Pontine reference frames for the sensory guidance of movement

The pontine nuclei (PN) are the major intermediary elements in the corticopontocerebellar pathway. Here we asked if the PN may help to adapt the spatial reference frames used by cerebrocortical neurons involved in the sensory guidance of movement to a format potentially more appropriate for the cerebellum. To this end, we studied movement-related neurons in the dorsal PN (DPN) of monkeys, most probably projecting to the cerebellum, executing fixed vector saccades or, alternatively, fixed vector hand reaches from different starting positions. The 83 task-related neurons considered fired movement-related bursts before saccades (saccade-related) or before hand movements (hand movement-related). About 40% of the SR neurons were "oculocentric," whereas the others were modulated by eye starting position. A third of the HMR neurons encoded hand reaches in hand-centered coordinates, whereas the remainder exhibited different types of dependencies on starting positions, reminiscent in general of cortical responses. All in all, pontine reference frames for the sensory guidance of movement seem to be very similar to those in cortex. Specifically, the frequency of orbital position gain fields of SR neurons is identical in the DPN and in one of their major cortical inputs, lateral intraparietal area (LIP).     

A model of movement coordinates in the motor cortex: posture-dependent changes in the gain and direction of single cell tuning curves.

This article outlines a methodology for investigating the coordinate systems by which movement variables are encoded in the firing rates of individual motor cortical neurons. Recent neurophysiological experiments have probed the issue of underlying coordinates by examining how cellular preferred directions (as determined by the center-out task) change with posture. Several key experimental findings have resulted that constrain hypotheses about how motor cortical cells encode movement information. But while the significance of shifts in preferred direction is well known and widely accepted, posture-dependent changes in the depth of modulation of a cell's tuning curve--that is, gain changes--have not been similarly identified as a means of coordinate inference. This article develops a vector field framework in which the preferred direction and the gain of a cell's tuning curve are viewed as dual components of a unitary response vector. The formalism can be used to compute how each aspect of cell response covaries with posture as a function of the coordinate system in which a given cell is hypothesized to encode its movement information. Such an integrated approach leads to a model of motor cortical cell activity that codifies the following four observations: (i) cell activity correlates with hand movement direction; (ii) cell activity correlates with hand movement speed; (iii) preferred directions vary with posture; and (iv) the modulation depth of tuning curves varies with posture. Finally, the model suggests general methods for testing coordinate hypotheses at the single-cell level and simulates an example protocol for three possible coordinate systems: Cartesian spatial, shoulder-centered, and joint angle.     

Multiple levels of representation of reaching in the parieto-frontal network

In daily life, hand and eye movements occur in different contexts. Hand movements can be made to a visual target shortly after its presentation, or after a longer delay; alternatively, they can be made to a memorized target location. In both instances, the hand can move in a visually structured scene under normal illumination, which allows visual monitoring of its trajectory, or in darkness. Across these conditions, movement can be directed to points in space already foveated, or to extrafoveal ones, thus requiring different forms of eye-hand coordination. The ability to adapt to these different contexts by providing successful answers to their demands probably resides in the high degree of flexibility of the operations that govern cognitive visuomotor behavior. The neurophysiological substrates of these processes include, among others, the context-dependent nature of neural activity, and a transitory, or task-dependent, affiliation of neurons to the assemblies underlying different forms of sensorimotor behavior. Moreover, the ability to make independent or combined eye and hand movements in the appropriate order and time sequence must reside in a process that encodes retinal-, eye- and hand-related inputs in a spatially congruent fashion. This process, in fact, requires exact knowledge of where the eye and the hand are at any given time, although we have no or little conscious experience of where they stay at any instant. How this information is reflected in the activity of cortical neurons remains a central question to understanding the mechanisms underlying the planning of eye-hand movement in the cerebral cortex. In the last 10 years, psychophysical analyses in humans, as well as neurophysiological studies in monkeys, have provided new insights on the mechanisms of different forms of oculo-manual actions. These studies have also offered preliminary hints as to the cortical substrates of eye-hand coordination. In this review, we will highlight some of the results obtained as well as some of the questions raised, focusing on the role of eye- and hand-tuning signals in cortical neural activity. This choice rests on the crucial role this information exerts in the specification of movement, and coordinate transformation.     

Cortical networks for control of voluntary arm movements under variable force conditions

A neural model of voluntary movement and proprioception is developed that offers an integrated interpretation of the functional roles of diverse cell types in movement-related areas of primate cortex. The model circuit maintains accurate proprioception while controlling voluntary reaches to spatial targets, exertion of force against obstacles, posture maintenance despite perturbations, compliance with an imposed movement, and static and inertial load compensations. Computer simulations show that properties of model elements correspond to the properties of many known cells types in areas 4 and 5. Among these properties are delay period activation, response profiles during movement, kinematic and kinetic sensitivities, and latency of activity onset. In particular, area 4 phasic and tonic cells, respectively, compute velocity and position commands that are capable of activating alpha and gamma motor neurons, thereby shifting the mechanical equilibrium point. Anterior area 5 cells compute the position of the limb using corollary discharges from area 4 and feedback from muscle spindles. Posterior area 5 neurons use the position perception signal and a target position signal to compute a desired movement vector. The cortical loop is closed by a volition-gated projection of this movement vector to the area 4 phasic cells. An auxiliary circuit allows phasic- tonic cells in area 4 to incorporate force command components needed to compensate for static and inertial loads. After reporting simulations of prior experimental results, predictions are made for both motor and parietal cell types under novel experimental protocols.      

Oculocentric Spatial Representation in Parietal Cortex

Parietal cortex comprises several distinct areas. Neurons ineach area are selective for particular stimulus dimensions andparticular regions of space. The representation of space ina given area reflects a particular motor output by which a stimuluscan be acquired. Neurons in the lateral intraparietal area (UP)are active in relation to both visual and motor events. UP neuronsdo not transmit an unambiguous sac-cadic command. Rather theysignal the location at which an event has occurred. These spatiallocations are encoded in oculocentric coordinates, that is,with respect to the current or anticipated position of the centerof gaze. When an eye movement brings the spatial location ofa recently flashed stimulus into the receptive field of an UPneuron, the neuron responds to the memory trace of that stimulus.This result indicates that for nearly all UP neurons, storedvisual information is remapped in conjunction with saccades.Remapping of the memory trace maintains the alignment betweenthe current image on the retina and the stored representationin cortex. Further when an eye movement is about to occur, morethan a third of UP neurons transiently shift the location oftheir receptive fields. This anticipatory remapping allows theneuron to begin to respond to a visual stimulus even beforethe saccade is initiated that will bring the stimulus into thefixation-defined receptive field. Both kinds of remapping serveto create a constantly updated representation of stimulus locationthat is always in terms of distance and direction from the fovea.This oculocentric representation has the advantage that it alreadymatches that known to exist in the frontal eye fields and thesuperior colliculus, the output targets of UP, and it does notrequire further coordinate transformation in order to contributeto spatially accurate behavior. These results indicate thatUP can analyze visual space without ever forming a representationof absolute target position.     

Neural resources associated with perceptual judgment across sensory modalities

Electrophysiological and brain imaging studies have shown that different populations of neurons contribute to perceptual decision making. Perceptual judgment is a complicated process that has several subprocesses, including the final step of a discrete choice among available possibilities. Using the psychophysical paradigm of difference scaling combined with functional magnetic resonance imaging, we identify an area within a distributed representation that is consistently invoked in perceptual decision. Difference judgments based on visual (color, form, and motion) cues and auditory cues show that a population of neurons in the posterior banks of the intraparietal sulcus (PIPS) is consistently activated for perceptual judgment across visual attributes and sensory modalities, suggesting that those neurons in PIPS are associated with perceptual judgment.     

Temporal evolution and strength of neural activity in parietal cortex during eye and hand movements

The role of area 7a in eye-hand movement was studied by recording from individual neurons while monkeys performed 7 different tasks, aimed at assessing the relative influence of retinal, eye, and hand information on neural activity. Parietal cell activity was modulated by visuospatial signals about target location, as well as by information concerning eye and/or hand movement, and position. The highest activity was elicited when the hand moved to the fixation point. The population activities across different memory tasks showed common temporal peaks when aligned to the visual instruction (visuospatial peak) or Go signal (motor peak) for eye, hand, and coordinated eye-hand movement. The motor peak was higher for coordinated eye-hand movement, and it was absent in a No-Go task. Two activation maxima were also observed during visual reaching. They had the same latency of the visuospatial and motor peaks seen in the memory tasks. Therefore, area 7a seems to operate through a common neural mechanism underlying eye, hand, or combined eye-hand movement. This mechanism is revealed by invariant temporal activity profiles and is independent from the effector selected and from the presence or absence of a visible target during movement. For comparative purposes, we have studied the temporal evolution of the population activity in the superior parietal lobule (SPL) during the same reaching tasks and during a saccade task. In SPL, the population activity was characterized by a single peak, time locked to the Go signal for eye, hand, or combined eye-hand movement. As in IPL, the time of occurrence of this peak was effector independent. The population activity remained unchanged when the position of the eye changed, suggesting that SPL is mostly devoted to the hand motor behavior.     

Involvement of the ventral premotor cortex in controlling image motion of the hand during performance of a target-capturing task

The ventral premotor cortex (PMv) has been implicated in the visual guidance of movement. To examine whether neuronal activity in the PMv is involved in controlling the direction of motion of a visual image of the hand or the actual movement of the hand, we trained a monkey to capture a target that was presented on a video display using the same side of its hand as was displayed on the video display. We found that PMv neurons predominantly exhibited premovement activity that reflected the image motion to be controlled, rather than the physical motion of the hand. We also found that the activity of half of such direction-selective PMv neurons depended on which side (left versus right) of the video image of the hand was used to capture the target. Furthermore, this selectivity for a portion of the hand was not affected by changing the starting position of the hand movement. These findings suggest that PMv neurons play a crucial role in determining which part of the body moves in which direction, at least under conditions in which a visual image of a limb is used to guide limb movements.     

Modulation of responses to optic flow in area 7a by retinotopic and oculomotor cues in monkey

Perception of two- and three-dimensional optic flow critically depends upon extrastriate cortices that are part of the 'dorsal stream' for visual processing. Neurons in area 7a, a sub-region of the posterior parietal cortex, have a dual sensitivity to visual input and to eye position. The sensitivity and selectivity of area 7a neurons to three sensory cues - optic flow, retinotopic stimulus position and eye position - were studied. The visual response to optic flow was modulated by the retinotopic stimulus position and by the eye position in the orbit. The position dependence of the retinal and eye position modulation (i.e. gain field) were quantified by a quadratic regression model that allowed for linear or peaked receptive fields. A local maximum (or minimum) in both the retinotopic fields and the gain fields was observed, suggesting that these sensory qualities are not necessarily linearly represented in area 7a. Neurons were also found that simply encoded the eye position in the absence of optic flow. The spatial tuning for the eye position signals upon stationary stimuli and optic flow was not the same, suggesting multiple anatomical sources of the signals. These neurons can provide a substrate for spatial representation while primates move in the environment.      

Transient neuronal correlations underlying goal selection and maintenance in prefrontal cortex

We reported previously that as monkeys used abstract response strategies to choose spatial goals, 1 population of prefrontal cortex neurons encoded future goals (F cells), whereas a largely separate population encoded previous goals (P cells). Here, to better understand the mechanisms of goal selection and maintenance, we studied correlated activity among pairs of these neurons. Among the 3 possible types of pairs, F-F and F-P pairs often exhibited significant correlations when and after monkeys selected future goals but P-P pairs rarely did. These correlations were stronger when monkeys shifted from a previous goal than when they stayed with that goal. In addition, members of F-F pairs usually preferred the same goal and thus shared both prospective coding and spatial tuning properties. In contrast, cells composing F-P pairs usually had different spatial preferences and thus shared neither coding nor spatial tuning properties. On the assumption that the neurons composing a pair send convergent outputs to target neurons, their correlated activity could enhance their efficacy in context-dependent goal selection, goal maintenance, and the transformation of goal choices into action.     

Ketamine effects on somatosensory cortical single neurons and on behavior in rats

The neurophysiological effects of ketamine were studied at the single-neuron level in the somatosensory cortex of unanesthetized rats behaving in a treadmill movement paradigm. Chronically implanted 25-microns microwire electrodes were used to record spontaneous discharge, sensory responses, and sensorimotor-correlated activity of single neurons before and after ketamine administration. Extracellular action potentials of up to six single neurons were simultaneously recorded for several days, allowing ketamine effects to be tested repeatedly on the same neurons. Videotaped recordings obtained during each experiment were used to measure both the sensorimotor properties of the neurons and the changes in these measures caused by different doses of ketamine. Behaviorally, ketamine produced restless-hyperactive behavior at subanesthetic doses from 5 to 20 mg/kg (intramuscularly). At higher doses (30-50 mg/kg) the rats became cataleptic and immobile after the initial hyperactive period. Whereas the spontaneous rates of most neurons were reduced or unchanged after subanesthetic doses, a subgroup (27% of the total) exhibited markedly increased firing rates. This excitation was of a tonic nature, persisting for a dose-dependent duration in a manner that was not correlated with any of the behavioral effects of the drug. In further analyses, ketamine suppressed the sensory responses of virtually all of the recorded neurons. In particular, low doses of ketamine suppressed "sensorimotor" firing (mainly proprioceptive responses) of neurons in relation to active limb movement. It also suppressed virtually all neuronal sensory responses to the sudden onset of treadmill movement, although the time-course of this effect varied from neuron to neuron. These results reveal two separable effects of ketamine: (a) a strong inhibition of all somatosensory responsiveness in this area and (b) a tonic excitatory influence expressed heterogeneously on a subgroup of neurons. This coexistence of cortical neuronal excitation and sensory suppression in the same cortical region may explain in part the mechanism of dissociative anesthesia and hallucinatory side effects observed in humans during emergence from ketamine anesthesia.     

Unsuspected plasticity of single neurons after connection of the corticospinal tract with peripheral nerves in spinal cord lesions

We sought to understand an unsuspected plasticity of single neurons found after connection of the cord with peripheral nerves in paraplegics. Our research aimed at making paraplegics walk again, after 20 years of experimental surgery in animals that, among other things, demonstrated the alteration of the motor end plate receptors from cholinergic to glutamatergic; the same connection was done in humans. The grafts were put in the corticospinal tract of the cord randomly, without possibility of choosing the axons coming from different areas of the brain cortex. As a result, the patient was able to selectively activate the muscles she wanted without cocontractions of the other muscles connected with the same cortical areas. We believe that unlike in nerve or tendon transfers, where the whole cortical area corresponding to the transfer changes its function (a phenomenon that we call "brain plasticity by areas"), in the connection of the lateral bundle of the thoracic cord (the CST) with different peripheral nerves and muscles, the brain plasticity occurs by single neurons; in fact, there are no cocontractions. We propose to call it "brain plasticity by single neurons." We speculate that this phenomenon is due to the simultaneous activation of neurons spread in different cortical areas for a given specific movement while the other neurons of the same areas connected with peripheral nerves of different muscles are not activated. Why different neurons of the same area fire at different times according to different voluntary demands remains to be discovered, and we are committed to solve this enigma.     

Physiological responses of New World monkey V1 neurons to stimuli defined by coherent motion

We studied the responses of neurons in area V1 of marmosets to visual stimuli that moved against dynamic textured backgrounds. The stimuli were defined either by a first-order cue ('solid' bars, which were either darker or lighter than the background) or by a second-order cue ('camouflaged' bars, defined only by coherent motion). Forty-two per cent of the neurons demonstrated a similar selectivity for the direction of motion of the solid and camouflaged bars, thereby characterizing a population of cue-invariant (CI) cells. The other cells either showed different selectivity to the movement of solid and camouflaged bars (non-cue-invariant, or NCI cells), or responded equally well to movement in all directions. CI neurons, which were rare in layer 4, tended to have larger receptive fields and to be more strongly direction selective than NCI cells. Although V1 neurons tended to show maximal responses to camouflaged bars that were longer than the 'optimal' solid bars, many CI neurons preferred first- and second-order stimuli of similar lengths. Finally, the activity evoked by the camouflaged bars was delayed in relation to that evoked by solid bars. These results demonstrate that motion CI responses are relatively common in primate V1, especially among a population of strongly direction-selective neurons. They also indicate that this response property may depend on feedback from extrastriate areas, or on complex intrinsic interactions within V1.     

The eye and the hand: neural mechanisms and network models for oculomanual coordination in parietal cortex

The coordinated action of the eye and the hand is necessary for the successful performance of a large variety of motor tasks based on visual information. Although at the output level the neural control systems for the eye and the hand are largely segregated, in the parietal cortex of the macaque monkey there exist populations of neurons able to combine ocular and manual signals on the basis of their spatial congruence. An expression of this congruence is the clustering of eye- and hand-related preferred directions of these neurons into a restricted region of the workspace, defined as field of global tuning. This domain may represent a neural substrate for the early composition of commands for coordinated oculo-manual actions. Here we study two different prototypical network models integrating inputs about retinal target location, eye position and hand position. In the first one, we model the interaction of these different signals, as it occurs at the afferent level, in a feed-forward fashion. In the second model, we assume that recurrent interactions are responsible for their combination. Both models account surprisingly well for the experimentally observed global tuning fields of parietal neurons. When we compare them with the experimental findings, no significant difference emerges between the two. Experiments potentially able to discriminate between these models could be performed.     

Behavioral influences on cortical neuronal responses to optic flow

Optic flow selectively activates neurons in medial superior temporal (MST) cortex. We find that many MST neurons yield larger and more selective responses when the optic flow guides a subsequent eye movement. Smaller, less selective responses are seen when optic flow is preceded by a flashed precue that guides eye movements. Selectivity can decrease by a third (32%) after a flashed precue is presented at a peripheral location as a small spot specifying the target location of the eye movement. Smaller decreases in selectivity (18%) occur when the precue is presented centrally with its shape specifying the target location. Shape precues presented centrally, but not linked to specific target locations, do not appear to alter optic flow selectivity. The effects of spatial precueing can be reversed so that the precue leads to larger and more selective optic flow responses: A flashed precue presented as a distracter before behaviorally relevant optic flow is associated with larger optic flow responses and a 45% increase in selectivity. Together, these findings show that spatial precues can decrease or increase the size and selectivity of optic flow responses depending on the associated behavioral contingencies.     

Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder

Reductions in glial cell density and neuronal size have been described recently in major depressive disorder (MDD). Considering the important trophic influence of glia on neurons, we hypothesized that this glial cell deficit is more prominent close to neurons. In this investigation we have characterized neuronal and glia cytoarchitecture in prefrontal area 9 using spatial point pattern techniques and two-dimensional measures of cell size and density. In post-mortem brain tissue of subjects with MDD, schizophrenia, bipolar disorder (BPD), and normal controls (15 subjects per group), we examined the laminar location and size of all neurons and glial nuclei in a 500 microm wide strip of cortex extending from the pia to the grey-white matter border. In MDD, we observed reductions in glial cell density (30%; P = 0.007) in layer 5 and neuronal size (20%; P = 0.003) in layer 6. We also found that glial cell density (34%; P = 0.003) was reduced in layer 5 in schizophrenia, while neuronal size was reduced in layers 5 (14%) (P = 0.006) and 6 (18%; P = 0.007) in BPD. The spatial pattern investigation of neurons and glia demonstrated no alteration in the clustering of glia about neurons between control and patient groups. These findings confirm that glial cell loss and neuronal size reductions occur in the deeper cortical layers in MDD, but provide no support for the hypothesis that an altered spatial distribution of glia about neurons plays a role in the development of these changes.     

Eye-hand coordination during reaching. II. An analysis of the relationships between visuomanual signals in parietal cortex and parieto-frontal association projections

The relationships between the distribution of visuomanual signals in parietal cortex and that of parieto-frontal projections are the subject of the present study. Single cell recording was performed in areas PEc and V6A, where different anatomical tracers were also injected. The monkeys performed a variety of behavioral tasks, aimed at studying the visual and motor properties of parietal cells, as well as the potential combination of retinal-, eye- and hand-related signals on cell activity. The activity of most cells was related to the direction of movement and the active position of the hand. Many of these reach-related cells were influenced by eye position information. Fewer cells displayed relationships to saccadic eye movements. The activity of most neurons related to a combination of both hand and eye signals. Many cells were also modulated during preparation for hand movement. Light-dark differences of activity were common and interpreted as related to the sight and monitoring of hand motion and/or position in the visual field. Most cells studied were very sensitive to moving visual stimuli and also responded to optic flow stimulation. Visual receptive fields were generally large and extended to the periphery of the visual field. For most neurons, the orientation of the preferred directions computed across different epochs and tasks conditions clustered within a limited sector of space, the field of global tuning. This can be regarded as an ideal frame to combine spatially congruent eye- and hand-related information for different forms of visuomanual behavior. All these properties were common to both PEc and V6A. Retinal, eye- and hand-related activity types, as well as parieto-frontal association cells, were distributed in a periodic fashion across the tangential domain of areas PEc and V6A. These functional and anatomical distributions were characterized and compared through a spectral and coherency analysis, which revealed the existence of a selective 'match' between activity types and parieto-frontal connections. This match depended on where each individual efferent projection was addressed. The results of the present and of the companion study can be relevant for a re-interpretation of optic ataxia as the consequence of the breakdown of the combination of retinal-, eye- and hand-related directional signals within the global tuning fields of parietal neurons.     

Selective output-discriminative signals in the motor cortex of waking monkeys.

Monkeys and humans have similar capacities to discriminate between the frequencies of mechanical sinusoids delivered to the glabrous skin of their hands. Combined psychophysical-electrophysiological experiments in monkeys discriminating in the range of flutter provided evidence that this capacity depends upon differences in the cycle lengths in the sets of periodically entrained activity, evoked by the stimuli discriminated, in neurons of areas 3b and 1 of the (sensory) hemisphere opposite the stimulated hand. Identical experiments have now been made, in similarly trained and discriminating monkeys, in the motor cortex (area 4) of the hemisphere opposite the arm projecting selectively to one of two targets, to indicate discrimination (five hemispheres, 1137 neurons studied). We observed a selective signal of the upcoming correct discrimination in about 25% of the neurons of area 4 active in the task. The neuronal discharge occurs selectively for stimuli either lower or higher in frequency than that of the base stimulus, and commonly begins within 200-300 msec after onset of the comparison stimulus. These neuronal discharges are aperiodic, with no sign of the stimulus frequencies. EMG recording during performance of the discrimination showed that the muscles of the arm opposite the side of recording were silent during the period of stimulus presentations. Recordings during trials in which the animal made errors showed most commonly that the output of the discrimination operation was itself in error, followed by an appropriate arm projection to the wrong target. We interpret the selective response during the comparison stimulus to be a postdiscrimination signal projected transcallosally from the sensory hemisphere to the motor area of the hemisphere controlling the responding arm. We obtained no evidence that the discrimination operation is localized to any particular area, and we surmise it to occur in the dynamic activity within the distributed system linking the sensory cortex of one hemisphere and the motor cortex of the other. One-third of the neurons of the motor cortex responded to indentation of the skin of the ipsilateral hand, at trial onset. These responses varied from those closely linked to that sensory stimulus to those linked to the upcoming movement of the contralateral hand. These onset responses did not occur when similar sequences of mechanical stimuli were delivered to alert but idling monkeys.