ABSTRACTABSTRACTPurpose.Purpose. To investigate why infantile nystagmus syndrome (INS) patients often complain that they To investigate why infantile nystagmus syndrome (INS) patients often complain that they are “slow to see.” Static measures of visual function (e.g., visual acuities) do not measure normal are “slow to see.” Static measures of visual function (e.g., visual acuities) do not measure normal dynamic demands on visual function. Time-sensitive measures are required to more fully measure dynamic demands on visual function. Time-sensitive measures are required to more fully measure and understand visual function. We investigated the dynamic properties of INS on saccadic latency and understand visual function. We investigated the dynamic properties of INS on saccadic latency (Ls) and target acquisition time (Lt)—new aspects of visual function. Our behavioral ocular motor (Ls) and target acquisition time (Lt)—new aspects of visual function. Our behavioral ocular motor system (OMS) model predicted system (OMS) model predicted stimulus-basedstimulus-based effects on target acquisition time in INS. effects on target acquisition time in INS. Measurements of the dynamics of INS foveation in patient responses to changes in target position Measurements of the dynamics of INS foveation in patient responses to changes in target position were used to evaluate both the patient complaint and model predictions.were used to evaluate both the patient complaint and model predictions.Methods.Methods. We used the responses of 4 INS subjects with different INS waveforms to test the model’s We used the responses of 4 INS subjects with different INS waveforms to test the model’s predictions. Infrared reflection was used for 1 INS subject, high-speed digital video for 3. We predictions. Infrared reflection was used for 1 INS subject, high-speed digital video for 3. We analyzed human responses to large and small target-step stimuli. We evaluated: time within the analyzed human responses to large and small target-step stimuli. We evaluated: time within the cycle (Tc), normalized Tc (Tc%), initial orbital position (Po), saccade amplitude, initial retinal error cycle (Tc), normalized Tc (Tc%), initial orbital position (Po), saccade amplitude, initial retinal error (e(eii), and final retinal error (e), and final retinal error (eff). Ocular motor simulations were performed in MATLAB Simulink and ). Ocular motor simulations were performed in MATLAB Simulink and the analysis was performed in MATLAB using OMLAB software.the analysis was performed in MATLAB using OMLAB software.Results.Results. Ls was a fixed value that was typically higher than normal. For Lt, Tc% was the most Ls was a fixed value that was typically higher than normal. For Lt, Tc% was the most influential factor for each waveform type. Model outputs accurately simulated human data. Refixation influential factor for each waveform type. Model outputs accurately simulated human data. Refixation strategies depended on the size of the required position change and used slow and fast nystagmus strategies depended on the size of the required position change and used slow and fast nystagmus phases, catch-up saccades, or combinations of them. These strategies allowed effective foveation phases, catch-up saccades, or combinations of them. These strategies allowed effective foveation after target movement, sometimes producing increased Lt.after target movement, sometimes producing increased Lt.Conclusions.Conclusions. Saccades disrupt the OMS’ ability to accurately calculate saccade amplitude and Saccades disrupt the OMS’ ability to accurately calculate saccade amplitude and refoveate. Idiosyncratic variations in Ls occur among INS subjects. OMS model simulations refoveate. Idiosyncratic variations in Ls occur among INS subjects. OMS model simulations demonstrated this emergent behavior; this robust model can be used to predict and reinforce data demonstrated this emergent behavior; this robust model can be used to predict and reinforce data analysis in future research.analysis in future research.

Nothing to Disclose

T&R PROCEDURET&R PROCEDUREDiscovery-Hypothesis-Demonstration-Trial-INS&AN TherapyDiscovery-Hypothesis-Demonstration-Trial-INS&AN Therapy

1978: Secondary effects of Kestenbaum surgery discovered1978: Secondary effects of Kestenbaum surgery discovered1979: Secondary effects of Kestenbaum surgery reported1979: Secondary effects of Kestenbaum surgery reported1979: T&R surgery hypothesized1979: T&R surgery hypothesized1992: Achiasmatic Belgian sheepdog model of INS found1992: Achiasmatic Belgian sheepdog model of INS found1998: Horizontal T&R procedure demonstrated on sheepdog1998: Horizontal T&R procedure demonstrated on sheepdog1998: Vertical T&R procedure demonstrated on sheepdog1998: Vertical T&R procedure demonstrated on sheepdog1999: Positive T&R procedure results in INS and SSN reported1999: Positive T&R procedure results in INS and SSN reported1999: Proprioceptive hypothesis for T&R procedure advanced1999: Proprioceptive hypothesis for T&R procedure advanced2000: NEI sponsored masked-data clinical trial begun2000: NEI sponsored masked-data clinical trial begun2002: Proprioceptive hypothesis for T&R procedure supported2002: Proprioceptive hypothesis for T&R procedure supported2003: Positive phase-1 (10 adults) clinical trial results reported2003: Positive phase-1 (10 adults) clinical trial results reported2003: First attempted T&R procedure for APN2003: First attempted T&R procedure for APN2004: Positive phase-2 (5 children) clinical trial results reported2004: Positive phase-2 (5 children) clinical trial results reported2004: Positive T&R procedure results in APN reported2004: Positive T&R procedure results in APN reported2005: Demonstration that T&R procedure affects only small signals2005: Demonstration that T&R procedure affects only small signals2005: Demonstration that T&R procedure broadens the null region2005: Demonstration that T&R procedure broadens the null region2006: Positive 2006: Positive T&R procedureT&R procedure results in acquired results in acquired DBN reportedDBN reported

BACKGROUNDBACKGROUNDT&R has been reported to increase visual acuities of T&R has been reported to increase visual acuities of

patients with patients with infantile nystagmus syndromeinfantile nystagmus syndrome (INS), (INS), asymmetric,asymmetric, (a)periodic alternating nystagmus(a)periodic alternating nystagmus (APAN), (APAN), acquired pendular acquired pendular (APN) and (APN) and downbeatdownbeat (DPN) (DPN) nystagmusnystagmus, and to , and to reduce oscillopsia in the reduce oscillopsia in the latter two.latter two.

The The broadeningbroadening of the NAFX peak of the NAFX peak post-therapy post-therapy demonstrated the need to assess demonstrated the need to assess pre-therapypre-therapy waveform qualitywaveform quality and and visual acuityvisual acuity at at different gaze different gaze angles.angles.

INS patients complain that they are INS patients complain that they are “slow to see.”“slow to see.”

QUESTIONSQUESTIONS

What causes the variable impression of being What causes the variable impression of being “slow “slow to see?”to see?”

Does INS Does INS lengthenlengthen saccadic reaction time?saccadic reaction time?Does INS Does INS lengthenlengthen target acquisition time?target acquisition time?

If any of the above are true, If any of the above are true, what target criteriawhat target criteria affect the changes and by affect the changes and by what mechanism(s)?what mechanism(s)?

Is there Is there a dynamica dynamic measuremeasure of of visual function visual function that that shouldshould be assessed in INS? be assessed in INS?

HYPOTHESESHYPOTHESES

Small saccadic Small saccadic latencylatency increases are increases are notnot the cause the cause of the of the “slow-to-see”“slow-to-see” phenomenon. phenomenon.

The The timingtiming of the target jump within an INS cycle will of the target jump within an INS cycle will adversely affect the total adversely affect the total target acquisition timetarget acquisition time.

METHODSMETHODSOcular motor simulations using a Ocular motor simulations using a behavioral OMS behavioral OMS

modelmodel were performed in MATLAB Simulink and were performed in MATLAB Simulink and the saccadic latency analysis was performed in the saccadic latency analysis was performed in MATLAB using “OMtools” softwareMATLAB using “OMtools” software ..

High-speed digital video High-speed digital video and and infrared reflectioninfrared reflection systems were used to measure the eye systems were used to measure the eye movements (fixation and saccades) of four movements (fixation and saccades) of four patients with INS. patients with INS.

Eye movement data were calibrated and analyzed for Eye movement data were calibrated and analyzed for the fixating eye. the fixating eye. Stimulus timing, orbital position,Stimulus timing, orbital position, and and retinal errorsretinal errors were examined. were examined.

METHODSMETHODS

Ls - Saccadic LatencyLs - Saccadic LatencyLt - Target Acquisition TimeLt - Target Acquisition TimeTc - Stimulus Time in INS CycleTc - Stimulus Time in INS Cycle

OCULAR MOTOR SYSTEM MODELOCULAR MOTOR SYSTEM MODEL

2004, Jacobs et al.

CN Block Diagram

TIAL+SPMotor Command

NI HoldSaccadic Motor

Command

Efference Copy[Vel]

ReconstructedTarget Velocity

Efference Copy[Pos]

Efference Copy[Pos + SP]

Retinal Position Error

E

e

E

T

Retinal Feedback

Evel'

E'

Tvel'

Retinal Slip VelocityRETINA

*

* Foveating Saccade Motor Cmd

1Eye

Position

k

s

SmoothPursuit

Saccadic[PG,NI Hold]

Neural Integrator

OMN[Tonic +Phasic]

TI

Light / DarkINTERNALMONITOR

[Sacc,FS/BS,SP,AL,

NI Control]

Fixation

EOM[2-PolePlant]

1Target

Position

INS Model Block Diagram

MODEL PREDICTIONSMODEL PREDICTIONSPfs (Model, Single Cycle)

0.3

0.4

0.5

0.6

0.7

0 0.2 0.4 0.6 0.8 1Tc %

Lt (sec)

PPfs (Model, Single Cycle)

0.2

0.4

0.6

0.8

1

1.2

0.0 0.2 0.4 0.6 0.8 1.0 1.2Tc %

Lt (sec)

PPfs (Model, Multiple Cycles)

R2 = 0.5121

0.2

0.4

0.6

0.8

1

1.2

0.0 0.2 0.4 0.6 0.8 1.0 1.2Tc %

Lt (sec)

Pfs (Model, Multiple Cycles)

R2 = 0.4695

0.3

0.5

0.7

0.9

0.0 0.2 0.4 0.6 0.8 1.0Tc %

Lt (sec)

MODEL PREDICTIONSMODEL PREDICTIONSDifferent Target TimingsDifferent Target Timings

Lt=510msLt=510ms

Lt=460msLt=460ms

Lt=620msLt=620ms

Lt=570msLt=570ms

Counter-intuitive? Target jumps during “stillstill” foveation periods have longerlonger target acquisition time

It’s the intrinsic saccades that matter!!It’s the intrinsic saccades that matter!!

RESULTSRESULTSSaccadic LatenciesSaccadic Latencies

0

0.1

0.2

0.3

0.4

0.5

Waveform Type

Ls (sec)

Pfs PPfs PC J (APAN) J

}Normal Saccadic Latency

RESULTSRESULTSTarget Acquisition TimesTarget Acquisition Times

Pfs

R2 = 0.5376

0.4

0.8

1.2

1.6

0.0 0.2 0.4 0.6 0.8 1.0Tc %

Lt (sec)

PPfs

R2 = 0.7714

0.5

0.7

0.9

1.1

1.3

1.5

0.0 0.2 0.4 0.6 0.8 1.0Tc %

Lt (sec)

Large StepsLarge Steps

RESULTSRESULTSTarget Acquisition TimesTarget Acquisition Times

J

R2 = 0.398

0.6

0.8

1

1.2

1.4

0.0 0.2 0.4 0.6 0.8 1.0Tc %

Lt (sec)

J (APAN)

R2 = 0.3238

0.2

0.7

1.2

1.7

0.0 0.2 0.4 0.6 0.8 1.0

Tc %

Lt (sec)

3.80

2.21

4.31

3.46

3.36

4.15

4.49

2.29

5.64

2.75

9.94

6.25

2.34

Large StepsLarge Steps

RESULTSRESULTSTarget Acquisition TimesTarget Acquisition Times

PC

R2 = 0.3523

0.4

0.6

0.8

1

1.2

1.4

0 0.2 0.4 0.6 0.8 1Tc

Lt (sec)

PC (transformed)

R2 = 0.4188

0.4

0.6

0.8

1

1.2

1.4

0 0.2 0.4 0.6 0.8 1Tc

Lt (sec)

Large StepsLarge Steps

RESULTSRESULTSTarget Acquisition TimesTarget Acquisition Times

Lt vs Tc

R2 = 0.1458

0

0.4

0.8

1.2

0 0.05 0.1 0.15 0.2Tc (sec)

Lt (sec)

Lt vs Tc %

R2 = 0.3671

0

0.4

0.8

1.2

0.0 0.2 0.4 0.6 0.8 1.0Tc %

Lt (sec)

6.93

3.06

4.48

2.43

2.14

12.04

3.82

5.492.78

Small StepsSmall Steps

RESULTSRESULTSTarget Acquisition TimesTarget Acquisition Times

Lt vs ei

0

0.4

0.8

1.2

-6 -5 -4 -3 -2 -1 0 1ei

Lt (sec)

Lt vs ef

0

0.4

0.8

1.2

-10 -5 0 5 10ef (°)

Lt (sec)

Lt vs Po

0

0.4

0.8

1.2

-30 -20 -10 0 10 20 30Po (°)

Lt (sec)

Small StepsSmall Steps(Same results (Same results for large steps)for large steps)

RESULTSRESULTSFoveating StrategyFoveating Strategy

Small StepsSmall Steps

Preprogrammed Fast PhasePreprogrammed Fast PhaseRefixation SaccadeRefixation Saccade

Lt~600msLt~600ms

RESULTSRESULTSFoveating StrategyFoveating Strategy

Small StepsSmall StepsSmall StepsSmall Steps

Inaccurate SaccadeInaccurate Saccade

Riding Slow PhaseRiding Slow Phase

Lt=1.1sLt=1.1s

RESULTSRESULTSFoveating StrategyFoveating Strategy

Small StepsSmall Steps

AnticipationAnticipation

RESULTSRESULTSFoveating StrategyFoveating Strategy

Large StepsLarge Steps

Refixation SaccadeRefixation Saccade

Altered Fast PhaseAltered Fast Phase

Lt~600msLt~600ms

RESULTSRESULTSFoveating StrategyFoveating Strategy

Large StepsLarge Steps

Hypometric SaccadeHypometric Saccade

Corrective SaccadeCorrective Saccade

Waveform ChangeWaveform ChangeLt=1sLt=1s

RESULTSRESULTSFoveating StrategyFoveating Strategy

Large StepsLarge Steps

Hypometric SaccadeHypometric Saccade

Riding Slow PhaseRiding Slow Phase

Lt=1sLt=1s

RESULTSRESULTSFoveating StrategyFoveating Strategy

Large StepsLarge Steps

Impaired Gaze HoldingImpaired Gaze Holding

Riding Slow PhaseRiding Slow Phase

Lt=900msLt=900ms

RESULTSRESULTSFoveating StrategyFoveating Strategy

Large StepsLarge Steps

Pulse-Step MismatchPulse-Step Mismatch

Direction ChangeDirection Change

Lt~800msLt~800ms

CONCLUSIONSCONCLUSIONS

Although Although saccadic latencysaccadic latency appears somewhat appears somewhat lengthenedlengthened in INS, the amount is insufficient to cause in INS, the amount is insufficient to cause the the “slow-to-see”“slow-to-see” impression. impression.

The variable The variable “slow-to-see”“slow-to-see” impression is caused by the impression is caused by the interaction of the interaction of the timetime of a target jump and the of a target jump and the intrinsic intrinsic saccadessaccades generated as part of INS waveforms. generated as part of INS waveforms.

Target jumps occurring near intrinsic saccades result in Target jumps occurring near intrinsic saccades result in inaccurate saccadesinaccurate saccades and and lengthenlengthen the total the total target target acquisition time acquisition time far beyond saccadic latencies and far beyond saccadic latencies and result in the result in the real phenomenonreal phenomenon of being of being “slow-to-see”“slow-to-see”.

CONCLUSIONSCONCLUSIONS

TheThe Behavioral OMS Model: Behavioral OMS Model:

1. Accurately 1. Accurately predictedpredicted increasesincreases in total target in total target acquisition timeacquisition time in the presence of INS waveforms. in the presence of INS waveforms.

2. Demonstrated that it was the 2. Demonstrated that it was the interactioninteraction between between intrinsic waveform saccadesintrinsic waveform saccades and the required and the required voluntary refixation saccadevoluntary refixation saccade that resulted in the that resulted in the increasedincreased target target acquisition timeacquisition time.

CONCLUSIONSCONCLUSIONS

Static Static measures of measures of visual functionvisual function (i.e., primary-position (i.e., primary-position and lateral gaze and lateral gaze visual acuity measurementsvisual acuity measurements) are ) are insufficientinsufficient measures of important visual function measures of important visual function variables like variables like targettarget acquisition timeacquisition time.

Individuals with INS should also be tested forIndividuals with INS should also be tested for targettarget acquisition timeacquisition time as part of their as part of their visual functionvisual function assessment.assessment.