An area for vergence eye movement in primate frontal cortex

To view objects at different distances, humans rely on vergence eye movements to appropriately converge or diverge the eyes and on ocular accommodation to focus the object. Despite the importance of these coordinated eye movements (the 'near response') very little is known about the role of the cerebral cortex in their control. As near-response neurons exist within the nucleus reticularis tegmenti pontis, which receives input from the frontal eye field region of frontal cortex, and this cortical region is known to be involved in saccadic and smooth-pursuit eye movements, we propose that a nearby region might play a role in vergence and ocular accommodation. Here we provide evidence from rhesus monkeys that a region of frontal cortex located immediately anterior to the saccade-related frontal eye field region is involved in vergence and ocular accommodation, and in the sensorimotor transformations required for these eye movements. We conclude that the macaque frontal cortex is involved in the control of all voluntary eye movements, and suggest that the definition of the frontal eye fields should be expanded to include this region.     

Representation of a perceptual decision in developing oculomotor commands

Behaviour often depends on the ability to make categorical judgements about sensory information acquired over time. Such judgements require a comparison of the evidence favouring the alternatives, but how the brain forms these comparisons is unknown. Here we show that in a visual discrimination task, the accumulating balance of sensory evidence favouring one interpretation over another is evident in the neural circuits that generate the behavioural response. We trained monkeys to make a direction judgement about dynamic random-dot motions and to indicate their judgement with an eye movement to a visual target. We interrupted motion viewing with electrical microstimulation of the frontal eye field and analysed the resulting, evoked eye movements for evidence of ongoing activity associated with the oculomotor response. Evoked eye movements deviated in the direction of the monkey's judgement. The magnitude of the deviation depended on motion strength and viewing time. The oculomotor signals responsible for these deviations reflected the accumulated motion information that informed the monkey's choices on the discrimination task. Thus, for this task, decision formation and motor preparation appear to share a common level of neural organization.     

Coding of smooth eye movements in three-dimensional space by frontal cortex

Through the development of a high-acuity fovea, primates with frontal eyes have acquired the ability to use binocular eye movements to track small objects moving in space. The smooth-pursuit system moves both eyes in the same direction to track movement in the frontal plane (frontal pursuit), whereas the vergence system moves left and right eyes in opposite directions to track targets moving towards or away from the observer (vergence tracking). In the cerebral cortex and brainstem, signals related to vergence eye movements--and the retinal disparity and blur signals that elicit them--are coded independently of signals related to frontal pursuit. Here we show that these types of signal are represented in a completely different way in the smooth-pursuit region of the frontal eye fields. Neurons of the frontal eye field modulate strongly during both frontal pursuit and vergence tracking, which results in three-dimensional cartesian representations of eye movements. We propose that the brain creates this distinctly different intermediate representation to allow these neurons to function as part of a system that enables primates to track and manipulate objects moving in three-dimensional space.     

Free choice activates a decision circuit between frontal and parietal cortex

We often face alternatives that we are free to choose between. Planning movements to select an alternative involves several areas in frontal and parietal cortex that are anatomically connected into long-range circuits. These areas must coordinate their activity to select a common movement goal, but how neural circuits make decisions remains poorly understood. Here we simultaneously record from the dorsal premotor area (PMd) in frontal cortex and the parietal reach region (PRR) in parietal cortex to investigate neural circuit mechanisms for decision making. We find that correlations in spike and local field potential (LFP) activity between these areas are greater when monkeys are freely making choices than when they are following instructions. We propose that a decision circuit featuring a sub-population of cells in frontal and parietal cortex may exchange information to coordinate activity between these areas. Cells participating in this decision circuit may influence movement choices by providing a common bias to the selection of movement goals.     

Involvement of secondary motor areas in externally-triggered single-finger movements of dominant and non-dominant hands

Abstract Whether the secondary motor areas are involved in simple voluntary movements remains controversial. Differences in the neural substrates of movements with the dominant and the non-dominant hands have not been well documented. In the present study, functional magnetic resonance imaging (fMRI) was used to investigate the hemodynamic response in the primary motor cortex (M1), supple-mentary motor area (SMA) and premotor cortex (PMC) in six healthy right-handed subjects while performing a visually-guided finger-tapping task with their dominant or non-dominant hands. Significant activation was observed in M1, SMA and PMC during this externally triggered simple voluntary movement task. While dominant hand movements only activated contralateral motor areas, non-domi-nant hand movements also activated ipsilateral SMA and PMC. The results provide strong evidence for the involvement of the secondary motor areas in simple voluntarymovements, and also suggest that movements of the dominant hand primarily engage the contralateral secondary motor areas, whereas movements of the non-dominant hand engage bilateral secondary motor areas.     

Dynamic coding of behaviourally relevant stimuli in parietal cortex.

A general function of cerebral cortex is to allow the flexible association of sensory stimuli with specific behaviours. Many neurons in parietal, prefrontal and motor cortical areas are activated both by particular movements and by sensory cues that trigger these movements, suggesting a role in linking sensation to action. For example, neurons in the lateral intraparietal area (LIP) encode both the location of visual stimuli and the direction of saccadic eye movements. LIP is not believed to encode non-spatial stimulus attributes such as colour. Here we investigated whether LIP would encode colour if colour was behaviourally linked to the eye movement. We trained monkeys to make an eye movement in one of two directions based alternately on the colour or location of a visual cue. When cue colour was relevant for directing eye movement, we found a substantial fraction of LIP neurons selective for cue colour. However, when cue location was relevant, colour selectivity was virtually absent in LIP. These results demonstrate that selectivity of cortical neurons can change as a function of the required behaviour.     

Direct control of paralysed muscles by cortical neurons

A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.     

Regulation of the gain of visually guided smooth-pursuit eye movements by frontal cortex

In studies of the neural mechanisms giving rise to behaviour, changes in the neural and behavioural responses produced by a given stimulus have been widely reported. This 'gain control' can boost the responses to sensory inputs that are particularly relevant, select among reflexes for execution by motoneurons or emphasize specific movement targets. Gain control is also an integral part of the smooth-pursuit eye movement system. One signature of gain control is that a brief perturbation of a stationary target during fixation causes tiny eye movements, whereas the same perturbation of a moving target during the active state of accurate pursuit causes large responses. Here we show that electrical stimulation of the smooth-pursuit eye movement region in the arcuate sulcus of the frontal lobe ('the frontal pursuit area', FPA) mimics the active state of pursuit. Such stimulation enhances the response to a brief perturbation of target motion, regardless of the direction of motion. We postulate that the FPA sets the gain of pursuit, thereby participating in target selection for pursuit.     

Left neglect for near but not far space in man

It has been suggested that, among the many visual areas of the human brain, there might be one set of spatial maps specialized for 'near' (peripersonal) and another for 'far' (extrapersonal) space. A distinction between 'grasping distance' and 'walking distance', or between a 'reaching field' and a pointing or throwing field has commonly been made. Evidence for such a division has been found in monkeys. Unilateral ablation of the frontal eye field (area 8) produces a more prominent inattention (or 'neglect') for objects in contralesional far space than in near space; by contrast, unilateral ablation of frontal area 6, which receives direct projections from area 7b (the rostral part of the inferior parietal lobules) results in inattention to visual stimuli limited to contralesional near space. Despite predictions that comparable dissociations should be found in man, there has been no convincing evidence. We report here such evidence in a patient with a unilateral right hemisphere stroke. Within peripersonal space, he showed severe left visuo-spatial neglect on conventional tests, including the highly sensitive task of line bisection. When line bisection was performed in extrapersonal space, neglect was abolished or attenuated.     

Influence of the thalamus on spatial visual processing in frontal cortex

Each of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.     

Control of visual cortical signals by prefrontal dopamine

The prefrontal cortex is thought to modulate sensory signals in posterior cortices during top-down attention, but little is known about the underlying neural circuitry. Experimental and clinical evidence indicate that prefrontal dopamine has an important role in cognitive functions, acting predominantly through D1 receptors. Here we show that dopamine D1 receptors mediate prefrontal control of signals in the visual cortex of macaques (Macaca mulatta). We pharmacologically altered D1-receptor-mediated activity in the frontal eye field of the prefrontal cortex and measured the effect on the responses of neurons in area V4 of the visual cortex. This manipulation was sufficient to enhance the magnitude, the orientation selectivity and the reliability of V4 visual responses to an extent comparable with the known effects of top-down attention. The enhancement of V4 signals was restricted to neurons with response fields overlapping the part of visual space affected by the D1 receptor manipulation. Altering either D1- or D2-receptor-mediated frontal eye field activity increased saccadic target selection but the D2 receptor manipulation did not enhance V4 signals. Our results identify a role for D1 receptors in mediating the control of visual cortical signals by the prefrontal cortex and suggest how processing in sensory areas could be altered in mental disorders involving prefrontal dopamine.     

Cortical control of a prosthetic arm for self-feeding

Arm movement is well represented in populations of neurons recorded from the motor cortex. Cortical activity patterns have been used in the new field of brain-machine interfaces to show how cursors on computer displays can be moved in two- and three-dimensional space. Although the ability to move a cursor can be useful in its own right, this technology could be applied to restore arm and hand function for amputees and paralysed persons. However, the use of cortical signals to control a multi-jointed prosthetic device for direct real-time interaction with the physical environment ('embodiment') has not been demonstrated. Here we describe a system that permits embodied prosthetic control; we show how monkeys (Macaca mulatta) use their motor cortical activity to control a mechanized arm replica in a self-feeding task. In addition to the three dimensions of movement, the subjects' cortical signals also proportionally controlled a gripper on the end of the arm. Owing to the physical interaction between the monkey, the robotic arm and objects in the workspace, this new task presented a higher level of difficulty than previous virtual (cursor-control) experiments. Apart from an example of simple one-dimensional control, previous experiments have lacked physical interaction even in cases where a robotic arm or hand was included in the control loop, because the subjects did not use it to interact with physical objects-an interaction that cannot be fully simulated. This demonstration of multi-degree-of-freedom embodied prosthetic control paves the way towards the development of dexterous prosthetic devices that could ultimately achieve arm and hand function at a near-natural level.     

Wavelength sensitivity in blindsight

Blindsight--the residual visual functions observed in visualfield defects resulting from destruction of part of the primary visual cortex (striate cortex) even though visual stimuli presented in the field defect are not consciously perceived--has generated new insights into the nature of consciousness and the role of the extrastriate pathways in visual processing. Some patients can detect and localize unseen stimuli when they are required to guess. Discrimination of movement, flicker and orientation may also be present, but residual colour discrimination is controversial. Negative results imply that only the pathways from eye to striate cortex can transmit information about colour in primates. By measuring sensitivity to light of different wavelengths in patients with blindsight we show that spectral sensitivity in the blind fields is surprisingly high, with a reduction of only 1 log unit or less across the visible spectrum. It is also essentially normal in form, whether the patients are adapted to light or dark. The shift in peak sensitivity from medium to shorter wavelengths in adaptation to the dark (the Purkinje shift) and the presence of discontinuities in the light-adapted curve together show that blindsight involves both rod and cone contributions, and that some colour opponency remains. As colour opponency requires input from primate beta retinal ganglion cells, two-thirds of which degenerate transneurally after a striate cortical lesion in juvenile monkeys, our results show that the surviving subpopulation of primate beta cells is functional.     

Predictable eye-head coordination during driving.

Large changes in the direction of gaze are made with a combination of fast saccadic eye movements and rather slower head movements. Since the first study on freely moving subjects, most authors have agreed that the head movement component of gaze is very variable, with a high 'volitional' component. But in some circumstances head and eye movements can be quite predictable, for example when a subject is asked to shift gaze as quickly as possible. Under these conditions, laboratory studies have shown that the eye and head motor-systems both receive gaze-change commands, although they execute them in rather different ways. Here I reconsider the way gaze direction is changed during free movement, but in the performance of a task where the subject is too busy to exert conscious control over head or eye movements. Using a new portable and inexpensive method for recording head and eye movements, I examine the oculomotor behaviour of car drivers, particularly during the large gaze changes made at road junctions. The results show that the pattern of eye and head movements is highly predictable, given only the sequence of gaze targets.     

Functional localization and lateralization of human olfactory cortex.

Anatomical and physiological investigations in monkeys indicate that olfaction is subserved by several cortical regions. But the areas implicated in the human olfactory system have not been definitively identified by functional criteria. Behavioural evidence has suggested that laterally specialized mechanisms for odour processing may exist, but the neuroanatomical substrate remains unknown. We used positron emission tomography to study the cortical representation of human olfactory processing by comparing cerebral blood flow changes evoked during olfactory stimulation with those of a control task. We report here significant cerebral blood flow increases at the junction of the inferior frontal and temporal lobes bilaterally, corresponding to the piriform cortex, and unilaterally, in the right orbitofrontal cortex. The results complement and extend previous data implicating these regions in olfactory processing, and indicate that a functional asymmetry exists in the human brain favouring the right orbitofrontal area in olfaction.     

Selective gating of visual signals by microstimulation of frontal cortex

Several decades of psychophysical and neurophysiological studies have established that visual signals are enhanced at the locus of attention. What remains a mystery is the mechanism that initiates biases in the strength of visual representations. Recent evidence argues that, during spatial attention, these biases reflect nascent saccadic eye movement commands. We examined the functional interaction of saccade preparation and visual coding by electrically stimulating sites within the frontal eye fields (FEF) and measuring its effect on the activity of neurons in extrastriate visual cortex. Here we show that visual responses in area V4 could be enhanced after brief stimulation of retinotopically corresponding sites within the FEF using currents below that needed to evoke saccades. The magnitude of the enhancement depended on the effectiveness of receptive field stimuli as well as on the presence of competing stimuli outside the receptive field. Stimulation of non-corresponding FEF representations could suppress V4 responses. The results suggest that the gain of visual signals is modified according to the strength of spatially corresponding eye movement commands.     

The perception of heading during eye movements.

When a person walks through a rigid environment while holding eyes and head fixed, the pattern of retinal motion flows radially away from a point, the focus of expansion (Fig. 1a). Under such conditions of translation, heading corresponds to the focus of expansion and people identify it readily. But when making an eye/head movement to track an object off to the side, retinal motion is no longer radial (Fig. 1b). Heading perception in such situations has been modelled in two ways. Extra-retinal models monitor the velocity of rotational movements through proprioceptive or efference information from the extraocular and neck muscles and use that information to discount rotation effects. Retinal-image models determine (and eliminate) rotational components from the retinal image alone. These models have been tested by measuring heading perception under two conditions. First, observers judged heading while tracking a point on a simulated ground plane. Second, they fixated a stationary point and the flow field simulated the effects of a tracking eye movement. Extra-retinal models predict poorer performance in the simulated condition because the eyes do not move. Retinal-image models predict no difference in performance because the two conditions produce identical patterns of retinal motion. Warren and Hannon observed similar performance and concluded that people do not require extra-retinal information to judge heading with eye/head movements present, but they used extremely slow tracking eye movements of 0.2-1.2 deg s-1; a moving observer frequently tracks objects at much higher rates (L. Stark, personal communication). Here we examine heading judgements at higher, more typical eye movement velocities and find that people require extra-retinal information about eye position to perceive heading accurately under many viewing conditions.     

Guarding the gateway to cortex with attention in visual thalamus

The massive visual input from the eye to the brain requires selective processing of some visual information at the expense of other information, a process referred to as visual attention. Increases in the responses of visual neurons with attention have been extensively studied along the visual processing streams in monkey cerebral cortex, from primary visual areas to parietal and frontal cortex. Here we show, by recording neurons in attending macaque monkeys (Macaca mulatta), that attention modulates visual signals before they even reach cortex by increasing responses of both magnocellular and parvocellular neurons in the first relay between retina and cortex, the lateral geniculate nucleus (LGN). At the same time, attention decreases neuronal responses in the adjacent thalamic reticular nucleus (TRN). Crick argued for such modulation of the LGN by observing that it is inhibited by the TRN, and suggested that "if the thalamus is the gateway to the cortex, the reticular complex might be described as the guardian of the gateway", a reciprocal relationship we now show to be more than just hypothesis. The reciprocal modulation in LGN and TRN appears only during the initial visual response, but the modulation of LGN reappears later in the response, suggesting separate early and late sources of attentional modulation in LGN.     

Numerical representation for action in the parietal cortex of the monkey

The anterior part of the parietal association area in the cerebral cortex of primates has been implicated in the integration of somatosensory signals, which generate neural images of body parts and apposed objects and provide signals for sensorial guidance of movements. Here we show that this area is active in primates performing numerically based behavioural tasks. We required monkeys to select and perform movement A five times, switch to movement B for five repetitions, and return to movement A, in a cyclical fashion. Cellular activity in the superior parietal lobule reflected the number of self-movement executions. For the most part, the number-selective activity was also specific for the type of movement. This type of numerical representation of self-action was seen less often in the inferior parietal lobule, and rarely in the primary somatosensory cortex. Such activity in the superior parietal lobule is useful for processing numerical information, which is necessary to provide a foundation for the forthcoming motor selection.     

Different time courses of learning-related activity in the prefrontal cortex and striatum

To navigate our complex world, our brains have evolved a sophisticated ability to quickly learn arbitrary rules such as 'stop at red'. Studies in monkeys using a laboratory test of this capacity--conditional association learning--have revealed that frontal lobe structures (including the prefrontal cortex) as well as subcortical nuclei of the basal ganglia are involved in such learning. Neural correlates of associative learning have been observed in both brain regions, but whether or not these regions have unique functions is unclear, as they have typically been studied separately using different tasks. Here we show that during associative learning in monkeys, neural activity in these areas changes at different rates: the striatum (an input structure of the basal ganglia) showed rapid, almost bistable, changes compared with a slower trend in the prefrontal cortex that was more in accordance with slow improvements in behavioural performance. Also, pre-saccadic activity began progressively earlier in the striatum but not in the prefrontal cortex as learning took place. These results support the hypothesis that rewarded associations are first identified by the basal ganglia, the output of which 'trains' slower learning mechanisms in the frontal cortex.