Neuronal Encoding of Self and Others' Head Rotation in the Macaque Dorsal Prefrontal Cortex.

Following gaze is a crucial skill, in primates, for understanding where and at what others are looking, and often requires head rotation. The neural basis underlying head rotation are deemed to overlap with the parieto-frontal attention/gaze-shift network. Here, we show that a set of neurons in monkey's Brodmann area 9/46dr (BA 9/46dr), which is involved in orienting processes and joint attention, becomes active during self head rotation and that the activity of these neurons cannot be accounted for by saccade-related activity (head-rotation neurons). Another set of BA 9/46dr neurons encodes head rotation performed by an observed agent facing the monkey (visually triggered neurons). Among these latter neurons, almost half exhibit the intriguing property of encoding both execution and observation of head rotation (mirror-like neurons). Finally, by means of neuronal tracing techniques, we showed that BA 9/46dr takes part into two distinct networks: a dorso/mesial network, playing a role in spatial head/gaze orientation, and a ventrolateral network, likely involved in processing social stimuli and mirroring others' head. The overall results of this study provide a new, comprehensive picture of the role of BA 9/46dr in encoding self and others' head rotation, likely playing a role in head-following behaviors.

Correcting for H2O interference using a RAD7 electrostatic collection-based silicon detector.

The effect of water molecules on the electrostatic collection of 218Po ions onto the surface of silicon detectors (neutralization) is evaluated through the comparison with a scintillation cell (ZnS), not affected by air humidity. A radon monitor (RAD7, Durridge Company) was connected to a stainless steel radon chamber, equipped with the scintillation cell. Radon gas, extracted from an acidified RaCl2 source, was injected into the chamber and the amount of water molecules in the system was alternatively lowered or increased (from 0.00075 to 0.014 g of water in RAD7) by connecting the chamber to a desiccant or to a bubbling water bottle. The relative efficiency of the silicon detector with respect to the scintillation cell decreases with the growth of water molecules inside RAD7. This dependence, with a fixed i) electrostatic chamber geometry and ii) nominal high voltage, diverges during the humidification or the drying phase because it is in turn influenced by the length of interaction of polonium atoms with water molecules, which impacts on the size of 218Po clusters and thus on the neutralization process. For water contents higher that 0.01 g in RAD7, this effect is greatly enhanced. Temperature in the investigated range (18.5-35.6 °C) does not affect the efficiency of electrostatic collection-based silicon detectors. Based on these experiments, admitting a certain error on the efficiency (from 1.8 to 7.5%, depending on the water content), proper corrections were developed to adjust soil radon readings, when a desiccant is removed. This operation is necessary if recent Non-Aqueous Phase Liquids (NAPLs) leakage has occurred in the subsoil to avoid the sorption and possible later release of radon by Drierite, with related partition between the solid and liquid phases (water and NAPL).

Orienting movements in area 9 identified by long-train ICMS.

The effect of intracortical microstimulation has been studied in several cortical areas from motor to sensory areas. The frontal pole has received particular attention, and several microstimulation studies have been conducted in the frontal eye field, supplementary eye field, and the premotor ear-eye field, but no microstimulation studies concerning area 9 are currently available in the literature. In the present study, to fill up this gap, electrical microstimulation was applied to area 9 in two macaque monkeys using long-train pulses of 500-700-800 and 1,000 ms, during two different experimental conditions: a spontaneous condition, while the animals were not actively fixating on a visual target, and during a visual fixation task. In these experiments, we identified backward ear movements, goal-directed eye movements, and the development of head forces. Kinematic parameters for ear and eye movements overlapped in the spontaneous condition, but they were different during the visual fixation task. In this condition, ear and eye kinematics have an opposite behavior: movement amplitude, duration, and maximal and mean velocities increase during a visual fixation task for the ear, while they decrease for the eye. Therefore, a top-down visual attention engagement could modify the kinematic parameters for these two effectors. Stimulation with the longest train durations, i.e., 800/1,000 ms, evokes not only the highest eye amplitude, but also a significant development of head forces. In this research article, we propose a new vision of the frontal oculomotor fields, speculating a role for area 9 in the control of goal-directed orienting behaviors and gaze shift control.

A new field in monkey's frontal cortex: premotor ear-eye field (PEEF).

In macaque monkey, area 8B is cytoarchitectonically considered a transitional area between the granular Brodmann area 9, rostrally, and the rostral part of the dorsal agranular Brodmann area 6, caudally. As for electrophysiological data, microstimulation of area 8B evokes ear and/or eye movements; unit activity recording shows neurons encoding different auditory environmental stimuli and ear and/or eye movements. Moreover, visual attentive fixation modulates the discharge of auditory environmental neurons and auditory-motor neurons. As for anatomical data, area 8B is connected with auditory cortical areas, superior colliculus and cerebellum. Current functional and anatomical evidences support that area 8B is a specific Premotor Ear-Eye Field (PEEF) involved in auditory stimuli recognition and in orienting processes. In conclusion, we suggest that PEEF could play an important role in engaging the auditory spatial attention for the purpose of orienting eye and ear towards the sound source.

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1.

Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo- to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses.

Auditory-motor and cognitive aspects in area 8B of macaque monkey's frontal cortex: a premotor ear-eye field (PEEF).

In previous reports, we showed the involvement of area 8B neurons in both spontaneous ear and eye movement and in auditory information processing. Audition-related cells responded to complex environmental stimuli, but not to pure tones, and their activity changed during visual fixation as a possible inhibitory expression of the engagement of attention. We observed auditory, auditory-motor and motor cells for both eye and ear movements. This finding suggests that area 8B may be involved in the integration of auditory input with ear and eye motor output. In this paper, we extended these previous studies by examining area 8B activity in relation to auditive orienting behaviour, as well as the ocular orientation (i.e., visual fixation) studied previously. Visual fixation led to inhibition of activity in auditory and auditory-motor cells, which suggests that attention may be involved in both, maintaining the eye position and reducing the response of these cell types. Accordingly, during a given task or natural behaviour, spatial attention seems to affect more than one sensorimotor channel simultaneously. These data add to our understanding of how the neural network, through a two-channel attentive process, accomplishes to switch between two effectors, namely eyes and ears. Considering the functional, anatomical and cytoarchitectonic differences among the frontal eye field (FEF), the supplementary eye field (SEF) and area 8B, we propose to consider area 8B as a separate premotor ear-eye field (PEEF).

Time-modulated neuronal activity in the premotor cortex of macaque monkeys.

A voluntary motor act, executed in response to a stimulus, requires both spatial and temporal computation. Even though electrophysiological and positron emission tomography (PET) investigations on humans suggest that SMA, medial prefrontal cortex and primary motor cortex play a role in temporal mechanisms, we have few data about neuronal time computation in the premotor cortex. The involvement of monkey premotor area (PM) in motor learning and cognitive processes, and the presence of buildup neurons, whose activity is closely related to the motor action, prompted us to investigate the involvement of these set-related neurons in the time domain. To this end we manipulated the duration of a pre-cue in a visuomotor task while recording unit activity. We found that, when the duration of the pre-cue was predictable and long (5 s), delay of the onset of cell activity in consecutive trials gradually increased. On the other hand, when the duration was unpredictable or predictable and short (1 s), this phenomenon could not be detected. The inconsistent discharge correlations with expected reward and attentional processes, and the specific discharge relationship to the time instruction, suggest that these buildup neurons reflect a learning process in the time domain.

Neglect syndrome for aversive stimuli in a macaque monkey with dorsomedial frontal cortex lesion.

After a session of unit activity recording, one of our monkeys presented an epileptic attack, which provoked contralateral tilting movements. The following days, the animal performed saccades and fixation tasks correctly in all directions, while contralateral arm reaching movements were severely impaired. To establish if the neurological lesion had changed the orienting performance we considered two types of stimuli, pleasant and aversive. Pleasant stimuli, presented in the ipsilateral or contralateral hemifield, readily drew the attention of the animal. If the same stimuli were presented simultaneously in both hemifields, the monkey oriented itself only toward the ipsilateral one. Aversive stimuli evoked an aggressive reaction only when the stimulus was localized in the ipsilateral hemifield. The animal clearly neglected the aversive stimulus presented in the contralateral hemifield. The animal recovered completely in 30 days. The postmortem examination revealed a lesion in the dorsomedial frontal cortex. The combined attentional and motor deficits suggest that this area may be involved in the preparation and execution of movements triggered by the affective meaning of the stimulus.

Activity of neurons related to eye movements during drowsiness in the frontal cortex of the macaca monkey.

During our extensive study of the supplementary eye field (SEF) in relation to eye and arm movements, we had the opportunity to record the activity of 25 out of 315 cells during both saccade task and drowsiness states. All 25 cells showed a phasic, spatially selective postsaccadic activity that was not related to fixation. During drowsiness, the discharge was time locked with the onset of the slow movement, had increased duration, and was not spatially selective. These preliminary data suggest that saccade neurons present in SEF are also involved in the motor processes of slow eye movements during drowsiness.

Motor programs of spontaneous and visually guided saccades in macaque monkey: an electrophysiological approach.

The discharge activity of 37 burst neurons in the paramedian pontine reticular formation and the saccades performed in the dark (spontaneous saccades) and between visual targets (attentive visually guided) were recorded in two macaque monkeys. Forty-five % of spontaneous saccades showed more than one maximum of velocity (irregular velocity profiles), while visually guided saccades were always characterized by a single maximum of velocity (regular velocity profiles). The discharge pattern of each burst neuron (short lead neuron) was different according to the saccade velocity profile. We observed a clear inhibition within the burst neuron discharge for irregular velocity profiles, thus giving rise to multiple maxima of discharge frequency, and to a clearly interrupted saccade. The same neuron showed only one maximum of discharge frequency for regular saccades. Then the hypothesis of two different neural networks generating the different motor programs of spontaneous and attentive visual guided saccades is put forward and discussed.

Attention-related neurons in the supplementary eye field of the macaque monkey.

This study investigated whether the neuronal activity of a cortical area involved in the control of eye fixation is affected by the covert orienting of attention. We recorded single-unit activity from the supplementary eye field (SEF) of two macaque monkeys performing fixation and peripheral-attention tasks. Ninety-nine out of four hundred and fifteen cells were related to eye movements. The other neurons showed relationship with postural adjustments, and arm and ear movements. Fifty-five neurons were active during fixation (fixation cells) and 44 discharged in relation to saccades. The experiments reported here primarily concern the fixation cells. The activity of 64% (35/55) of fixation cells started with the onset of visual stimulus, before the visual input reached the fovea, and continued during active fixation. The activity of 27% (15/55) of fixation cells started with the onset of fixation. The activity of 9% (5/55) of fixation cells modified their timing trial by trial. Sixty-four percent of the fixation cells (35/55) were position-dependent, showing a selective spatial field of activity, 36% (20/55) were position-independent and characterized by a full spatial field. None of the 55 cells showed a visual receptive field. We tested both types of fixation cells by means of a peripheral attention task. When attention was oriented peripherally toward a target located in the selective spatial field, the cells discharged as if the gaze was held toward it. When attention was oriented peripherally toward a target, lying outside the selective spatial field the cells were inactive as if gaze was held in that position. These results suggest that the supplementary eye field neurons may code for oriented attention in space and might be involved in the preparation of motor action.

Ear and eye representation in the frontal cortex, area 8b, of the macaque monkey: an electrophysiological study.

We evoked both ear and eye movements in area 8b, the rostral area of frontal cortex, in two monkeys. In some sites it was possible to evoke only ear movements or only eye movements; in other locations we evoked both ear and eye movements by varying the intensity of electrical stimulation. The electrically evoked ear movements were forward, or backward, or oblique (upward-forward; upward-backward). In two penetrations the ear movements were bilateral, in the other penetrations they were contralateral. Ipsilateral ear movements were not observed. The evoked eye movements were mainly fixed-vector saccades, contralateral and with an upward orientation of about 45 degrees. If we considered only the sites where the threshold was equal to or lower than 50 microA, the stimulation of this area evoked mainly ear movements. In addition we recorded the electrical activity of 195 neurons. Of these neurons: 74% (145/195) discharged before ear movements (ear cells); 20% (40/195) discharged before ear and eye movements (ear-eye cells); 5% (10/195) discharged only before eye movements (eye cells). Ninety-one percent (132/145) of ear cells presented a preferred direction; 90% (36/40) of ear-eye cells presented a preferred direction for ear movements, and 15% (6/40) presented a preferred direction for eye movements. Eighty-five percent (34/40) of cells did not present a preferred direction for visually guided saccades and were active when the monkey made saccades toward the unlit targets (checking saccades). Our results show that a field of area 8b is related to ear movements and to eye-ear movements. The findings that it is possible to obtain both ear and eye movements with low-intensity currents and that there are cells firing for the two types of movements suggest that area 8b may be involved in the orientation and coordination of both ear and eye. This area might be considered a rostral extension of supplementary eye field (SEF) or a different region. However, based on its distinct functional characteristics and connectivity, it is probably better regarded as a separate field. Regardless, the combination of 8b and SEF may constitute a cortical center for orienting processes.

The effects of maturation on spontaneous eye movements in the macaque monkey.

The spontaneous eye movements of infant and adult monkeys were studied both in the dark and in the laboratory light by a magnetic search-coil technique and analysed comparatively. The spatio-temporal organization of the infant monkey's eye movements is predominantly vertical; by contrast it is predominantly horizontal in adults. Moreover, the infant monkey's eye movements have smaller amplitudes and slower velocities than adult's in both visual conditions. The linear relationships between amplitude and maximum velocity suggest that rapid eye movements of the infant monkey are saccades but with a lower rate of velocity increase than the adult's. We conclude that the eye movements in the infant and in the adult monkeys differ in many aspects and that maturation acts on both the static and dynamic characteristics of ocular motility.

The dorsomedial frontal cortex of the macaca monkey: fixation and saccade-related activity.

The activity of 249 neurons in the dorsomedial frontal cortex was studied in two macaque monkeys. The animals were trained to release a bar when a visual stimulus changed color in order to receive reward. An acoustic cue signaled the start of a series of trials to the animal, which was then free to begin each trial at will. The monkeys tended to fixate the visual stimuli and to make saccades when the stimuli moved. The monkeys were neither rewarded for making proper eye movements nor punished for making extraneous ones. We found neurons whose discharge was related to various movements including those of the eye, neck, and arm. In this report, we describe the properties of neurons that showed activity related to visual fixation and saccadic eye movement. Fixation neurons discharged during active fixation with the eye in a given position in the orbit, but did not discharge when the eye occupied the same orbital positions during nonactive fixation. These neurons showed neither a classic nor a complex visual receptive field, nor a foveal receptive visual field. Electrical stimulation at the site of the fixation neurons often drove the eye to the orbital position associated with maximal activity of the cell. Several different kinds of neurons were found to discharge before saccades: 1) checking-saccade neurons, which discharged when the monkeys made self-generated saccades to extinguish LED's; 2) novelty-detection saccade neurons, which discharged before the first saccade made to a new visual target but whose activity waned with successive presentations of the same target. These results suggest that the dorsomedial frontal cortex is involved in attentive fixation. We hypothesize that the fixation neurons may be involved in codifying the saccade toward a target. We propose that their involvement in arm-eye-head motor-planning rests primarily in targeting the goal of the movement. The fact that saccade-related neurons discharge when the saccades are self initiated, implies that this area of the cortex may share the control of voluntary saccades with the frontal eye fields and that the activation is involved in intentional motor processes.

Behavioral and motor mechanisms of dorsomedial frontal cortex of macaca monkey.

The activity of 249 neurons in the dorsomedial frontal cortex was recorded in two macaca monkeys. The animals had been trained for saccades and fixation tasks in an unrestrained condition. We found 51 burst neurons that showed a double-firing discharge. We observed two different patterns of discharge. In one case the first burst occurred before the arm movement, the second before the related eye movement. In the second case, the first discharge took place before a neck contraction followed by a second burst before eye movement. Some cells showed two discharges, one that preceded the bar-press and the other the saccade. With other cells the discharges preceded the bar-release and then saccade. Still other cells discharged three times: first before the bar-press, second before release and third before the orienting saccade. Some cells were active for the bar-press and for the first orienting saccades. These cells were active also for a large range of movement tested at the presentation of natural stimuli. Electrical stimulation failed to evoke either arm or eye movement. Neck-eye cells are related to movement of the eye and to an increase of EMG activity independent of eye position. The electrical stimulation evoked eye movements and EMG increases at low threshold. The activity of arm-eye cells related to purposeful movement with the ineffectiveness of electrical stimulation may be ascribed to a motor reactivation or an ordering signal. The neck-eye cells may be considered trigger commands for neck-eye coordination.(ABSTRACT TRUNCATED AT 250 WORDS)

Does attention affect the motor programs of pharmacologically induced eye movements?

Attention plays an important role in oculomotor function. We studied the effect of attentional stimuli on eye movements induced by ketamine. The experiments were carried out on three monkeys. Ketamine injected intramuscularly induced nystagmus. When we switched on a new stimulus these eye movements stopped and the animal made a saccade toward it. This may be due to a new motor program, triggered by a visual stimulus, that among its characteristics is able to engage the animal's attention. The program of evoked saccade is overwritten on induced oculomotor activity. Our results suggest that attentional processes modify the dynamic characteristics and induce in particular behavioral condition a new motor program.

Neurons signalling the maintenance of attentive fixation in frontal area 6a beta of macaque monkey.

Twelve out of 140 neurons recorded in a restricted region of the frontal agranular cortex (area 6a beta) of trained macaque monkeys, discharged only during attentive fixation of a target in the straight ahead position. These cells, lacking a visual receptive field, were silent when the animal's eye was in the same position during spontaneous oculomotor behaviour. Our preliminary results suggest that this area is involved in the codification of attentive fixation.

The motor programs of monkey's saccades: an attentional hypothesis.

We analyzed the dynamics of saccadic eye movements performed by monkeys in three different conditions: as a part of an ocular motor task, spontaneously when the monkey was alert but not performing a task in ordinary room illumination, and spontaneously when the monkey was alert but not performing a task in total darkness. We found three general classes of saccades: 1) regular-symmetric, in which the rise time of the velocity profile was equal to the falling time; 2) regular-asymmetric, in which the rise time was less than the falling time; 3) irregular, in which there were multiple velocity maxima or inflection points. The monkeys made irregular saccades half the time in the two spontaneous saccade conditions, and almost never during the task. In order to see if the regularity of saccades was an artifact of reward, we then evoked saccades by presenting the monkeys with novel visual and acoustic stimuli to which they made saccades. Such guided saccades to novel stimuli had regular velocity profiles. We suggest that saccades made as a part of attentive behavior differ in their motor programming from saccades made spontaneously in darkness, or saccades made in the light without a purpose relevant to visual behavior.