Eidactics ("eye-DAK-tics") is a California company (EIN 20-4569747) conducting pure and applied oculomotor research.

Staff

Joel M Miller, PhD

Director & Senior Scientist at Eidactics.
Director of Research at The Strabismus Research Foundation (SRF).
Senior Scientist at The Smith-Kettlewell Eye Research Institute (SKERI; 1982-2013).
https://sites.google.com/a/eidactics.com/eidactics/home/people/abs
Alan B Scott, MD

Senior Scientist at Eidactics.
Director and Senior Scientist at SRF.
Senior Scientist at SKERI (1959-2016).
TCM
Talita Cunha Namgalies MD

Clinical Scientist.
Ophthalmologist, Brazilian Air Force, IOBH & Guimaraes Hospital (2015-2017).


Collaborators

Taliva D Martin, MD
Taliva D Martin, MD

Pediatric ophthalmologist at California Pacific Medical Center.
Iara @ PBL
Iara Debert, MD, PhD

Former Research Fellow at Eidactics (2014-2015).
Former Clinical Fellow at SRF (2014-2015).
Attending Ophthalmologist at Hospital das Clinicas, Univ of São Paulo (2012-present).

Critiques

  • Clark RA, Demer JL (2018b). Magnetic Resonance Imaging of the Globe-Tendon Interface for Extraocular Muscles: Is there an “Arc of Contact”? American Journal of Ophthalmology, doi: 10.1016/j.ajo.2018.07.002. (PDF). The experimental manipulation is inappropriate, the MRI analysis, fallacious, and the effect sizes claimed, miniscule.
  • Clark RA, Demer JL (2018a). The Globe’s Eccentric Rotational Axis: Why Medial Rectus Surgery Is More Potent than Lateral Rectus Surgery. Ophthalmology ;125:1234-8 (PDF). Learn why Ophthalmology retracted this paper.

Classes & Presentations

  • Miller JM (2017). SRF Board of Directors Meeting, 2017.07.13. SRF (Keynote, Powerpoint, PDF).
  • Akhtar N (2017). Insulin-like Growth Factor-1 (IGF-1) and muscle hypertrophy. SRF (PDF).
  • Miller JM (2017)Explanatory & pragmatic research. Eidactics (PDF).
  • Miller JM (2017). Non-inferiority testing. Eidactics (PDF).
  • Miller JM (2016)The Orbit™ Gaze Mechanics Simulation. Eidactics (PDF).
  • Miller JM, Debert I (2016)History of Botulinum Toxin Therapy. SRF (PDF).
  • Miller JM, Scott AB, Debert I (2016)Bupivacaine Injection Treatment Of Strabismus. SRF (PDF).

Projects

Myotox
Pharmacologic Injection Treatment of Strabismus
MYOTOX Correction Timecourse & Dosages


Strabismus, misalignment of the eyes, is mostly treated surgically by compensatory impairment of healthy muscles, rather than by correcting the underlying disorder. Incisional surgery is costly, results in scarring that makes frequently-needed followup surgery difficult, and requires general anesthesia that may be problematic in some populations (smarttots.org). We have therefore long been interested in pharmacologic injection treatments to supplement or provide alternatives to surgery:
  • Debert I, Miller JM (2015)Injection Treatment of Strabismus. Eidactics (PDF).
Oculinum® (now called Botox®) was originally developed in our lab to relax and lengthen "tight" eye muscles (Scott 1980). It was the first successful pharmacologic injection treatment for strabismus, and the first therapeutic application of botulinum toxin. So dauntingly counterintuitive was the notion of injecting this most toxic substance, without visual guidance, alongside the healthy eye of an alert patient, that its safe and efficacious development, and the many and varied applications that followed, make a uniquely fascinating story of medical discovery:
  • Debert I, Miller JM (2015)History of Botulinum Toxin Therapy. Eidactics (PDFOn Wikipedia).
We’ve now turned our attention to the problem of strengthening and shortening "weak" muscles. Bupivacaine (BUP) is a selective myotoxin with effects similar to mechanical overloading – myofiber damage followed by hypertrophy – and we have been developing BUP injection as a practical method for correcting eye misalignmentsBupivacaine dissociates sarcomeres (the muscle's contractile elements), triggering satellite cells (a kind of stem cell) to rebuild the damaged fibers, stronger, stiffer, and at reduced length. Almost 200 volunteer strabismus patients have received BUP injection treatments, most also with botulinum toxin in the antagonist muscle to prevent stretching while the BUP-injected muscle rebuilt. Here are two recent reports:
  • Debert I, Miller JM, Danh KK, Scott AB (2016). Pharmacologic Injection Treatment of Comitant Strabismus. Journal of AAPOS, vol 20, pgs 106-111. (Authors' Cut PDFPublisher's site).
  • Cunha TM, Miller JM, Scott AB (2018) Injection of Bupivacaine & Botulinum Type A Toxin to Treat Strabismus. Transactions of ISA. (Manuscript PDF)
Results support and extend findings previously reported (Scott, Alexander et al. 2007Scott, Miller et al. 2009Miller, Scott et al. 2013). In our most recent series, initial misalignments of 24.6∆ (13.8°) were reduced at 31mo by 17.5∆ (9.9°), with successful outcomes (residual deviation ≤10∆) in 69% of patients. Injection treatment for horizontal strabismus achieves stable corrections lasting up to 10 yrs (each curve in the graph shows alignment data for a cohort of patients who all returned for the same followup measurements). Dosage guidelines are shown in the tableHaving demonstrated the clinical effectiveness of BUP treatment in comitant adult strabismus, we are now developing injection techniques suitable for children. BUP injection may also have clinical applications in other small muscles.
KTEF

Accurate Injection of Eye Muscles in Children (Knights Templar Eye Foundation • Taliva D Martin, MD & Alan B Scott, MD)

Bud Ramsey, Knights Templar Past Grand Commander makes presentation
Early treatment of infantile strabismus facilitates normal development of stereopsis (depth perception from binocular vision), prevents amblyopia (suppression of vision in one eye), and improves cosmesis. But surgical correction in young children is problematic: [1] additional surgery is often necessary, and is made more difficult by scarring from the initial surgery; it would be better if non-surgical treatment were used, at least initially, and [2] strabismus surgery requires prolonged general anesthesia, which may cause cognitive deficits in a developing brain (eg, Rappaport et al 2015).


Botulinum toxin A (BTXA) injection treatment of Extraocular muscles (EOMs) is an effective and widely-accepted alternative to conventional surgical treatment of esotropia. Because EOMs lie deep in the orbit, a technique is needed to accurately place the injection needle within the target muscle. In awake, cooperative adults, electromyography (EMG) signals are recorded from the tip of the injection needle, which is advanced until the relationship of the EMG signal to the patient’s voluntary eye movement indicates desired placement. But most strabismus patients are children, who must be briefly anesthetized to accept injection treatment, and anesthetized muscles show little or no movement-related electrical activity. Injection treatment in children is therefore currently performed without EMG guidance, and so, cannot target the deeper neuromuscular junctions, resulting in reduced treatment effect and increased unwanted effects on adjacent muscles. Although no useful EMG signal can be recorded, an anesthetized muscle can be readily stimulated. We have determined from animal studies (funded by The Pacific Vision Foundation) that brief trains of negative, 0.5-5.0 mA, 1 ms square-wave pulses at 150-200 Hz produce eye movements characteristic of optimal needle placement. We now propose to develop a suitable stimulating device, and evaluate its effectiveness on young strabismus patients in improving efficacy and reducing side effects of EOM injection treatment. Stimulation-guided injection is expected to be similarly useful in extending to children other pharmacologic injection treatments now under development.

We thank the Knights Templar Eye Foundation for supporting this clinically significant work in its early stages. In the photo, Bud Ramsey, Past Grand Commander, tours SRF's labs and presents the grant check to Drs Martin & Scott.
FES Electrode

Activating the Levator to Elevate the Eyelid

Blepharospasm sufferers may be functionally blind despite having normal eyes because of spasms in surrounding facial muscles and eyelid apraxia, inability to raise the eyelids or keep them raised. It is a disorder of central control, possibly related to abnormal function of the basal ganglia, but its cause is unknown. The disorder typically affects otherwise healthy adults age 40-60, progresses for a few months and then remains stable for decades. Muscles and nerves are normal, and most patients have periods of normal function – dark rooms, looking downward, even swimming under water are situations that patients report to be helpful.

Botulinum toxin injection can relieve the spasms, but eyelid apraxia often remains. Surgical lid elevation and botulinum toxin injection of the pretarsal orbicularis of the upper lid can be helpful, but static repositioning makes normal eye blinking and lid closure problematic. Functional electrical stimulation (FES) of the muscle that raises the eyelid (the levator palpebrae superioris or LPS), could provide these functionally blind patients with useful vision. Programmable, coordinated, binocular FES would be far superior to surgery, both functionally and cosmetically.
  • Scott AB, Miller JM, Namgalies TC (2018). Activating the levator to elevate the eyelid. In preparation (Authors' Cut PDF, Video).
STA-MFT

Motor Unit Diversity in Horizontal Eye Movement Control (NIH/NEI)

The oculomotor final common path hypothesis (FCP) supposed a fixed relationship between ensemble motoneuron (MN) firing rate and muscle force for all eye movements. Given FCP, however, the finding that abducens MN activity was higher in converged gaze implied co-contraction of lateral rectus (LR) and medial rectus (MR) muscles. Using chronically-implantable muscle force transducers (MFTs) we found, on the contrary, that LR and MR muscle forces were slightly lower in convergence (Miller et al 2002; the "missing force paradox"). Miller, Davison & Gamlin (2011) then simultaneously measured both muscle forces and unit activity, confirming that abducens neurons decreased activity less, and further, that MR MNs increased activity more, during convergent compared to conjugate adduction. Despite stronger innervation, they found both LR and MR muscle forces to be slightly lower in convergence. Evidently, the relationship of MN activity to muscle force is not as simple as has been thought, and in particular, is different in converged gaze than when convergence is relaxed.

STA-MFT
We believe that "paradoxical MNs" (LR MNs with kv < kc 
and MR MNs with kv > kc) innervate muscle fibers that are weak, have mechanical coupling that attenuates their oculorotary force, or serve some non-oculorotary function. It is already clear that some motor units don't directly rotate the eye (eg, Oh, 2001), and that nonlinear interactions among fibers (eg, Goldberg et al, 1997) may be the norm. We are therefore keen to characterize individual motor units and determine their participation in various types of eye movement.
 
Extraocular muscle (EOM) fibers are of several distinct types (egs, Spencer and Porter, 1988; McLoon etal 2011), and a given motoneuron (MN) innervates fibers of only one type, implying that there are different types of motor units (MUs; each a motor neuron and its muscle fibers). Nevertheless, classical studies of oculomotor physiology consider all MNs to be fundamentally the same, differing only quantitatively. Individual MUs have been studied only crudely, using electrical stimulation in anesthetized animals. To study MUs in alert behaving NHPs we recorded MN activity with extracellular electrodes, and extraocular muscle force with muscle force transducers (MFTs). During steady fixation with low motoneuron firing rates, we used spike-triggered averaging of MFT signals (STA-MFT) to extract single muscle twitches, thereby characterizing individual MUs. (It would then possible to measure participation of a characterized MU during eye movements involving high or rapidly-varying MN firing rates).
  • Gamlin PD, Miller JM (2012). Extraocular muscle motor units characterized by spike-triggered averaging in alert monkey. Journal of Neuroscience Methods, vol 204, pgs 159-167 (Authors' Cut PDFPublisher's site).
MFT
Missing Force Paradox

For a given eye position, firing rates of abducens neurons (ABNs) generally (Mays et al 1984), and lateral rectus (LR) motoneurons (MNs) in particular (Gamlin et al 1989a), are higher in converged gaze than when convergence is relaxed, whereas LR and medial rectus (MR) muscle forces are slightly lower (Miller et al 2002). Here, we confirm this finding for ABNs, report a similarly paradoxical finding for neurons in the MR subdivision of the oculomotor nucleus (MRNs), and, for the first time, simultaneously confirm the opposing sides of these paradoxes by recording physiological LR and MR forces.

Consistent with earlier findings, we found in 44 ABNs that the slope of the rate-position relationship for symmetric vergence (kv) was lower than that for conjugate movement (kc) at distance, ie, mean kv/kc = 0.50, which implies stronger LR innervation in convergence. We also found in 39 MRNs that mean kv/kc = 1.53, implying stronger MR innervation in convergence as well. Despite there being stronger innervation in convergence at a given eye position we found, confirming previous measurements, that both LR and MR muscle forces were slightly lower in convergence, -0.40 and -0.20 g, respectively.

This implies that the relationship of ensemble MN activity to total oculorotary muscle force is different in converged gaze than when convergence is relaxed. We conjecture that LRMNs with kv < kc and MRMNs with kv > kc innervate muscle fibers that are weak, have mechanical coupling that attenuates their effective oculorotary force, or serve some nonoculorotary, regulatory function.
  • Miller JM, Davison RC, Gamlin PD (2011). Motor nucleus activity fails to predict extraocular muscle forces in ocular convergence. Journal of Neurophysiology, vol 105, pgs 2863-2873 (Paper PDF).

FabLab

Devices developed for our work and possibly useful for yours
MFT
Extraocular Muscle Force Transducers (MFTs)

The only way to measure physiological oculorotational eye muscle forces.
Eye Holding Device
Eye Stabilization Devices

 Several clinical and experimental procedures require that the eye of an alert subject be held steady. This is conventionally done with special forceps or suction devices (and topical anesthesia), but neither is safe and effective for more than a few minutes. We're developing two devices: [1] A corneal suction ring that prevents globe deformation and the increase in intraocular pressure that limits application time of existing suction devices. Fabrication is by stereolithography, which makes it possible to customize size and shape for individual eyes. [2] An implantable magnetic detent, also customizable.

MethLab

Unique methodologies for oculomotor research
Orbit
Orbit™ 1.8.1 on Intel® (OOI)

Run Orbit under OSX on your Intel Mac! The Orbit 1.8 Gaze Mechanics Simulation remains the most powerful, reliable, and informative simulation of ocular static mechanics and strabismus.

Orbit 1.8 is a unique research and educational tool that provides a sophisticated biomechanical model able to simulate classical strabismus syndromes and data from individual cases, clarifying diagnostic and treatment possibilities in well-defined physiologic terms. It is is used all over the world by Ophthalmologists, Optometrists, and Orthoptists to model complex cyclo-vertical and innervational disorders and refine their diagnostic and treatment-planning skills, by researchers in vision and oculomotility to study orbital mechanics (eg, to distinguish orbital from central factors), by teachers to supplement the ophthalmology curriculum with strabismus simulation laboratories, and by students to consolidate loosely connected facts and observations into a solid sense of how the extraocular muscles work. 


Orbit analyzes extraocular mechanical (eg, globe dimensions, contractile forces, and muscle insertions, lengths, and stiffnesses) and innervational factors in eye alignment. It contains model eyes one uses to test suspected causes of motility disorders and proposed treatments, and a simulated eye alignment test, which shows how the model eyes behave, for comparison with clinical data or desired treatment outcomes. Orbit is related to the ophthalmotropes of Ruete (1845), Wundt (1862), and others, its main advantage being that its behavior is constrained only by knowledge of orbital mechanics, and not by the materials and mechanisms feasible in a physical model. Orbit solves for forces, innervations, and other parameters, according to equations given, in part, by Robinson (1975) and Miller and Robinson (1984).


OS X 10.11, El Capitan, required some changes to the emulation environment in which Orbit runs. Orbit 1.8.1 is Orbit 1.8, unchanged except for the updated environment.

MRI Analysis
Extraocular Muscle Scan Analysis

Since we introduced measurement of EOMs in alert humans using MRI (Miller, 1989), our methods have been used (and sometimes misused) to conduct scientific and clinical studies of muscle size, path, and contractile state. Improved methods are now available for quantifying crossectional areas and volumes, and for minimizing measurement errors and biases.
Muscle Fiber Segmentation
Segmenting & Quantifying Muscle Fibers in Stained EOM Crossections
 

Quantitative histology of extraocular muscles (EOMs) has required sampling because of the many thousands of fibers in a crossectional slice, but unfortunately EOM is highly inhomogeneous making it difficult or impossible to avoid biasWe’ve developed an operator-aided automatic process to segment essentially all the fibers in a section, calculating fiber areas and other statistics, while excluding voids, connective tissues, blood vessels, and nerves. Exhaustive measurement is achieved with only the labor normally required for sampling.

A watershed algorithm segments the histological image, and filters then select the segments with shapes and colors of muscle fibers. Omitted fibers are added, grouped fibers are split, and fiber fragments are merged manually, with computer-aided tools (IPP-9.1).

Early results suggest that BPX injection changes the distribution of muscle fiber diameters in favor of larger fibers, clarifying the nature of the muscle size changes and alignment corrections observed in the clinicTime-course studies may tell if selective destruction or biased rebuilding is responsible.

 
 
 EOM Fiber Segmentation. Fibers outlined in yellow were automatically segmented (~80%); those in other colors required manual intervention.  Effect of BPX Injection On Muscle Fiber Size. Crossectional areas of all fibers in posterior sections (6 mm anterior to the muscle origin) of rabbit SR muscles 30 days after injection with BPX or saline are shown.

Fellowships

In cooperation with the Strabismus Research Foundation, we are offering combined research-clinical fellowships to a few carefully-chosen candidates. Research would be conducted at Eidactics, and clinical experiences arranged with physicians at CPMC and UCSF. Funding is limited. Contact fellowships@eidactics.com.

Facilities

MAB

 
In Jan 2013 we left the troubled Smith-Kettlewell Eye Research Institute, and moved our offices and lab to San Francisco's landmark Medical Arts Building. Our new facilities are configured for micro-device development and fabrication, CAD and machining, immunohistochemistry, image analysis, and project management.

Our clinical studies are now conducted in collaboration with the Strabismus Research Foundation, at California Pacific Medical Center under supervision of their IRB, and our physiological studies are conducted with SRF at Bay Area CROs under supervision of their IACUCs.