Visuomotor control in mice and primates.

We conduct a comparative evaluation of the visual systems from the retina to the muscles of the mouse and the macaque monkey noting the differences and similarities between these two species. The topics covered include (1) visual-field overlap, (2) visual spatial resolution, (3) V1 cortical point-image [i.e., V1 tissue dedicated to analyzing a unit receptive field], (4) object versus motion encoding, (5) oculomotor range, (6) eye, head, and body movement coordination, and (7) neocortical and cerebellar function. We also discuss blindsight in rodents and primates which provides insights on how the neocortex mediates conscious vision in these species. This review is timely because the field of visuomotor neurophysiology is expanding beyond the macaque monkey to include the mouse; there is therefore a need for a comparative analysis between these two species on how the brain generates visuomotor responses.

Eye movements modulate visual receptive fields of V4 neurons.

The receptive field, defined as the spatiotemporal selectivity of neurons to sensory stimuli, is central to our understanding of the neuronal mechanisms of perception. However, despite the fact that eye movements are critical during normal vision, the influence of eye movements on the structure of receptive fields has never been characterized. Here, we map the receptive fields of macaque area V4 neurons during saccadic eye movements and find that receptive fields are remarkably dynamic. Specifically, before the initiation of a saccadic eye movement, receptive fields shrink and shift towards the saccade target. These spatiotemporal dynamics may enhance information processing of relevant stimuli during the scanning of a visual scene, thereby assisting the selection of saccade targets and accelerating the analysis of the visual scene during free viewing.

Look and see: how the brain moves your eyes about.

Two major cortical streams are involved in the generation of visually guided saccadic eye movements: the anterior and the posterior. The anterior stream from the frontal and medial eye fields has direct access to brainstem oculomotor centers. The posterior stream from the occipital cortices reaches brainstem oculomotor centers through the superior colliculus. The parietal cortex interconnects with both streams. Our findings suggest that the posterior stream plays an unique role in the execution of rapid, short-latency eye movements called 'express saccades'. Both the anterior and posterior streams play a role in the selection of targets to which saccades are to be generated, but do so in different ways. Areas V1, V2 and LIP contribute to decisions involved in where to look as well as where not to look. In addition, area LIP is involved in decisions about how long to maintain fixation prior to the execution of a saccade. Area V4 does not appear to be directly involved in eye-movement generation. In the anterior stream, the frontal eye fields, and to a lesser extent the medial eye fields, are involved in the correct execution of saccades subsequent to decisions made about where to look and where not to look.

Electrical stimulation of neural tissue to evoke behavioral responses.

This review yields numerous conclusions. (1) Both unit recording and behavioral studies find that current activates neurons (i.e., cell bodies and axons) directly according to the square of the distance between the electrode and the neuron, and that the excitability of neurons can vary between 100 and 4000 microA/mm2 using a 0.2-ms cathodal pulse duration. (2) Currents as low as 10 microA, which is considered within the range of currents typically used during micro-stimulation, activate from a few tenths to several thousands of cell bodies in the cat motor cortex directly depending on their excitability; this indicates that even low currents activate more than a few neurons. (3) Electrode tip size has no effect on the current density--or effect current spread--at far field, but tip size limits the current-density generated at near field. (4) To minimize neuronal damage, the electrode should be discharged after each pulse and the pulse duration should not exceed the chronaxie of the stimulated tissue. (5) The amount of current needed to evoke behavioral responses depends not only on the excitability of the stimulated substrate but also on the type of behavior being studied.

Effective spread and timecourse of neural inactivation caused by lidocaine injection in monkey cerebral cortex.

We studied the effective spread of lidocaine to inactivate neural tissue in the frontal cortex of the rhesus monkey. Injections of 2% lidocaine at 4 microl/min were made while units were recorded 1 or 2 mm away. To inactivate units 1 mm away from the injection site 100% of the time, 7 microl of lidocaine had to be injected. To inactivate units 2 mm away from the injection site 100% of the time, 30 microl of lidocaine were required. Units were maximally inactivated around 8 min after the start of a lidocaine injection, and they gradually recovered, regaining most of their initial activity by around 30 min after the start of an injection. The volume of lidocaine required to inactivate neurons > 90% of the time could be estimated by the spherical volume equation, V = 4/3 pi (r)3. To prolong the inactivation, a slower infusion of lidocaine subsequent to an initial bolus was effective. Saline control injections had no effect. These results allow both a prediction of the timecourse of neural inactivation and an estimate of the spread of neural inactivation following injection of lidocaine into the monkey cerebral cortex.

Excitability of neural elements within the rat corpus striatum.

The excitability of cholinergic, glutamatergic and dopaminergic elements within the rat neostriatum was studied in both in vivo and in vitro preparations. In vivo, the microdialysis technique was used to measure the release of striatal acetylcholine and dopamine under basal and electrically evoked conditions. For comparison, acetylcholine, dopamine and glutamate release was assayed in media obtained from superfused rat striatal slices. Electrical stimulation was used to derive the strength-duration functions and their chronaxies of stimulated elements containing the three neurotransmitter types. The chonaxies for experiments in vitro and in vivo were similar: the chronaxy values for elements containing acetylcholine were the shortest, the values for glutamate were intermediate, and the values for those containing dopamine were the longest. Based on the chronaxy estimates, it is proposed that the elements containing acetylcholine are the large cholinergic interneurons of striatum, and the elements containing glutamate and dopamine are the terminals of corticostriatal and nigrostriatal neurons, respectively. These results indicate that electrical stimulation of neural elements surrounding a microdialysis probe can be an additional tool to examine the factors that regulate neurotransmitter release. Likewise, investigators can activate specific striatal elements by using pulse durations that coincide with their chronaxies.

Head and body movements evoked electrically from the caudal superior colliculus of rats: pulse frequency effects.

The effects of pulse frequency and current intensity on circling elicited from the caudal superior colliculus (SC) of rats were studied. The displacement of the head with respect to the body were measured for different levels of frequency (20, 29, and 50 Hz) and current (200 or 500 microA) at a pulse duration of 0.1 ms. The rate of circling increased monotonically with frequency and current. The rate at which the head was displaced laterally varied as a function of frequency. It is postulated that lateral head and body movements are affected by the firing frequency of SC output neurons.

The dorsomedial frontal cortex: eye and forelimb fields.

This review yields three conclusions: first, the eye field as described using unit recording and electrical stimulation on behaving monkeys trained to fixate visual targets is much larger than the 4 mm2 area originally described. Second, the eye field and forelimb field share a similar neural space within the dorsomedial frontal cortex (DMFC); thus the electrophysiogical studies that have been conducted on visually guided and sensory-triggered forelimb movements must be re-evaluated, since none of these studies controlled eye movement and eye position independently. Third, a topographic map representing eye position in orbit has been discovered in the DMFC; it is proposed that this topographic map records the order of positions of the eyes and forelimbs during the acquisition of visually guided movement sequences.

Efferent projections of the anteromedial cortex of the rat as described by Phaseolus vulgaris leucoagglutinin immunohistochemistry.

Phaseolus vulgaris leucoagglutinin (PHA-L) immunohistochemistry was used to describe the corticofugal projections of the anteromedial cortex (AMC) of rats. PHA-L was injected iontophoretically into an area of the AMC which, when stimulated electrically, is known to induce contraversive head and body movements. It was found that the AMC innervates the midbrain via three separate pathways: a dorsal transthalamic pathway terminating in the pretectum, superior colliculus, and central grey area; and a ventral transthalamic pathway and a ventral capsular-peduncular pathway projecting to the central grey and mesencephalic and pontine reticular formation. The strongest terminations were found bilaterally in the mediodorsal thalamic nucleus and nucleus caudato-putamen. The functional significance of the pathways and terminations is discussed.

Effects of training on saccadic eye movements elicited electrically from the frontal cortex of monkeys.

It has been reported that training affects motor responses evoked electrically from the dorsomedial frontal cortex (DMFC). Once a monkey had been trained to generate visually-guided saccadic eye movements of a particular size and direction, electrical stimulation of the DMFC elicited saccades of only that size and direction [7]. The current study re-investigates this finding. Monkeys were trained to produce saccadic eye movements to a visual target. After training, electrical stimulation was delivered to the DMFC. It was found that stimulation of the DMFC always evoked saccadic eye movements of the same size and direction before and after training, such that training had little effect on the responses evoked electrically from the DMFC. Differences between the current results and previous results have disclosed new clues as to how the DMFC might be modulated by learning.

Circling elicited from the anteromedial cortex and medial pons: refractory periods and summation.

Contraversive circling is evoked by stimulating the anteromedial cortex (AMC) of rats, and ipsiversive circling is evoked by stimulating the medial pons (PONS). During AMC circling, lateral and vertical head movements and vibrissae movements were exhibited. During PONS circling, although lateral head movements were exhibited, vertical head movements and vibrissae movements were not exhibited. Refractory periods were estimated by delivering trains of paired pulses and measuring the frequency thresholds for circling at various intrapair intervals. Refractory periods at AMC circling sites were much longer (range 1.4-3.3 ms) than at PONS circling sites (range 0.5-1.0 ms). To determine the degree of summation between the AMC and contralateral PONS, the two sites were stimulated concurrently. Summation of 95-100% was observed for AMC and PONS circling. No collision was observed at short intrapair intervals of paired pulses. Thus, the AMC and PONS are not connected axonally but are related, perhaps serially, for the production of circling.

Two converging brainstem pathways mediating circling behavior.

Ipsiversive circling results from stimulation of the rostromedial tegmentum (RMT) or medial pons (PONS), and contraversive circling results from stimulation of the superior colliculus (SC). To determine whether these sites are functionally connected, the collision method of Shizgal, Bielajew, Corbett, Skelton and Yeomans (1980) was used in rats. Pairs of stimulation pulses were presented to two sites, and the degree of collision between stimulation-evoked action potentials was assessed by measuring the frequency required for circling at short and long intrapair conditioning-testing (C-T) intervals. Collision was evidenced when the required frequencies were higher at short C-T intervals than at long C-T intervals. Collision of 46-62% was observed between RMT and PONS, and collision of 15-29% was observed between SC and PONS. Sites from which collision was obtained were located along the trajectories of the medial tegmental tract and the crossed tectospinal pathway. Refractory periods in all sites were similar, ranging from 0.3 to 1.7 ms. Conduction velocities of axons connecting RMT and PONS and SC and PONS were comparable, ranging from 0.8 to 13.3 m/s and 1.7 to 13.8 m/s, respectively, with lower conduction velocities associated with more ventral pontine sites. Thus, RMT and PONS, and SC and PONS are connected by myelinated axons that mediate circling.

Compensatory saccades made to remembered targets following orbital displacement by electrically stimulating the dorsomedial frontal cortex or frontal eye fields of primates.

If the eye-position signal during visually-evoked saccades is dependent on the dorsomedial frontal cortex (DMFC), one would expect that saccades generated to briefly presented visual targets would be disrupted after displacement of the eyes via electrical stimulation of this cortical area. Compared are compensatory saccades evoked to brief targets following stimulation of the DMFC and frontal eye fields (FEF). Compensatory saccades produced to brief targets following perturbation via the DMFC were not affected. Accordingly, electrical stimulation of the DMFC does not disrupt the eye-position signal during the execution of visually-evoked saccades.

Contraversive circling elicited from the internal capsule and substantia nigra: evidence for a continuous axon bundle mediating circling.

Electrical stimulation of many brain sites (e.g., anteromedial cortex, internal capsule, substantia nigra, superior colliculus, rostro-medial tegmentum, and medial pons) evokes circling. The collision method of Shizgal et al. (J. Comp. Physiol. Psychol., 94 (1980) 227-237) was used to determine whether these sites are functionally connected for the production of circling in rats. If connectivity was evidenced, then refractory period and conduction velocity distributions were determined for axons passing through the connected stimulation sites. Collision of up to 90% was found between electrodes placed in internal capsule and substantia nigra, suggesting that these sites are connected by continuous axons that mediate circling. The refractory periods of these axons ranged from 0.5 to 4.5 ms, and the conduction velocities of these axons ranged from 0.9 to 4.4 ms. These velocities are similar to those of striatonigral axons. No collision was found between anteromedial cortex and any other sites tested, nor between pontine sites and internal capsule or substantia nigra.

Turning responses evoked by stimulation of visuomotor pathways.

Lateral eye, head, and body movements are produced by electrical stimulation of many brain regions from frontal cortex to pons. A new collision method shows that at least 5 separate axon bundles mediate stimulation-elicited lateral head and body movements in rats. One bundle passes between the rostromedial tegmentum and medial pons, with conduction velocities of 0.8-18 m/s. A second bundle passes between the superior colliculus and contralateral medial pons, with conduction velocities of 1.7-13 m/s. A third bundle passes between the superior colliculus and ventrolateral pons, with conduction velocities of 1.3-20 m/s. A fourth bundle passes between the internal capsule and medial substantia nigra, with conduction velocities of 0.9-4.4 m/s. A fifth bundle passes between the anteromedial cortex and rostral striatum, with conduction velocities of 2.4-36 m/s. Collision effects have not been observed between the anteromedial cortex and the internal capsule, medial substantia nigra, superior colliculus, rostromedial tegmentum, or medial pons, which suggests that these sites are not connected by axons mediating turning. Possible synaptic linkages between the 5 bundles and possible transmitters are discussed.

Saccades induced electrically from the dorsomedial frontal cortex: evidence for a head-centered representation.

The amplitude and direction of saccadic eye movements evoked electrically from the dorsomedial frontal cortex (DMFC) of monkeys vary with starting eye position. This observation has been used to argue that the DMFC codes saccadic eye movements in head-centered coordinates. Whether the amplitude and direction of the evoked saccades are also affected by changes in head position has never been demonstrated. Such a result would argue against a head-centered representation, and instead would suggest a representation anchored to another body part. Tests were conducted on rhesus monkeys to determine whether changing the position of the head with respect to the trunk or changing the position of the head with respect to the gravitational axis alters saccadic parameters. The amplitude and direction of saccadic eye movements remained invariant to such manipulations. These findings confirm the claim that the DMFC encodes saccadic eye movements in head-centered coordinates.

Two-photon imaging and the activation of cortical neurons.

Based on two-photon calcium imaging, Histed et al. (2009) concluded that electrical microstimulation of cortical tissue in mammals activates a sparse and distributed population of neurons. This work has been cited by many as proof that electrical microstimulation is nonfocal, which means it may lack the precision needed for applications in neuroprosthetics. We affirm that the generation of stimulation-evoked behaviour is based primarily on the orthodromic conduction of signals originating mainly from the deepest layers of cortex, while the work of Histed et al. is effectively limited to investigating the antidromic activation of lateral projection neurons of the superficial cortex. The apparent sparse activation is a consequence of the pattern of axonal projections based on activating a volume of axons while imaging cell bodies transecting a single plane through the cortex. This creates the false impression that the distribution of activated neurons is sparse and nonfocal. We recommend how two-photon calcium imaging, which is superb for the study of individual and groups of neurons, might be more effectively used to ascertain how electrical stimulation affects the brains of mammals. This is a timely topic since investigators are using electrical microstimulation in animals to develop prosthetic devices to restore sensory and motor functions in disabled patients.

Transfer of information by BMI.

Brain machine interfaces (BMI) have become important in systems neuroscience with the goal to restore motor function in paralyzed patients. We assess the current ability of BMI devices to move objects. The topics discussed include: (1) the bits of information generated by a BMI signal, (2) the limitations of including more neurons for generating a BMI signal, (3) the superiority of a BMI signal using single cells versus electroencephalography, (4) plasticity and BMI, (5) the selection of a neural code for generating BMI, (6) the suppression of body movements during BMI, and (7) the role of vision in BMI. We conclude that further research on understanding how the brain generates movement is necessary before BMI can become a reasonable option for paralyzed patients.

Direct and indirect activation of cortical neurons by electrical microstimulation.

Electrical microstimulation has been used to elucidate cortical function. This review discusses neuronal excitability and effective current spread estimated by using three different methods: 1) single-cell recording, 2) behavioral methods, and 3) functional magnetic resonance imaging (fMRI). The excitability properties of the stimulated elements in neocortex obtained using these methods were found to be comparable. These properties suggested that microstimulation activates the most excitable elements in cortex, that is, by and large the fibers of the pyramidal cells. Effective current spread within neocortex was found to be greater when measured with fMRI compared with measures based on single-cell recording or behavioral methods. The spread of activity based on behavioral methods is in close agreement with the spread based on the direct activation of neurons (as opposed to those activated synaptically). We argue that the greater activation with imaging is attributed to transynaptic spread, which includes subthreshold activation of sites connected to the site of stimulation. The definition of effective current spread therefore depends on the neural event being measured.

Phosphene induction and the generation of saccadic eye movements by striate cortex.

The purpose of this review is to critically examine phosphene induction and saccadic eye movement generation by electrical microstimulation of striate cortex (area V1) in humans and monkeys. The following issues are addressed: 1) Properties of electrical stimulation as they pertain to the activation of V1 elements; 2) the induction of phosphenes in sighted and blind human subjects elicited by electrical stimulation using various stimulation parameters and electrode types; 3) the induction of phosphenes with electrical microstimulation of V1 in monkeys; 4) the generation of saccadic eye movements with electrical microstimulation of V1 in monkeys; and 5) the tasks involved for the development of a cortical visual prosthesis for the blind. In this review it is concluded that electrical microstimulation of area V1 in trained monkeys can be used to accelerate the development of an effective prosthetic device for the blind.