Contributions of parietal cortex to reach planning

Sensory-motor circuits course through the parietal cortex of the human and monkey brain. How parietal cortex manipulates these signals has been an important question in behavioral neuroscience. This thesis presents experiments that explore the contributions of monkey parietal cortex to sensory-motor processing, with an emphasis on the area's contributions to reaching. First, it is shown that parietal cortex is organized into subregions devoted to specific movements. Area LIP encodes plans to make saccadic eye movements. A nearby area, the parietal reach region (PRR), plans reaches. A series of experiments are then described which explore the contributions of PRR to reach planning. Reach plans are represented in an eye-centered reference frame in PRR. This representation is shown to be stable across eye movements. When a sequence of reaches is planned, only the impending movement is represented in PRR, showing that the area is more related to movement planning than to storing the memory of reach targets. PRR resembles area LIP in each of these properties: the two areas may provide a substrate for hand-eye coordination. These findings yield new perspectives on the functions of the parietal cortex and on the organization of sensory-motor processing in primate brains.

Analog VLSI-based, neuromorphic sensorimotor systems: modeling the primate oculomotor system

Using neuromorphic analog VLSI techniques for modeling large neural systems has several advantages over software techniques. By designing massively-parallel analog circuit arrays which are ubiquitous in neural systems, analog VLSI models are extremely fast, particularly when local interactions are important in the computation. While analog VLSI circuits are not as flexible as software methods, the constraints posed by this approach are often very similar to the constraints faced by biological systems. As a result, these constraints can offer many insights into the solutions found by evolution. This dissertation describes a hardware modeling effort to mimic the primate oculomotor system which requires both fast sensory processing and fast motor control. A one-dimensional hardware model of the primate eye has been built which simulates the physical dynamics of the biological system. It is driven by analog VLSI circuits mimicking brainstem and cortical circuits that control eye movements. In this framework, a visually-triggered saccadic system is demonstrated which generates averaging saccades. In addition, an auditory localization system, based on the neural circuits of the barn owl, is used to trigger saccades to acoustic targets in parallel with visual targets. Two different types of learning are also demonstrated on the saccadic system using floating-gate technology allowing the non-volatile storage of analog parameters directly on the chip. Finally, a model of visual attention is used to select and track moving targets against textured backgrounds, driving both saccadic and smooth pursuit eye movements to maintain the image of the target in the center of the field of view. This system represents one of the few efforts in this field to integrate both neuromorphic sensory processing and motor control in a closed-loop fashion.

Responses to auditory stimuli in macaque lateral intraparietal area

The lateral intraparietal area (LIP) of macaque posterior parietal cortex participates in the sensorimotor transformations underlying visually guided eye movements. Area LIP has long been considered unresponsive to auditory stimulation. However, recent studies have shown that neurons in LIP respond to auditory stimuli during an auditory-saccade task, suggesting possible involvement of this area in auditory-to-oculomotor as well as visual-to-oculomotor processing. This dissertation describes investigations which clarify the role of area LIP in auditory-to-oculomotor processing.

Extracellular recordings were obtained from a total of 332 LIP neurons in two macaque monkeys, while the animals performed fixation and saccade tasks involving auditory and visual stimuli. No auditory activity was observed in area LIP before animals were trained to make saccades to auditory stimuli, but responses to auditory stimuli did emerge after auditory-saccade training. Auditory responses in area LIP after auditory-saccade training were significantly stronger in the context of an auditory-saccade task than in the context of a fixation task. Compared to visual responses, auditory responses were also significantly more predictive of movement-related activity in the saccade task. Moreover, while visual responses often had a fast transient component, responses to auditory stimuli in area LIP tended to be gradual in onset and relatively prolonged in duration.

Overall, the analyses demonstrate that responses to auditory stimuli in area LIP are dependent on auditory-saccade training, modulated by behavioral context, and characterized by slow-onset, sustained response profiles. These findings suggest that responses to auditory stimuli are best interpreted as supramodal (cognitive or motor) responses, rather than as modality-specific sensory responses. Auditory responses in area LIP seem to reflect the significance of auditory stimuli as potential targets for eye movements, and may differ from most visual responses in the extent to which they arc abstracted from the sensory parameters of the stimulus.

Macaque lateral intraparietal area and oculomotor behaviors

Neurons in the primate lateral intraparietal area (area LIP) carry visual, saccade-related and eye position activities. The visual and saccade activities are anchored in a retinotopic framework and the overall response magnitude is modulated by eye position. It was proposed that the modulation by eye position might be the basis of a distributed coding of target locations in a head-centered space. Other recording studies demonstrated that area LIP is involved in oculomotor planning. These results overall suggest that area LIP transforms sensory information for motor functions. In this thesis I further explore the role of area LIP in processing saccadic eye movements by observing the effects of reversible inactivation of this area. Macaque monkeys were trained to do visually guided and memory saccades and a double saccade task to examine the use of eye position signal. Finally, by intermixing visual saccades with trials in which two targets were presented at opposite sides of the fixation point, I examined the behavior of visual extinction.

In chapter 2, I will show that lesion of area LIP results in increased latency of contralesional visual and memory saccades. Contralesional memory saccades are also hypometric and slower in velocity. Moreover, the impairment of memory saccades does not vary with the duration of the delay period. This suggests that the oculomotor deficits observed after inactivation of area LIP is not due to the disruption of spatial memory.

In chapter 3, I will show that lesion of area LIP does not severely affect the processing of spontaneous eye movement. However, the monkeys made fewer contralesional saccades and tended to confine their gaze to the ipsilesional field after inactivation of area LIP. On the other hand, lesion of area LIP results in extinction of the contralesional stimulus. When the initial fixation position was varied so that the retinal and spatial locations of the targets could be dissociated, it was found that the extinction behavior could best be described in a head-centered coordinate.

In chapter 4, I will show that inactivation of area LIP disrupts the use of eye position signal to compute the second movement correctly in the double saccade task. If the first saccade steps into the contralesional field, the error rate and latency of the second saccade are both increased. Furthermore, the direction of the first eye movement largely does not have any effect on the impairment of the second saccade. I will argue that this study provides important evidence that the extraretinal signal used for saccadic localization is eye position rather than a displacement vector.

In chapter 5, I will demonstrate that in parietal monkeys the eye drifts toward the lesion side at the end of the memory saccade in darkness. This result suggests that the eye position activity in the posterior parietal cortex is active in nature and subserves gaze holding.

Overall, these results further support the view that area LIP neurons encode spatial locations in a craniotopic framework and is involved in processing voluntary eye movements.

Value Estimation and Comparison in Multi-Attribute Choice

The following work explores the processes individuals utilize when making multi-attribute choices. With the exception of extremely simple or familiar choices, most decisions we face can be classified as multi-attribute choices. In order to evaluate and make choices in such an environment, we must be able to estimate and weight the particular attributes of an option. Hence, better understanding the mechanisms involved in this process is an important step for economists and psychologists. For example, when choosing between two meals that differ in taste and nutrition, what are the mechanisms that allow us to estimate and then weight attributes when constructing value? Furthermore, how can these mechanisms be influenced by variables such as attention or common physiological states, like hunger?

In order to investigate these and similar questions, we use a combination of choice and attentional data, where the attentional data was collected by recording eye movements as individuals made decisions. Chapter 1 designs and tests a neuroeconomic model of multi-attribute choice that makes predictions about choices, response time, and how these variables are correlated with attention. Chapter 2 applies the ideas in this model to intertemporal decision-making, and finds that attention causally affects discount rates. Chapter 3 explores how hunger, a common physiological state, alters the mechanisms we utilize as we make simple decisions about foods.

Neural Prosthetics and Parietal Cortex

In the last decade, research efforts into directly interfacing with the neurons of individuals with motor deficits have increased. The goal of such research is clear: Enable individuals affected by paralysis or amputation to regain control of their environments by manipulating external devices with thought alone. Though the motor cortices are the usual brain areas upon which neural prosthetics depend, research into the parietal lobe and its subregions, primarily in non-human primates, has uncovered alternative areas that could also benefit neural interfaces. Similar to the motor cortical areas, parietal regions can supply information about the trajectories of movements. In addition, the parietal lobe also contains cognitive signals like movement goals and intentions. But, these areas are also known to be tuned to saccadic eye movements, which could interfere with the function of a prosthetic designed to capture motor intentions only. In this thesis, we develop and examine the functionality of a neural prosthetic with a non-human primate model using the superior parietal lobe to examine the effectiveness of such an interface and the effects of unconstrained eye movements in a task that more closely simulates clinical applications. Additionally, we examine methods for improving usability of such interfaces.

The parietal cortex is also believed to contain neural signals relating to monitoring of the state of the limbs through visual and somatosensory feedback. In one of the world’s first clinical neural prosthetics based on the human parietal lobe, we examine the extent to which feedback regarding the state of a movement effector alters parietal neural signals and what the implications are for motor neural prosthetics and how this informs our understanding of this area of the human brain.

Control mechanisms in the human binocular oculomotor system

A study of human eye movements was made in order to elucidate the nature of the control mechanism in the binocular oculomotor system.

We first examined spontaneous eye movements during monocular and binocular fixation in order to determine the corrective roles of flicks and drifts. It was found that both types of motion correct fixational errors, although flicks are somewhat more active in this respect. Vergence error is a stimulus for correction by drifts but not by flicks, while binocular vertical discrepancy of the visual axes does not trigger corrective movements.

Second, we investigated the non-linearities of the oculomotor system by examining the eye movement responses to point targets moving in two dimensions in a subjectively unpredictable manner. Such motions consisted of hand-limited Gaussian random motion and also of the sum of several non-integrally related sinusoids. We found that there is no direct relationship between the phase and the gain of the oculomotor system. Delay of eye movements relative to target motion is determined by the necessity of generating a minimum afferent (input) signal at the retina in order to trigger corrective eye movements. The amplitude of the response is a function of the biological constraints of the efferent (output) portion of the system: for target motions of narrow bandwidth, the system responds preferentially to the highest frequency; for large bandwidth motions, the system distributes the available energy equally over all frequencies. Third, the power spectra of spontaneous eye movements were compared with the spectra of tracking eye movements for Gaussian random target motions of varying bandwidths. It was found that there is essentially no difference among the various curves. The oculomotor system tracks a target, not by increasing the mean rate of impulses along the motoneurons of the extra-ocular muscles, but rather by coordinating those spontaneous impulses which propagate along the motoneurons during stationary fixation. Thus, the system operates at full output at all times.

Fourth, we examined the relative magnitude and phase of motions of the left and the right visual axes during monocular and binocular viewing. We found that the two visual axes move vertically in perfect synchronization at all frequencies for any viewing condition. This is not true for horizontal motions: the amount of vergence noise is highest for stationary fixation and diminishes for tracking tasks as the bandwidth of the target motion increases. Furthermore, movements of the occluded eye are larger than those of the seeing eye in monocular viewing. This effect is more pronounced for horizontal motions, for stationary fixation, and for lower frequencies.

Finally, we have related our findings to previously known facts about the pertinent nerve pathways in order to postulate a model for the neurological binocular control of the visual axes.

Study of ion movements in isolated chicken retinas during spreading depression

Spreading depression (SD) is a phenomenon observed in several sections of vertebrate central nervous system. It can occur spontaneously or be evoked by a variety of stimuli, and consists of a wave of depression of the normal electrical activity of the nervous tissue which spreads slowly in all directions in the tissue. This wave of depression is accompanied by several concomitants including ion movements. All the concomitants of SD can be explained by an increase in the sodium permeability of the plasma membranes of cellular elements involved in this phenomenon.

In the chicken retina, SD is accompanied by a transparency change which can be detected with the naked eye. The isolated retina is a thin (0.1 mm) membrane in which the extracellular fluid quickly and completely equilibrates with the incubation solutions. This preparation was therefore used to study the ion movements during SD by measuring and comparing the ion contents and the extracellular space (ECS) of retinas incubated in various solutions of which some inhibited SD, whereas others allowed this phenomenon to occur.

The present study has shown that during SD there is a shift of extracellular sodium into the intracellular compartment of the retina, a release of intracellular K and a decrease in the magnitude of ECS. These results are in agreement with previous postulates about SD, although the in vitro experimental condition makes the ion movements appear larger and the loss of ECS smaller than observed in the intact cortical tissue. The movements of Na and K, in opposite directions, are reversible. The development and magnitudes of SD is very little affected by deprivation of the oxygen supply.

It was established that the inward sodium shift is not a consequence of an arrest of the Na-pump. It can be prevented, together with SD by the membrane stabilizers, magnesium and procaine. Spreading depression and the ion movements are incompletely inhibited by tetrodotoxin, which blocks the sodium influx into nerve fibers during the action potential. The replacement of Na in the bathing solution by Li does not prevent SD, which is accompanied by Li accumulation in the intracellular compartment. From these experiments and others it was concluded that the mechanism underlying SD and the ion shifts is an increase in the sodium permeability of cell membranes.

Molecular neurogenetics of eye development in Drosophila

The compound eye of Drosophila melanogaster begins to differentiate during the late third larval instar in the eye-antennal imaginal disc. A wave of morphogenesis crosses the disc from posterior to anterior, leaving behind precisely patterned clusters of photoreceptor cells and accessory cells that will constitute the adult ommatidia of the retina. By the analysis of genetically mosaic eyes, it appears that any cell in the eye disc can adopt the characteristics of any one of the different cell types found in the mature eye, including photoreceptor cells and non-neuronal accessory cells such as cone cells. Therefore, cells within the prospective retinal epithelium assume different fates presumably via information present in the environment. The sevenless^+ (sev^+) gene appears to play a role in the expression of one of the possible fates, since the mutant phenotype is the lack of one of the pattern elements, namely, photoreceptor cell R7. The sev^+ gene product had been shown to be required during development of the eye, and had also been shown in genetic mosaics to be autonomous to presumptive R7. As a means of better understanding the pathway instructing the differentiation R7, the gene and its protein product were characterized.

The sev+ gene was cloned by P-element transposon tagging, and was found to encode an 8.2 kb transcript expressed in developing eye discs and adult heads. By raising monoclonal antibodies (MAbs) against a sev^+- β-galactosidase fusion protein, the expression of the protein in the eye disc was localized by immuno-electronmicroscopy. The protein localizes to the apical cell membranes and microvilli of cells in the eye disc epithelium. It appears during development at a time coincident with the initial formation of clusters, and in all the developing photoreceptors and accessory cone cells at a time prior to the overt differentiation of R7. This result is consistent with the pluripotency of cells in the eye disc. Its localization in the membranes suggests that it may receive information directing the development of R7. Its localization in the apical membranes and microvilli is away from the bulk of the cell contacts, which have been cited as a likely regions for information presentation and processing. Biochemical characterization of the sev^+ protein will be necessary to describe further its role in development.

Other mutations in Drosophila have eye phenotypes. These were analyzed to find which ones affected the initial patterning of cells in the eye disc, in order to identify other genes, like sev, whose gene products may be involved in generating the pattern. The adult eye phenotypes ranged from severe reduction of the eye, to variable numbers of photoreceptor cells per ommatidium, to sub de defects in the organization of the supporting cells. Developing eye discs from the different strains were screened using a panel of MAbs, which highlight various developmental stages. Two identified matrix elements in and anterior to the furrow, while others identified the developing ommatidia themselves, like the anti-sev MAb. Mutation phenotypes were shown to appear at many stages of development. Some mutations seem to affect the precursor cells, others, the setting up of the pattern, and still others, the maintenance of the pattern. Thus, additional genes have now been identified that may function to support the development of a complex pattern.