a higher hierarchical role of F6 in comparison to F3.