Joel M. Miller - US grants

Aims and Methods. (1) Refine and test a binocular computer model of the static mechanics of the globe, muscles, fascia, and innervation, and investigate its usefullness as an aid in the diagnosis and treatment of strabismus. (a) Measure orbital anatomy and muscle paths in different positions of gaze with high-resolution CT scans. Develop CT scan method as an aid in diagnosis of certain strabismic disorders. (b) Measure translational stiffness of intact globe and (c) length-tension of abnormal (e.g., contractured) muscles using instrumented forceps. (d) Re-measure latter after contracture is resolved by botulinum injection treatment. (e) Measure deviations (Hess charts) before and after (i) intramuscular lidocaine injection (ii) intramuscular botulinum injection (iii) muscle surgery. Model parameters are specified in measurements a-d above; model is tested with measurements e. (2) Develop and test a similar monkey model. Using monkeys with binocular eye coils who have been trained to hold fixation, make measurements similar to la-ld above. Also, (e) evaluate and model experimental surgeries (e.g., on ligament of Lockwood), (f) directly measure muscle forces with implanted strain gauges to verify model calculations, and (g) verify anatomic CT scans with orbital dissection and measurement. (3) Develop a method, using implanted strain gauges in monkeys, to study effects of muscle proprioception that may be relevant to strabismus. Significance. This work shouuld advance our understanding and treatment of strabismus by helping us to: (1) understand and think clearly about orbital mechanics; (2) better diagnose specific cases; (3) customize treatment to each patient; (4) develop new surgeries and other treatments; (5) better understand the involvement of altered innervation in strabismus.

biomedical equipment resource; biomedical equipment purchase;

Significance Experiments with rapid hand pointing demonstrate an extraretinal eye position signal (ERS) that is more accurate than intravisual comparison experiments and studies of visual stability once seemed to allow. Gaze pointing studies have drawn similar conclusions, but these experiments are seriously flawed and replication is long overdue. The motor system dependence and detailed time course of the ERS have not been studied in a well-controlled egocentric localization paradigm. The adaptability of saccadic eye movements raises the question of whether eye position can be decoupled from the ERS; the answer would have important implications for the locus of adaptive change and the source of the ERS. Finally, it has been suggested that slow or delayed motor movements might be programmed on a different basis, and therefore reflect errors not seen with rapid movements. Objectives and Methods Our objective is to address these questions with a within-subjects, factorial study. For each of several localization measures and states of saccadic gain adaptation, we will accurately determine the time course of localizations of dim and bright flashes presented in the dark, before, during, and after horizontal saccades. Normal human subjects will perform four different localization tasks: immediate or delayed pointing either with the eye or with unseen hand. Saccades will be: normal, gain-adapted early in training, and gain-adapted late in training. Saccades will be adapted with manipulated visual feedback, and eye position monitored by diffuse limbus-reflection. The proposed studies should help clarify the functional connectivity of the perceptual-motor system, particularly as it determines visually-based motor performance.

biomedical equipment purchase;

vision; computer center; biomedical facility;

DESCRIPTION (Adapted from Applicant's abstract): Significance: Strabismus, misalignments of the visual axes, is prevalent in the US and usually treated surgically. Misdiagnoses and sub-optimal outcomes are predictable consequences of inadequate understanding of extraocular anatomy and oculomotor control. Our overall aim is to develop a quantitative, physiologically realistic understanding of extraocular biomechanics, applied to diagnosis and treatment of strabismus. We previously showed that distributed midorbital connective and smooth muscle tissues function as rectus extraocular muscle (EOM) pulley, crucial to normal ocular kinematics. Recent studies suggest that the global lamina of each EOM rotates the eye, whereas the orbital lamina translates the pulley that determines the global lamina's functional origin. More complete characterization of extraocular tissue architecture should reveal other mechanically significant structures, also not easily discriminable because distributed. These findings, and out direct physiologic muscle force measurements have cast doubt on the classic and fundamental oculomotor concept of the Final Common Path. Validation and development of these ideas will continue to have broad impact on laboratory studies of ocular motility and on diagnosis and treatment of strabismus. Studies: We will: (01) test predictions of differential contraction of global and orbital EOM laminae and movements of connective tissue pulleys with conjugate and vergence eye movements, using implanted gold microspheres and digital X-ray imaging in alert monkeys; (2) characterize extraocular tissue architecture by reconstructing multiple interlaced immunohistochemically stained thin serial sections of cadaveric human and monkey orbits; (3) test the Active Pulley Hypothesis, a challenge to the classic notion of the Final Common Path, using physiologic muscle force measurement in alert monkeys, and (4) develop scientifically and clinically useful biomechanical modeling tools that reflect current physiologic findings and hypotheses.

DESCRIPTION (provided by applicant): Significance: Almost 40 years of oculomotor physiology have been based on the powerful simplifying notion that the oculomotor nuclei, their cranial nerves, and the extraocular muscles (EOMs) constitute a simple, homogeneous Final Common Path (FCP), in which supernuclear signals controlling the several types of eye movement combine anonymously. It was, therefore, surprising when studies of vergence eye movement using direct muscle force measurements and magnetic resonance imaging (MRI) failed to confirm predictions that would follow from earlier, well-replicated motoneuron (MN) studies, if the FCP hypothesis were correct. This hypothesis now appears untenable, and the oculomotor plant ripe for exploration of its long-neglected functional richness. Supernuclear disorders are mostly inaccessible to treatment, whereas functions localized to the oculomotor periphery may be readily subject to pharmacologic, surgical and genetic manipulations. An understanding of related motoneuron and muscle fiber specializations would make it possible to effect subtle changes, compared to the gross manipulations of muscle action currently available to treat strabismus and related disorders. Studies: Our first overall aim is to delineate failures of the FCP hypothesis: (1) We will strongly verify the "missing lateral rectus (LR) force paradox" by recording identified abducens MNs and simultaneously measuring LR forces in vergence, continuing (2) to distinguish changes in slopes and Y-intercepts of MN rate-position curves, and to study the variation of LR and medial rectus (MR) convergence forces across the horizontal gaze plane. (3) We will replicate in monkeys, an MRI study in humans that found no globe retraction in convergence, and will extend it using "gold bead fiducials" (GBFs) to visualize orbital contents. (4) Using our muscle force transducers (MFTs) we will determine if LR and MR forces are consistent with globe translation, muscle paths and connective tissue movements observed with GBFs. Our second overall aim is to characterize complex articulations of the oculomotor plant. (5) We will determine if decreases in LR path length offset the convergence-related increase in contractile force predicted by the MN studies. (6) We will microstimulate MNs and use GBFs to visualize globe, pulley and other tissue movements, (7) determine if MN recruitment order varies with vergence state, and (8) if muscle forces vary with fixation accuracy. (9) We will study EOM unit summation in-vivo using multi-electrode stimulation and MFTs.

Description (provided by applicant): Most existing treatments for strabismus rely on compensatory impairment of extraocular muscles (EOMs);we are developing an alternative to strengthen EOMs and alter their stiffnesses and lengths in controllable ways. Hypertrophy of fast muscle, such as EOM, is a consistent consequence of intramuscular injection of bupivacaine (BUP) in animals. BUP is a locally acting myotoxin that causes muscle fiber degeneration, satellite cell activation, and muscle fiber regeneration, continuing to hypertrophy. Inadvertent injection of BUP into human EOM during retrobulbar anesthesia causes a pattern of strabismus that modeling suggests is due to significantly increased contractility in the muscle's field of action and slightly increased stiffness affecting the opposite field. We also have preliminary results suggesting that muscles are regenerated at a length determined by eye posture during regeneration. This project aims to explore the types, amount, persistence, and mechanisms of changes in EOM after BUP injection by means of biomechanical and histological studies in rabbits, and by clinical, MR imaging, muscle force, and simulation studies in strabismus patients. We will inject BUP into normal and experimentally paralyzed rabbit eye muscles, with some eyes held in predetermined postures during regeneration. We will measure changes in muscle dimensions, elasticity, and contractile force. We will histologically assess muscle fiber counts, sizes and separations, and structural and ultrastructural changes, including scarring and fibrosis. We will vary injected volume and concentration to determine the dosage of BUP needed to safely produce beneficial effects. We have begun a pilot trial of BUP injection into EOMs of adult strabismus patients with very encouraging results in comitant horizontal cases. This will be extended to vertical and oblique muscles and to paretic disorders. We will use magnetic resonance imaging (MRI) before and at intervals after injection to verify injection sites and measure changes in muscle size. We will measure and compare binocular alignment, ocular motility, saccadic velocities, and muscle forces before and after injection, and note any side effects or complications. As data on dosage, injection technique, and safety become available and standardized, we will design a randomized trial comparing BUP injection and strabismus surgery for horizontal strabismus. Controlled muscle strengthening by BUP injection appears poised to provide a powerful and valuable new tool for strabismus management. Regenerating muscles at reduced lengths would mimic the effects of surgical resection. Regenerating muscles at increased lengths would produce effects unobtainable with surgery. Fully understanding the basic muscle changes in animal experiments and accurately documenting muscle size changes and function in patients with various disorders are both essential to this end. BUP injection also holds promise for treatment of eyelid ptosis and for muscle disorders beyond ophthalmology. PUBLIC HEALTH RELEVANCE: Injection of the local anesthetic bupivacaine can increase the size and strength, and alter the lengths of muscles. We will develop this finding as an alternative to surgical treatment for strabismus, or crossed eyes. Extension of this approach holds great promise for treatment of many muscle disorders.