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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.

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.

We injected neural tracers into the lateral funiculus of the spinal cord in order to relate the sites of origin of the spinal projections from the mesial cortical surface with the cytoarchitectonic organization of this region. We found a close correlation between the origin sites and density of corticospinal projections and the areal organization. The areas most densely labelled were F3 (SMA-proper) and area 24d, whereas F6 (pre-SMA) and area 24c showed a low density of labelling. The segmental topography of the corticospinal projections fitted well with the somatotopy of the mesial cortical areas. We conclude that in the agranular mesial cortex there are four independent motor representations: F3 and 24d where the whole body is represented, and F6 and 24c which are mostly related to arm movements.

The monkey mesial area 6 comprises two distinct cytoarchitectonic areas: F3 [supplementary motor area properly defined (SMA-proper)], located caudally, and F6 (pre-SMA), located rostrally. The aim of the present study was to describe the corticocortical connections of these two areas. To this purpose restricted injections of neuronal tracers (wheat germ-agglutinin conjugated to horseradish peroxidase, fluorescent tracers) were made in different somatotopic fields of F3, F6, and F1 (area 4) and their transport plotted. The results showed that F3 and F6 differ markedly in their cortical connections. F3 is richly linked with F1 and the posterior premotor and cingulate areas (F2, F4, 24d). Connections with the anterior premotor and cingulate areas (F6, F7, F5, 24c) although present, are relatively modest. There is no input from the prefrontal lobe. F3 is also connected with several postrolandic cortical areas. These connections are with areas PC, PE, and PEa in the superior parietal lobule, cingulate areas 23 and PEci, the opercular parietal areas (PFop, PGop, SII) and the granular insula. F6 receives a rich input from the anterior premotor areas (especially F5) and cingulate area 24c, whereas its input from the posterior premotor and cingulate areas is very weak. A strong input originates from area 46. There are no connections with F1. The connections with the postrolandic areas are extremely meagre. They are with areas PG and PFG in the inferior parietal lobule, the disgranular insula, and the superior temporal sulcus. A further result was the demonstration of a differential connectivity pattern of the cingulate areas 24d and 24c. Area 24d is strongly linked with F1 and F3, whereas area 24c is connected mostly with F6. The present data support the notion that the classical SMA comprises two functionally distinct areas. They suggest that F6 (the rostral area) is responsible for the "SMA" so-called high level motor functions, whereas F3 (the caudal area) is more closely related to movement execution.

Many neurons in inferior area 6, a cortical premotor area, respond to visual stimuli presented in the space around the animal. We were interested to learn whether the receptive fields of these neurons are coded in retinotopic or in body-centered coordinates. To this purpose we recorded single neurons from inferior area 6 (F4 sector) in a monkey trained to fixate a light and detect its dimming. During fixation visual stimuli were moved towards the monkey both within and outside the neuron's receptive field. The fixation point was then moved and the neuron retested with the monkey's gaze deviated to the new location. The results showed that most inferior area 6 visual neurons code the stimulus position in spatial and not in retinal coordinates. It is proposed that these visual neurons are involved in generating the stable body-centered frame of reference necessary for programming visually guided movements.

A class of putative synaptic terminals with concentrated cAMP binding sites are labelled in unfixed sections of rat brain by means of the ligand 8-thioacetamido fluorescein cAMP (SAF-cAMP), a fluorescent analogue of cAMP. The labelled terminals appear as sharply delimited bouton-like structures in close proximity but external to the cell body of neurons. The SAF-cAMP binding, measured at equilibrium in competition with other nucleotides, indicates that the binding site recognizes the cAMP moiety of SAF-cAMP. In the labelled terminals of the frontal cortex the concentration of SAF-cAMP binding sites is estimated to be in the millimolar range (at least 2.1 +/- 1.0 mM). In a brain homogenate, labelled terminals are visualized only in the membrane fraction enriched in synaptosomes. The cAMP binding activity of the synaptosomes is insoluble in high and in low ionic strength solution and is only partially solubilized by detergents, suggesting that the binding sites are intrinsic membrane proteins and/or proteins associated with the cytoskeleton. There is the possibility that SAF-cAMP labels new cAMP binding sites highly concentrated in a class of synaptic terminals. SAF-cAMP labelling is prominent in well defined regions of the rat brain: (i) the frontal and entorhinal areas of the cortex; (ii) the field CA1 of the hippocampus; (iii) the olfactory system; (iv) the medial nuclei of the thalamus; (v) the parabrachial nuclei and other less defined regions of the reticular substance; (vi) the substantia gelatinosa of Rolando in the spinal cord; and (vii) the neo- and paleocerebellum in the Purkinje cell layer, the archicerebellum in the granular cell layer. SAF-cAMP labelling is absent in specific motor and sensory structures, with the exception of the olfactory system. It is proposed that SAF-cAMP binding sites single out a new type of synaptic terminals involved in complex nervous functions.

Neuronal tracers (diamidino yellow or wheat germ agglutinin conjugated with horseradish peroxidase) were injected in the arm representations of area 6a alpha (mesial surface, area F3), in the arm representation of area 6a beta (mesial surface) as well as in the eye field of area 6a beta (dorso-medial surface). The results showed that the arm representation of area F3 receives topographically organized afferents from motor and premotor areas (areas F1, F2, F4 and F5). A further connection was found with that part of cingulate cortex that sends projections to the spinal cord. In contrast, the arm representation of area 6a beta receives afferents chiefly from area F5, the prefrontal cortex and that part of cingulate sulcus which has few, if any, connections with the spinal cord. No connections were found with the precentral motor cortex (area F1). The area 6a beta eye field receives afferents mostly from the frontal eye field. Further connections are with the prefrontal cortex and cingulate gyrus. It is suggested that the so called "low level" motor functions of supplementary motor area are due to the activity of area F3, whereas the so called "high level" motor functions depend upon an independent area located in area 6a beta.

Single neurons were recorded from the rostral part of the agranular frontal cortex (area 6a beta) in awake, partially restrained macaque monkeys. In the medialmost and mesial sectors of this area, rostral to the supplementary motor area, neurons were found which were activated during arm reaching-grasping movements. These neurons ("reaching-grasping neurons") did not appear to be influenced by how the objects were grasped nor, with some exceptions, by where they were located. Their activity changed largely prior to the arm movement and continued until the end of it. The premovement modulation (excitatory or inhibitory) could start with stimulus presentation, with the saccade triggered by the stimulus or after stimulus fixation. The distance of the stimulus from the monkey was an important variable for activating many neurons. About half of the recorded neurons showed a modulation of the same sign during movement and premovement period. The other half showed an increase/decrease in activity which was of the opposite sign during movement and premovement period or part of it. In this last case the discharge changes were of the same sign when the stimulus was close to the monkey and when the monkey moved its arm to reach the objects, whereas they were of opposite sign when the stimulus was outside the animal's reach. Microstimulation of area 6a beta and the reconstruction of the locations of eye movement and arm movement related cells showed that the arm field was located more medially (and mesially) than the eye field described by Schlag and Schlag-Rey (1987). It is suggested that, unlike inferior area 6, which is mostly involved in selection of effectors on the basis of the physical properties of the objects and their spatial location (Rizzolatti and Gentilucci 1988), area 6a beta plays a role in the preparation of reaching-grasping arm movements and in their release when the appropriate conditions are set.

Lateralized presentations of verbal stimuli yield faster reaction times in the right visual field-left hemisphere, whereas nonverbal stimuli yield faster reaction times in the left visual field-right hemisphere. However, the problem of how lateral asymmetries in response latency are determined is still unsolved. The hypothesis of an absolute functional specialization of the two hemispheres suggests that information presented in the visual field connected with the unspecialized hemisphere has to travel along a less direct pathway, implying a crossing through the forebrain commissures, to reach the processing center. The hypothesis of a relative functional specialization assumes that stimuli are processed by the hemisphere contralateral to the field of presentation but speed of processing varies as a function of hemispheric specialization. The present study tried to find empirical evidence in favor of one of the two hypotheses. Choice reaction times to lateralized verbal stimuli were studied in normal subjects. In half of the trials the subjects had to carry out a concomitant task known to interfere selectively with mechanisms responsible of the organization of the responses of the left hemisphere. Both with and without concomitant task reaction times were significantly faster in the right visual field-left hemisphere. While the concomitant task produced an overall lengthening of reaction time, it did not affect interhemispheric asymmetry. This finding was discussed as evidence in favor of the absolute specialization hypothesis.

On the basis of its cytoarchitectonic and enzymatic properties area 6 of the macaque monkey can be subdivided into two large sectors: a superior sector lying medial to the spur of the arcuate sulcus (superior area 6 or F2) and an inferior sector lying lateral to it (inferior area 6). Inferior area 6 is constituted by two enzymatic areas: F4 and F5. In this study we investigated the somatotopic organization of inferior area 6 and the adjacent area 4 combining single-neuron recording and intracortical electrical microstimulation. We found that two separate movement representations exist in this region. The caudal one corresponds to area F1 (primary motor cortex), the rostral one to inferior area 6. The two representations are mirror images one of the other with the axioproximal movements being adjacently located. In the rostral map the proximal movements are mostly located in F4, the distal movements in F5. Neuronal properties indicate that the rostral map has characteristics that are more complex than the caudal map. We propose that the rostral map is involved in transforming visual information in motor commands. F4 should be involved in the control of arm movements based on the location of the objects in respect to the body, whereas F5 should play a role in the control of grasping movements on the basis of the size of the stimuli.

Two series of experiments are reported in this paper. The first concerns the movement representation in the macaque inferior area 6, the second the functional properties of neurons located in the caudal part of this area (histochemical area F4). By combining single neuron recording and intracortical microstimulation, we found that inferior area 6 is somatotopically organized. The axio-proximal movements are represented caudally, the distal movements are represented near the arcuate sulcus. The mouth field is located laterally, the hand field medially. There is no leg field. A comparison between neuron properties and histochemical characteristics of inferior area 6 showed that the proximal movements representation includes most of area F4, whereas the distal movements representation corresponds to area F5 and to the rostral part of F4. Neurons located in that part of F4 where proximal movements are represented respond very well to tactile stimuli. They have large receptive fields mostly located on the face and on the upper part of the body. A large number of these neurons respond to visual stimuli. Objects approaching the animal are particularly effective. The tactile and the visual receptive fields are in register. The most represented movements are reaching movements, movements bringing the hand to the mouth or to the body and facial movements. There is a congruence between location of visual fields and preferred arm movements. It is argued that the receptive field arrangement and the response properties are more complex in area F4 than in the primary motor cortex and that area F4 neurons are involved in the control of arm movements towards different space sectors.

The laminar pattern of cytochrome oxidase activity was studied in the agranular frontal cortex (area 4-6 complex) of the macaque monkey. The cortex, stained with this method, showed 6 stripes of different enzymatic activity. On the basis of their characteristics and of the presence of highly active cells, the agranular frontal cortex could be parcellated in 5 areas (F1-F5). F1 very likely corresponds to area FA of von Bonin and Bailey. Rostral to F1 two large regions could be distinguished, one located medial to the spur of the arcuate sulcus and its imaginary caudal extension, the other laterally. The superior region was formed by areas F2 and F3. The first was located on the dorsomedial cortical surface, the other on the mesial surface. F3 possibly corresponds to the supplementary motor area. The inferior region was formed by areas F4 and F5. The rostral area (F5) showed transition characteristics that rendered it somehow similar to the prefrontal areas. It may correspond to the cytoarchitectonic area FCBm. The cytocrome oxidase technique is a useful means of parcellating the agranular frontal cortex and may greatly help in physiological and behavioral experiments.

Simple reaction times to lateralized visual stimuli were studied in normal subjects while they were carrying out a concomitant task. The concomitant task consisted in the exploration of a visual maze presented in the middle of a screen. Regardless of the hand used, the concomitant task produced a specific lengthening of the responses to stimuli located in the left visual field. It is concluded that the right hemisphere plays a major role in the organization of ocular movements during active exploration of visual environment.

Recent cytoarchitectonic, histochemical, and hodological studies in primates have shown that area 6 is formed by three main sectors: the supplementary motor area, superior area 6, which lies medial to the spur of the arcuate sulcus, and inferior area 6, which is located lateral to it. Inferior area 6 has been further subdivided into two histochemical areas: area F5, located along the inferior limb of the arcuate sulcus, and area F4, located between area F5 and area 4 (area F1). The present study traced the thalamocortical projections of inferior area 6 and the adjacent part of area 4 by injecting small amounts of WGA-HRP in specific sectors of the agranular frontal cortex. Our data showed that each histochemical area receives a large projection from one nucleus of the ventrolateral thalamus (motor thalamus) and additional projections from other nuclei of this thalamic sector. Area F5 receives a large projection from area X of Olszewski ('52) and additional projections from the caudal part of the nucleus ventralis posterior lateralis, pars oralis (VPLo), and the nucleus ventralis lateralis, pars caudalis (VLc) (VPLo-VLc complex). Area F4 receives a large projection from the nucleus ventralis lateralis, pars oralis (VLo), and additional projections from area X and the VPLo-VLc complex. The rostral part of area F1 is innervated chiefly by VLo, plus smaller contributions from rostral VPLo and the VPLo-VLc complex. The caudal part of F1 receives its greatest input from VPLo, with a small contribution from VLo. In addition, each histochemical area receives projections originating from the intralaminar thalamic nuclei, the posterior thalamus, and--for area F4 and area F5--also from the nucleus medialis dorsalis (MD). Analysis of the physiological properties of the various histochemical areas in relation to their main thalamic input showed that those cortical fields in which distal movements are predominant (area F5, caudal part of area F1) are innervated chiefly by area X and VPLo, whereas those cortical fields in which proximal movements are predominant receive their main input from VLo. Because VPLo and area X are targets of cerebellothalamic pathways, whereas VLo receives a pallidal input, we propose that the cortical fields in which distal movements are most heavily represented are mainly under the influence of the cerebellum, whereas the cortical fields in which proximal movements are most heavily represented are mainly under the influence of the basal ganglia.

The functional properties of neurons located in the rostral part of inferior area 6 were studied in awake, partially restrained macaque monkeys. The most interesting property of these neurons was that their firing correlated with specific goal-related motor acts rather than with single movements made by the animal. Using the motor acts as the classification criterion we subdivided the neurons into six classes, four related to distal motor acts and two related to proximal motor acts. The distal classes are: "Grasping-with-the-hand-and-the-mouth neurons", "Grasping-with-the-hand neurons", "Holding neurons" and "Tearing neurons". The proximal classes are: "Reaching neurons" and "Bringing-to-the-mouth-or-to-the-body neurons". The vast majority of the cells belonged to the distal classes. A particularly interesting aspect of distal class neurons was that the discharge of many of them depended on the way in which the hand was shaped during the motor act. Three main groups of neurons were distinguished: "Precision grip neurons", "Finger prehension neurons", "Whole hand prehension neurons". Almost the totality of neurons fired during motor acts performed with either hand. About 50% of the recorded neurons responded to somatosensory stimuli and about 20% to visual stimuli. Visual neurons were more difficult to trigger than the corresponding neurons located in the caudal part of inferior area 6 (area F4). They required motivationally meaningful stimuli and for some of them the size of the stimulus was also critical. In the case of distal neurons there was a relationship between the type of prehension coded by the cells and the size of the stimulus effective in triggering the neurons. It is proposed that the different classes of neurons form a vocabulary of motor acts and that this vocabulary can be assessed by somatosensory and visual stimuli.

Stimulus-response compatibility effects have been hypothesized to result (a) from a subject's innate tendency to respond in the direction of the source of stimulation, (b) from a correspondence between the spatial codes associated with the effector and the stimulus, or (c) from an attentional bias favoring the effector located in the same hemispace as the command signal. Two experiments were conducted to test these three hypotheses. In Experiment 1 the subjects were requested to make unimanual discriminative key-pressing responses to two light stimuli, both appearing to either the right or left of the fixation point. In one condition the two hands were in anatomical position (uncrossed); in the other they were crossed. The procedure of Experiment 2 was similar to that of Experiment 1 with the exception that both hands, always in an uncrossed position, were placed on the same side of the body midline (on the right or left). The results showed that the compatibility effect depends on a correspondence between the spatial codes associated with the location of the effector and the location of the command stimulus.

A new class of neurons was identified in the rostral part of inferior area 6 in the macaque monkey (Macaca nemestrina). These neurons fire in relation to motor acts which have a particular aim such as reaching, grasping or holding. The same neuron discharges when the animal uses the right hand, the left hand and, frequently, also the mouth. Furthermore most of these neurons specify how the aim can be achieved (e.g. precision grip vs whole hand prehension). Different types of goal-related neurons form a vocabulary of simple motor acts localized in inferior area 6.

The study was aimed at testing various models that can explain visual lateral asymmetries due to hemispheric specialization. In Experiments 1-3 the subjects had to perform a lateralized "go-no go" discrimination of words (primary task) either alone or in association with secondary tasks that interfered with the processing of the left hemisphere (ordered tapping) or the right hemisphere (finger flexion). In Experiment 4 the primary task was one of lateralized "go-no go" discrimination of faces while the secondary tasks were again those of ordered tapping and finger flexion. The results showed that in the case of word discrimination the advantage in speed of response in favour of the right visual field/left hemisphere (RVF/LH), which was observed for the primary task alone, did not change when the secondary task was added. This held true irrespective of whether the secondary task loaded the left or right hemisphere. The advantage for the left visual field/right hemisphere (LVF/RH) observed for face discrimination alone, disappeared when the secondary task interfered with the processing of the right hemisphere and did not change when the secondary task concerned the left hemisphere. It was concluded that each hemisphere is able to elaborate in parallel the incoming information, but, in normal conditions, interhemispheric transmission is responsible for the lateral asymmetries in perception (conditional interhemispheric transmission model).