Neeraj J. Gandhi - US grants

Based on experiments in head-restrained animals, past studies have implicated a role for many cortical and subcortical regions in the control of saccadic eye movements. Neurons in the superior colliculus, for example, have since been investigated during head-free gaze shifts actually and were found to exhibit discharge properties that are correlated better with the coordinated eye-head movements than just the ocular component. Since the eyes and the head provide independent means of changing orientation, how does one gaze signal control movements of both? Is the gaze signal decomposed into eye and head components since different motor neurons innervate extraocular and neck muscles? If so, where and how does this decomposition occur? Is the accuracy of gaze shifts maintained by feedback mechanisms that monitor the coupled or independent contributions of the eyes and head? As higher structures have already been shown to code gaze, a bottom-up approach must be used to search for potential site(s) of decomposition of gaze. The aims of this proposal are, therefore, to study the contributions of brainstem burst, tonic, pause and motoneurons to gaze shifts. Specifically, the neural activity of these cells will initially be recorded during gaze shifts (head-free condition) and saccades (head-restrained condition) of equal amplitude, while systematically varying initial eye position. Then, the activity in these neurons will be altered by microstimulation and chemical microinjections. This latter experiment serves to perturb the oculomotor system and measure the accuracy maintained by its feedback mechanisms. A functional understanding of how a desired gaze signal results in a coordinated eye-head movement will consequently provide insights into potential circuitry malfunctions in patients with neurological disorders of the oculomotor system.

DESCRIPTION (provided by applicant): The long-term objective of the research program is to understand the neural integration of multiple motor systems. The oculomotor system has long served as a model for the study of neural control of movement. In the natural environment, however, an orienting response consists of multiple oculomotor and skeletomotor actions combined to form a complex yet coordinated movement. An integrated action ideal for scientific investigation is a coordinated eye-head movement because it builds on our advanced knowledge of the oculomotor system. The research also offers diagnostic value for spatial orientation deficits resulting from oculomotor, vestibular and cervical disorders. Recent experiments suggest that familiar oculomotor structures, such as the superior colliculus (SC) and pontomedullary reticular formation (PMRF), output a motor command to displace the line of sight (gaze shift) by a desired amplitude and direction. The gaze shift can be executed as a coordinated eye-head movement, implying that the outputs of these oculomotor structures also control premotor circuits that innervate the neck muscles. An association between neural discharge and extraocular motor neurons is demonstrated by recording activity during head-restrained saccades. In contrast, a relationship between spikes and neck motor neurons is only inferred by observing activity during coordinated eye-head movements. A direct evaluation of the activity with head movements has not been performed yet because, under ordinary circumstances, the eye and head components of the coordinated movement are temporally correlated. Hence, four specific aims are proposed to characterize activity and identify neurons associated with head movement control. Using behavioral tasks developed to temporally uncouple head movements from saccadic eye movements, SC neurons will be recorded for head movement related activity, both when no gaze shift is required (Specific Aim 1) and when a gaze shift is planned or being executed (Specific Aim 2). Similar manipulations will be employed to investigate the distribution of PMRF neurons that encode eye-only, head-only and coordinated eye-head movements (Specific Aim 3). Finally, anatomical techniques will be used to determine whether SC neurons send divergent axon collaterals or segregated projections to the eye and head control regions of PMRF (Specific Aim 4).

[unreadable] DESCRIPTION (provided by applicant): Humans and nonhumans alike interact with the environment by orienting to objects of interest. Such responses are typically generated by integrating movements across multiple effectors. The long- term objective of the research program is to understand the coordinated eye-head movements that produce a change in the line of sight (gaze). The specific aims are designed to delineate feedforward, feedback and interactive mechanisms that result in the coordinated control of two different groups of muscles. A gaze shift is thought to be triggered by a command encoding the desired change in gaze, and structures in the brain stem determine the eye and head components required to generate the gaze shift. Specific Aim 1 seeks to identify where in the pontine reticular formation are the separate commands of eye and head movement control formulated. Head-restrained saccadic eye movements are controlled by an error-sensing feedback circuit that preserves its accuracy. Specific Aim 2 will investigate how the feedback principle extrapolates to head-unrestrained gaze shifts. Does it preserve accuracy of the gaze signal or just its saccadic eye component? Specific Aim 3 will test whether head movement commands can influence the dynamics of the eye component of gaze shift. Specific Aim 4 will revisit the gain of the vestibulo-ocular reflex during gaze shifts by evaluating the saccadic input into the extraocular motoneurons during gaze shifts. Overall, the results of these experiments will provide insights into the neural control of gaze shifts and offer diagnostic value for deficits resulting from oculomotor, vestibular and cervical disorders. PUBLIC HEALTH RELEVANCE We interact with our environment by orienting to objects of interest. A coordinated eye-head movement is a basic orienting response that shifts the line of sight, but many questions remain about the mechanisms that cooperatively control the two groups of muscles. Delineating the neural circuits that produce such integrated movements will provide diagnostic value for understanding spatial orientation deficits (vertigo) and motor control disorders (torticollis, Parkinsonism, strabismus). [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The oculomotor and vestibular systems are two of the oldest and most thoroughly studied topics in systems neuroscience. The wealth and breadth of knowledge these systems offer produces progress at a rapid pace and in divergent directions, yielding a multidisciplinary view of oculomotor and vestibular functions in health and disease. It is increasingly apparent that a forum to forge interdisciplinary links among oculomotor and vestibular researchers would be of great benefit. This proposal requests support for a conference, whose objective is to bring together scientists and physicians of these mature fields to take a fresh look at how the diverse components of the oculomotor and vestibular systems interact and to stimulate increased interdisciplinary research. The proposed conference, entitled "Advances in Oculomotor and Vestibular Systems," is a satellite to the Annual Meeting of the Society for the Neural Control of Movement and will be held April 18-20, 2010, at the Naples Beach Hotel in Naples, Florida. The specific program will emphasize four emerging topics in oculomotor and/or vestibular systems. First, we will re-evaluate the actions of the superior colliculus. We will examine whether sensory signals are color-dependent (traditionally, they are assumed not to be) and visit the controversy of whether its motor command encodes the desired goal or the actual movement vector. Second, we will consider the role of the cortical and subcortical structures in visual cognition. Research that uses visual, oculomotor, and vestibular cues to gain insights into attention, target selection, and spatial orientation will be represented. Third, the framework of internal models has become another emerging topic. The oculomotor system is an ideal model system for the study of internal models because of the accurate response of eye movements and because of the insights that can be gained from perturbing them. The vestibular system has also shared the limelight with its use to study efference copy concepts. The cerebellum has been proposed as the locus of internal models, and studies that address this hypothesis will be emphasized. Finally, we will highlight the recent collaborative efforts of clinicians and computational scientists to simulate the pathophysiology of several ocular motility disorders. One uniqueness of the present approach has been to attribute the dysfunction to specific cell membrane properties, in contrast to the traditional view of a generic lesion to an oculomotor structure. In addition to the thematic sessions, scholarship recipients and other attendees will also have the opportunity to present posters of their research. Collectively, our objective is to create a scientifically vibrant atmosphere that brings together ideas and investigators that are often not at the same venue. PUBLIC HEALTH RELEVANCE: Disorders of oculomotor and vestibular systems include strabismus, nystagmus, vertigo, and postural imbalance. Contributions of these systems are reflected in motor control diseases (Parkinson's, torticollis), sensation syndromes (vertigo), and cognitive deficits (spatial neglect). Other disorders such as congenital fibrosis can also alter mechanistic properties of the extraocular muscle itself. Hence, the oculomotor and vestibular systems are of immense relevance to health.

DESCRIPTION (provided by applicant): The oculomotor repertoire is governed by alternating activity patterns in competing networks that generate saccades and preserve fixation. When the operation between the two networks is properly maintained, eye movement function is normal. A bias in the balance of activity, however, can lead to dysfunction. For example, decreasing the efficacy of the fixation network or enhancing the activity of the saccade generation network compromises the ability to delay or inhibit movements. This proposal seeks to examine the activity of neural elements in these networks and the consequence on behavior during a perturbation that alters the balance between the two. The focus is specifically on the superior colliculus, whose rostral pole is involved in preserving fixation and caudal region is essential fo generating saccades. The perturbation of choice is to induce a blink by delivering an air-puff to an eye as subjects perform various oculomotor tasks. Blinks have been shown to compromise the integrity of the saccadic inhibition network at the level of the pons, and if the blink is triggered after presentation of the saccade target (and permission to initiate the movement), the goal-directed movement accompanies the blink at a reduced latency. Specific Aim 1 examines the effects of a blink on the fixation and saccade generation networks in the superior colliculus. It specifically tests the hypothesis that blinks suppress activity in the fixation network (rostral region) and increases the excitability of the saccade generation network (caudal region). Specific Aim 2 examines whether the underlying neural activity at the time of prematurely triggered saccades encodes premotor information. It will specifically test the threshold principle of the motor preparation hypothesis and whether spatial attention and motor preparation can be dissociated. We anticipate that the combination of behavioral and neurophysiological approaches will provide insights into neural mechanisms that are altered in neuropsychiatric disorders (e.g., ADHD, schizophrenia) characterized by an inability to suppress reflexive movements.

DESCRIPTION (provided by applicant): Sensorimotor transformation is fundamental for survival. Neurons in many visuomotor structures in the oculomotor axis discharge an initial visual burst of activity to register the visual stimulus and later a motor burst to trigger a movement that redirects the visual axis to the object of interest. Given that such neurons project to the saccade generating circuitry in the brainstem, a long standing enigma of sensorimotor transformation is why the visual response is insufficient to trigger a movement while the second motor burst is. One leading theory states that the saccade is triggered when activity reaches a threshold. This view is unsatisfactory because the threshold level could be crossed by the visual burst also but without triggering a saccade. Another theory contends that movement onset occurs when variability in neural activity is reduced. Support for this hypothesis is based on variability measured across trials. This is not a feasible mechanism for neurons decoding their input spikes to decide when to trigger a saccade. Ideally, the decoding must be based on the structure of neural activity within a trial. We propose an innovative perspective - our central hypothesis - that saccade initiation occurs when an increase in firing rate is coupled with temporal stability in the population activity throughout the oculomotor neuraxis. More specifically, we suggest that the visual burst in all visuomotor elements is unstable and therefore cannot trigger a saccade, while the premotor burst is stable and initiates the movement when the firing rate crosses a threshold. Temporal stability is defined by a metric that tracks similarty or consistency as a function of time within a normalized neural trajectory defined by a population of neurons recorded either simultaneously or serially. Preliminary data from superior colliculus and frontal eye field neurons recorded sequentially during the delayed saccade task indicate that firing rate is unstable during the transient visual response but remains stable during the premotor burst that precedes saccade onset. We propose to address the following emerging questions using a combination of electrophysiological and computational approaches: What are the dynamics of temporal stability profile when visual and motor bursts overlap or merge, such as during reactive and express saccades, respectively? Does temporal stability exhibit similar properties when analyzed over many neurons recorded simultaneously? Do insights on neural variability obtained from across trials (e.g., Fano factor, optimal subspace) and within trials (temporal stability) analyses complement each other? How would temporal stability be implemented in a generic downstream neuron? How can this decoder algorithm be incorporated in a circuit-level model of saccade control?

PROJECT SUMMARY A high-velocity eye movement or saccade is typically the first motor action we make to orient to an object of interest. While the neural mechanisms of saccade generation to stationary targets have been thoroughly investigated, very little is known about the neural control of interceptive saccades that acquire moving targets. Current dogma based on studies of saccades to stationary targets states that the visual and motor bursts in the superior colliculus (SC), a major hub in the oculomotor neuraxis, are represented as Gaussians; that the population activity is centered at the site encoding the target location and, equivalently, desired saccade vector; that its width remains invariant across different target locations and saccade vectors; and that these spatial features emerge from a balance of excitation and inhibition mediated through intrinsic, intra-laminar connectivity. Fundamentally non-overlapping mechanisms must be involved when the target is moving, because accurate interception can only occur if target velocity information is incorporated in the saccade command. We reason that as a moving target?s image streaks across the retina, activity sweeps across the SC too. We hypothesize that the population activity, which starts as a Gaussian to represent the initial visual response, becomes skewed as it sweeps across the SC; that the extent to which SC population activity is modified depends on the intra-laminar connectivity weights, the logarithmic map of visual space in SC, and target speed; that the altered spatial distribution persists during the peri-movement burst; and that an appropriate computational algorithm must be able to decode the saccade goal from the skewed population response. We propose to test these hypotheses using a combination of experimental and computational approaches. Specific Aim 1 will employ an innovative method for simultaneously recording neural activity of many SC neurons within a functional layer in nonhuman primates performing oculomotor tasks and compare the spatiotemporal properties of population activity during saccades to stationary and moving targets (different speeds and directions). Specific Aim 2 will construct a computational model that simulates population activity in SC and associated saccades to stationary and moving targets. We will employ a distributed architecture for the superficial and deeper layers of the SC and a lumped block-diagram circuit for the brainstem burst generator elements, like that done by Arai and colleagues (Neural Networks, 7:1115-1135, 1994). Collectively, these projects will provide an in-depth insight into the mechanisms for generation of interceptive saccades and enable a comparison with mechanisms of saccades to stationary targets.

PROJECT SUMMARY Sensorimotor transformations are mediated by premotor brain networks where individual neurons represent sensory, cognitive, and movement-related information. In the superior colliculus (SC), a central hub for producing visually-guided saccadic eye movements, many neurons are active during all three stages, emitting transient, high-frequency bursts of spikes during the sensory and motor events and exhibiting persistent, lower firing rate activity in-between the bursts. The mixed-selectivity to multiple dimensions of information exemplifies a potentially efficient mode of information representation by the nervous system, but it also raises crucial questions: What features differentiate the two bursts, and how does a decoder know precisely when to initiate a movement if its inputs are active at times when a movement is not desired (e.g., in response to sensory stimulation)? What information is encoded in the low-frequency activity, and how is it modulated during different cognitive demands? We reason that the answers to these questions lie not in the activity of individual neurons but rather across the population of active neurons and in the temporal dynamics. Specific Aim 1 tests various neural mechanisms of movement initiation by quantifying features that differentiate the sensory and motor bursts across the SC population. Specific Aim 2 focuses on the low-frequency activity that intervenes between the two bursts. We will use a dynamical systems approach to characterize how the neural trajectory evolves during sensorimotor transformation and how it differs for tasks with different cognitive loads. The ability to discriminate neural trajectories according to task demands indicates a potential mechanism by which different dimensions of information can be multiplexed into the same population of neurons.

PROJECT SUMMARY Sensorimotor transformations are mediated by premotor brain networks where individual neurons represent sensory, cognitive, and movement-related information. In the superior colliculus (SC), a central hub for producing visually-guided saccadic eye movements, many neurons emit a burst of action potentials both in response to a visual stimulus and when generating an eye movement command. These so-called visuomotor neurons project to the brainstem burst generator that produces the saccade. Thus, this downstream element is challenged to differentiate between the incoming ?visual? and ?motor? bursts. Multiple mechanisms have been proposed to account for movement generation. The ?fixed threshold? hypothesis posits that a saccade is produced once the firing rate of either an individual neuron or across a population crosses a threshold, which only happens during the motor burst. Existing data, however, indicate that a simple thresholding mechanism is likely not sufficient and requires consideration of other frameworks. The ?optimal subspace? hypothesis uses a dynamical systems approach to propose that a movement is generated when the population activity enters or resides within a particular region of state space. This implies that the state space representations of SC visual and motor bursts are dissociable. The ?temporal stability? hypothesis states that a movement is generated when bursting activity across a population of neurons preserves consistent temporal structure for a period of time. Indeed, the stability of SC population activity is reduced during a visual response (?unstable? temporal structure) and increased during an eye movement (?stable? temporal structure). We seek a framework that reconciles these models. Our central hypothesis is that SC population activity is decoded as a movement command when it both exhibits high temporal structure and resides within an optimal subspace. Our specific aim is to employ a closed-loop brain-computer interface in which monkeys are trained to control an auditory cursor by volitionally modulating the activity pattern across multiple SC neurons to lie within a visual or motor subspace and to be temporally stable or unstable. We will first test the optimal subspace and temporal stability frameworks individually before pitting the two against each other in a 2x2 design. Examining the trials in which an eye movement is observed will reveal the patterns used by population activity to represent a movement command. We predict that the animals will be able to modulate population activity along both visual-motor subspace and stable-unstable dimensions, but that the likelihood of movement generation will be the highest when the population activity is both stable and in the optimal subspace.