MILITARY MEDICINE, 179, 11:1212,2014
Proposed Objective Visual System Biomarkers for Mild Traumatic Brain Injury Kenneth J. Ciuffreda, OD, PhD*; Diana P. Ludlam, BS, COVT*; Preethi Thiagarajan, BS, MS, PhD*; Naveen K. Yadav, BS, MS, PhD*; LTC Jose Capo-Aponte, MS U S A f
ABSTRACT The challenge and search for objectively based biomarkers to assess for the presence of concussion/mild traumatic brain injury is a high priority for the military establishment. We present a documented overview of specific test areas and related targeted, high-yield, objectively based parameters that may be potential “vision biomarkers” for the detection of concussion/mild traumatic brain injury based on results from our laboratory and others, with emphasis on oculomotor aspects. These findings have military relevance with respect to the initial diagnosis in the battlefield and in the far-forward medical facilities, pre-/postdeployment issues, pre-/postvisual rehabilitation evaluation, fitness-for-duty assessment, and establishment of a return-to-duty timeline.
INTRODUCTION Traumatic brain injury (TBI) has been, and remains, a major public health concern and medical problem in the United States. Over the past decade, it has been brought to the attention of the general public in two primary ways. First, TBI was the “sig nature injury” of the recent wars in Iraq and Afghanistan.1 Second, there has been heightened awareness of sports-related concussions, especially in the National Football League2 and boxing.'1 The resultant short- and long-term economic impact and ramifications of TBI are staggering because of such fac tors as the related medical expenditures and disability claims, as well as fitness-for-duty and return-to-duty (RTD) delays in the military.4,5 TBI results in a constellation of medical problems of a sensory, motor, perceptual, linguistic, behavioral, attentional, and psychological nature (e.g., post-traumatic stress disorder).6 These dysfunctions can be remediated to some extent by appropriate medical and therapeutic interventions.6-8 One such area that is frequently adversely affected in mild traumatic brain injury (mTBI) is the visual domain. Since approximately 30 areas of the brain,9 and 8 of the 12 cranial nerves,6-8 deal with vision, it is not unexpected that the patient with TBI may manifest a host of visual problems,810'11 many of which frequently persist beyond the natural recovery period of 6-9 months.12 Unfortunately, it is frequently difficult to assess visual dys functions fully and carefully in the TBI population, especially in those with mTBI/concussion. First, most types of brain imaging (e.g., functional magnetic resonance imaging) do not reveal any abnormality in mTBI. Second, the symptoms may be vague, and inconclusive, and the brain imaging findings may not appear to correlate with the symptoms. Third, pres
*Department of Biological and Vision Sciences, SUNY State College of Optometry, 33 West 42nd Street, New York City, NY 10036. IDepartment of Optometry, Womack Army Medical Center, Fort Bragg, NC 28310. doi: 10.7205/MILMED-D-14-00059
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ence of a cognitive impairment may confound testing and the related findings because of instructional set confusion and short-term memory deficits. Fourth, standard vision testing in the primary care clinic may not be sufficiently sophisticated to detect subtle abnormalities (e.g., slight intermittent blur). In fact, the notion of testing for oculomotor and related vision abnormalities has led to several requests by the Department of Defense (DoD)/Army for research proposals to develop vision tests that would circumvent the presence of many of these possible obstacles, such as cognitive impairment,13 by employing relatively simple, rapid, sensitive, noninvasive, targeted, and high yield, “objectively based” testing.1314 Related to the above is the notion of detecting for the presence of a concussion/mTBI itself, as the signs, symptoms, and related case history may be vague and inconclusive in some cases, as described above for the resultant visual sequelae. This is a continuing and serious underlying problem in formulating the diagnosis of concussion and mTBI. A goal of many, such as the DoD and Veterans Affairs, is to develop an objective test, or objective test battery, that can rapidly detect for the presence of a concussion/mTBI with a high degree of probability (>90%).14,15 Over the past decade, our laboratory has been developing and testing several devices and protocols to assess objectively, rapidly, and noninvasively many aspects of the oculomotor system, as well as cortical visual processing, in concussion/mTBI. It included two DoDfunded, randomized clinical trials that provided considerable insight and guidance into these critical areas. Furthermore, and very importantly, the specific response parameters of these tests may serve as “objectively-based” biomarkers for suspected concussion/mTBI. The present brief report discusses the use of objectively based tests in the assessment of mTBI. Details of the exact test conditions, instrumentation for the specified test areas, and the related targeted test parameters, are provided in the aforementioned references, as well as those cited below. These proposed ideas are based on extensive development and testing in our laboratory, as well as in others.
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SPECIFIC TEST AREAS AND PROPOSED VISION BIOMARKERS The high incidence of oculomotor dysfunctions resulting from mTBI is well documented in the civilian,16 military,4 and Veteran17 populations. Oculomotor functions affected by mTBI include accommodation, version, and vergence eye movements. Moreover, recent technological advancements in pupillary and electrophysiological testing provide new objective tools for the assessment of visual function in these domains. The specific tests areas and related targeted param eters that may potentially serve as objectively based, vision biomarkers for detecting the presence of concussion/mTBl are briefly described here.
Saccadic Latency3
This refers to the reaction time to initiate a saccade in response to a rapid, stepwise change in target position. This parameter has been demonstrated to be useful to detect for the presence of a “very” recent (e.g., minutes, hours, days after the initial insult) concussion/mTBI. Latency is immediately abnormal and significantly elevated following the insult in many such cases (~75%), with gradual return to normalcy in 12 days. In long-term concussion, this is not typically the case, as latency is normal.24 Similarly, increased horizontal saccadic latency was present in military personnel with blast-induced mTBI (n = 51) compared with the control group (n = 26) using the Neuro-Kinetics I-Portal Neuro-Otologic Test Center.211 Pursuit6
Version Simulated Reading Saccadic Ratio11,18,19
This is a pure “oculomotor” test free of any linguistic and higher level cognitive demands (Fig. 1). The individual sim ply follows a “single” dot moving horizontally and stepwise across an otherwise blank computer monitor to simulate the eyes rapidly shifting (i.e., saccading) from one word to another, either as a single repetitive line of print or across and down a single page of print. The ratio of the total number of saccades executed to the total number of target displace ments is calculated. A ratio of 1.00 is ideal; in this case, a single and accurate saccade would have been used to track each positional change of the target. In contrast, a high ratio (e.g., 3.0) demonstrates that many more saccades (i.e., three times more) were executed than ideally required, thus suggesting marked saccadic dysmetria (i.e., saccadic inaccu racy).11,18'19 Markedly elevated saccade ratios have been found in those with chronic mTBI.11'18,19 This finding of saccadic dysmetria and an overall excessive number of saccades for predictable tracking is consistent with several earlier studies in the civilian population,16,20-23 as well as in the military population including those with blastinduced injury.17
FIGURE 1.
This refers to the eye’s ability to track a smoothly moving target.26 The goal is for eye velocity to match target velocity. Disruption of smooth pursuit eye movement has been charac terized in military personnel with blast-induced mTBI using computerized screening4,27 and specific diagnostic tools,25 as well as the civilian population.6 Vergence Peak Velocity28,29
This refers to the maximum velocity of a vergence response to a target change in depth in an attempt to fuse sensorily, and binocularly fixate motorically, an object of interest. In chronic mTBI, this parameter is significantly reduced (i.e., slowed). Thus, the vergence system response time is increased up to three-fold (i.e., to approximately 3 seconds). This finding is consistent with the pilot work of Alvarez et al30 in which this objectively based vergence deficit correlated with functional magnetic resonance imaging-based regions of interest in the mTBI brain. Near Point of Convergence28’29
This refers to the closest point of binocular motor fixation and sensory fusion, with maximal effort exerted by the individual,
Simulated reading test stimuli. Full-screen, multiple lines stimulus pattern (left). Single-line, stimulus pattern (right).
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in response to inward movement of a very near target (e.g., 5 cm) along the midline. In mTBI, this parameter is signifi cantly receded per clinical studies in both civilian31,32 and military blast-induced4,27 populations. This key clinical parameter has not yet been assessed objectively in a labora tory setting, but it would be a simple and rapid test to perform (i.e., approximately 1 minute). A c c o m m o d a tio n
Peak Velocity33'34
This refers to the maximum velocity of an accommodative response to a target change in depth to produce in-focus retinal imagery. In mTBI, this parameter is significantly reduced (i.e., slowed). Thus, the accommodative system response time would be increased by up to three-fold (i.e., to approximately 3 seconds). This finding of reduced peak velocity is consistent with the overall slowed dynamics of accommodation found in the civilian31 and military27 mTBI clinic populations.
to a brief, stepwise increase in the light stimulus level. In a military population that experienced subacute concussion/ mTBI, this parameter was significantly increased (i.e., delayed)5; however, in chronic nonmilitary individuals with concussion/mTBI, latency was normal.35 The above findings regarding dynamic pupillary responses in mTBI are consistent with recent findings of the Kardon group. In a basic science investigation in rodents,36 they found that following a blast-induced brain injury, pupil responses were reduced for red and blue light stimuli, but not for white light. This implicated the melanopsin receptor system. This testing was later extended, in part, to the normal human population,37 with future directions for the mTBI population as an objective test for concussion/mTBI. Thus, the preliminary findings from our laboratory as well as Kardon,37 Capo-Aponte,5 and others38,39 present compelling data that the objectively based and “reflexive” pupillary response has a high likelihood of being a vision-based “biomarker”39 for detecting mTBI/concussion in the acute, subacute, and chronic phases of mTBI.
Amplitude o f Accommodation33 34
This refers to the maximum amount of accommodation in response to inward movement of a very near target (e.g., 5 10 cm), with maximal effort exerted by the individual, to obtain and sustain target clarity. In mTBI, this parameter is significantly receded (i.e., reduced dioptrically) when com pared with age-based, normative data.33,34 Similarly, another study showed a statistically significant decrease in monocular amplitude of accommodation in Soldiers with blast-induced mTBI.27 It has not yet been assessed objectively in a labora tory setting, but this would be a simple and rapid test to perform (i.e., approximately 1 minute). P u p il
Peak Velocity5,35
This refers to the maximum response velocity to a brief (e.g., 500 milliseconds), stepwise increase in the light stimulus level. In mTBI, this parameter is significantly reduced (i.e., slowed). This has been found in both civilian35 and blast-induced mili tary5 populations. For example, military personnel with sub acute, blast-induced mTBI have slower average constriction velocity than controls, when measured objectively with a dig ital infrared pupillometer.5 Similarly, the average dilation velocity after the initial stimulation was reduced by nearly 22% in the mTBI population versus controls. Amplitude5 '35
This refers to the maximum response amplitude to a brief, stepwise increase in the light intensity level. In mTBI, this parameter is significantly reduced. Latency
This refers to the reaction time (i.e., time difference between the onset of the stimulus and the initiation of the response)
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V is u a l-E v o k e d C o rtic a l P o te n tia l
Amplitude With Binasal Occlusion40
This refers to the visual-cortical response amplitude found with the addition of binasal occluders in place over an individual’s spectacle lens prescription (Fig. 2). The technique of binasal occlusion (BNO) is helpful in many of those with mTBI having symptomatic visual motion sensitivity (VMS), as it reduces some of the excessive and bothersome visual motion in the temporal-peripheral visual fields. In mTBI, the visual-evoked potential (VEP) amplitude is significantly “increased” from the baseline value “with” the BNO added. Our present findings are consistent with the earlier results of Padula et a l41 regarding the high diagnostic value of the BNO test in TBI, especially in those with VMS as well as with other more general studies in the VEP-mTBI domain.42,43 DISCUSSION Currently, there is a lack of objective biomarkers, or diagnostic tools, to accurately diagnose mTBI, especially those in the acute phase. This is particularly important for military health care providers caring for Warfighters in the battlefield, who have to make a determination of either to RTD or to evacuate from theater to receive additional care. The ideal biomarker test would be objective, noninvasive, easy to administer by first responders, portable, and with high sensitivity and specificity.14,15 Several vision parameters have been proposed here as potential, objectively based biomarkers for the detection of a new concussion/mTBI. Preliminary evidence exists regarding the use of these visual functions and specific tests to accu rately diagnose mTBI in military personnel.27 Moreover, a recent Delphi study44 completed by scientists and clinicians caring for Veterans at a Veterans Affairs treatment facility
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Biomarkers for Mild Traumatic Brain Injury gated and differentiated 10 out of 10 cases (100%) of medi cally documented mTBI from a matched, visually normal control group (n = 10). In a more detailed and related study in our laboratory (N.K. Yadav, K.J. Ciuffreda, unpublished data, 2014), the detection rate with the BNO-VEP was 90%. These two recent studies confirmed and extended the earlier work of Padula et al41 with his high (80%) detection rate. Lastly, one may also elect to use either, or the combined, parameters of vergence peak velocity and accommodative peak velocity, with each having a very high rate of detection of >90%28'29,33,34; in combination, it would be even higher (approaching 99%).
Pre-/Postdeployment
recommended measuring the oculomotor functions discussed earlier, since they are commonly adversely affected in mTBI patients.25 These proposed test protocols are not meant to replace the basic vision and neurological examinations conducted in the military and civilian sectors. They function as a very impor tant and objectively based “adjunct.” For example, from the basic neurological examination, one cannot detect/resolve an abnormal 40 milliseconds increase in saccadic latency, as found in acutely concussed boxers.3 The same would be true for reduced peak velocity of either vergence28-30 or accom modation,3334 although these too are targeted, high-yield parameters for detection of concussion/mTBI. How might this research-based information and documen tation be translated into the military clinical environment for improved diagnostic and therapeutic care in the future? There are several possible routes.
Objective Assessment for Detection of Concussion/mTBI Any one, or combination, of the aforementioned vision-based parameters has the potential to be a biomarker to detect for the presence of concussion/mTBI. Incorporating more than 1 parameter would increase the likelihood of detection. For example, the BNO-VEP test alone would have a very high probability of detection. In a recent study,40 this test segre
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As described above, use of any one, or combination, of these objectively documented parameters could be employed as part of the predeployment general medical health component of the Soldier Readiness Processing testing.45 This would establish one’s predeployment medical health status, including the presence of a prior concussion/mTBI. Similarly, it could also be used for postdeployment, namely as part of the Postdeployment Health Assessment Process,46 for the detection of a brain injury (e.g., concussion/TBI) that may be attribut able to one’s subsequent combat/military-related activities, with direct comparison to the predeployment findings for the purposes of documentation and disability assessment. For example, a test station for objective assessment of the highyield, vergence peak velocity parameter could be established having a total test time of only 2 minutes, with automated data processing of the dynamic vergence response to obtain its peak velocity immediately, which would then be entered directly into the Armed Forces Health Longitudinal Technology Appli cation electronic health records. The same would be true for many of the other specified, high-yield parameters.
Pre-/Postvision Rehabilitation It has been documented in several recent laboratory-based studies that vision rehabilitation, especially oculomotorbased, can be used successfully to remediate to a significant extent, and in as little as 9 hours,11' 19’20’24'30'31'34 a full range of oculomotor dysfunctions, with objective recording and automated analysis of the targeted parameter value. This could be performed before and after vision rehabilitation to assess the therapeutic efficacy of a visual intervention objec tively. Furthermore, detailed oculomotor protocols have been established18'29'34'47 and tested with a high degree of suc cess19’20'29’34’47 in this population.
Battlefield and Far-Forward Medical Facilities Per the above discussions, testing could be performed directly and in an automated manner on the battlefield (e.g., hand-held dynamic pupillometry)5’35 and/or in the far-forward medical facilities, for new concussion/mTBI detection. Testing in the visual domain may be combined with
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assessment in the neuropsychological domain in the subacute phase. This would include the Automated Neuropsychological Assessment Metrics48 and/or Immediate Postconcussion Assessment and Cognitive Test,49 for confirmation and exten sion to a broader skill set critical for an appropriate RTD time table. Additional nonvision-based objective tests could also be incorporated, such as blood biomarkers50 and newer imaging techniques (e.g., diffusion tension imaging).51 Lastly, lack of concussion/mTBI detection and persistence of the visual abnormalities (e.g., blur and diplopia), in conjunction with the typical attentional deficits 4 could adversely affect one’s military performance in a number of practical and critical ways. For example, residual visual deficits may result in slowed visual acquisition and visual processing of one’s war fare environment, especially under the stress of the battle field, where unnecessary time and confusion could result in a life-threating situation.4
STUDY LIMITATIONS There are some potential study limitations. First, sample sizes for most studies were relatively small. This may limit gener ality of the findings and proposed tests at present. Thus, future large-scale studies are needed. Second, nearly all of the studies involved mTBI. Testing should be extended to the moderate and severe TBI populations. Third, the robust BNO-VEP findings as a key diagnostic test in those with VMS should be tested in those without VMS to assess its generality and wider appeal. Fourth, there is a volitional component to some of the oculomotor testing (e.g., saccadic tracking). That is, a malingerer may decide not to track the target with a saccade, although we have never encountered this. However, if they can be enticed to track, they cannot volitionally execute a purposefully abnormally slowed response (e.g., reduced peak velocity). Fifth, for the dynamic pupillary testing, steady fixation on the central light source is required over the 5 seconds or so required recording time. Recording systems should be developed that track the pupil during testing to maintain optical alignment for attainment of artifact-free responses.
ACKNOWLEDGMENTS We thank LTC James Truong for his helpful comments during manuscript preparation. Our studies were supported from the following sources: Depart ment of Defense (DoD grants (W81XWH-12-1-0240 and W81XWH-10-10141), Langeloth Foundation, College of Optometrists in Vision Development (COVD), and the William C. Ezell Fellowship.
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Proposed Objective Visual System Biomarkers for Mild Traumatic Brain Injury Kenneth J. Ciuffreda, OD, PhD*; Diana P. Ludlam, BS, COVT*; Preethi Thiagarajan, BS, MS, PhD*; Naveen K. Yadav, BS, MS, PhD*; LTC Jose Capo-Aponte, MS U S A f
ABSTRACT The challenge and search for objectively based biomarkers to assess for the presence of concussion/mild traumatic brain injury is a high priority for the military establishment. We present a documented overview of specific test areas and related targeted, high-yield, objectively based parameters that may be potential “vision biomarkers” for the detection of concussion/mild traumatic brain injury based on results from our laboratory and others, with emphasis on oculomotor aspects. These findings have military relevance with respect to the initial diagnosis in the battlefield and in the far-forward medical facilities, pre-/postdeployment issues, pre-/postvisual rehabilitation evaluation, fitness-for-duty assessment, and establishment of a return-to-duty timeline.
INTRODUCTION Traumatic brain injury (TBI) has been, and remains, a major public health concern and medical problem in the United States. Over the past decade, it has been brought to the attention of the general public in two primary ways. First, TBI was the “sig nature injury” of the recent wars in Iraq and Afghanistan.1 Second, there has been heightened awareness of sports-related concussions, especially in the National Football League2 and boxing.'1 The resultant short- and long-term economic impact and ramifications of TBI are staggering because of such fac tors as the related medical expenditures and disability claims, as well as fitness-for-duty and return-to-duty (RTD) delays in the military.4,5 TBI results in a constellation of medical problems of a sensory, motor, perceptual, linguistic, behavioral, attentional, and psychological nature (e.g., post-traumatic stress disorder).6 These dysfunctions can be remediated to some extent by appropriate medical and therapeutic interventions.6-8 One such area that is frequently adversely affected in mild traumatic brain injury (mTBI) is the visual domain. Since approximately 30 areas of the brain,9 and 8 of the 12 cranial nerves,6-8 deal with vision, it is not unexpected that the patient with TBI may manifest a host of visual problems,810'11 many of which frequently persist beyond the natural recovery period of 6-9 months.12 Unfortunately, it is frequently difficult to assess visual dys functions fully and carefully in the TBI population, especially in those with mTBI/concussion. First, most types of brain imaging (e.g., functional magnetic resonance imaging) do not reveal any abnormality in mTBI. Second, the symptoms may be vague, and inconclusive, and the brain imaging findings may not appear to correlate with the symptoms. Third, pres
*Department of Biological and Vision Sciences, SUNY State College of Optometry, 33 West 42nd Street, New York City, NY 10036. IDepartment of Optometry, Womack Army Medical Center, Fort Bragg, NC 28310. doi: 10.7205/MILMED-D-14-00059
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ence of a cognitive impairment may confound testing and the related findings because of instructional set confusion and short-term memory deficits. Fourth, standard vision testing in the primary care clinic may not be sufficiently sophisticated to detect subtle abnormalities (e.g., slight intermittent blur). In fact, the notion of testing for oculomotor and related vision abnormalities has led to several requests by the Department of Defense (DoD)/Army for research proposals to develop vision tests that would circumvent the presence of many of these possible obstacles, such as cognitive impairment,13 by employing relatively simple, rapid, sensitive, noninvasive, targeted, and high yield, “objectively based” testing.1314 Related to the above is the notion of detecting for the presence of a concussion/mTBI itself, as the signs, symptoms, and related case history may be vague and inconclusive in some cases, as described above for the resultant visual sequelae. This is a continuing and serious underlying problem in formulating the diagnosis of concussion and mTBI. A goal of many, such as the DoD and Veterans Affairs, is to develop an objective test, or objective test battery, that can rapidly detect for the presence of a concussion/mTBI with a high degree of probability (>90%).14,15 Over the past decade, our laboratory has been developing and testing several devices and protocols to assess objectively, rapidly, and noninvasively many aspects of the oculomotor system, as well as cortical visual processing, in concussion/mTBI. It included two DoDfunded, randomized clinical trials that provided considerable insight and guidance into these critical areas. Furthermore, and very importantly, the specific response parameters of these tests may serve as “objectively-based” biomarkers for suspected concussion/mTBI. The present brief report discusses the use of objectively based tests in the assessment of mTBI. Details of the exact test conditions, instrumentation for the specified test areas, and the related targeted test parameters, are provided in the aforementioned references, as well as those cited below. These proposed ideas are based on extensive development and testing in our laboratory, as well as in others.
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SPECIFIC TEST AREAS AND PROPOSED VISION BIOMARKERS The high incidence of oculomotor dysfunctions resulting from mTBI is well documented in the civilian,16 military,4 and Veteran17 populations. Oculomotor functions affected by mTBI include accommodation, version, and vergence eye movements. Moreover, recent technological advancements in pupillary and electrophysiological testing provide new objective tools for the assessment of visual function in these domains. The specific tests areas and related targeted param eters that may potentially serve as objectively based, vision biomarkers for detecting the presence of concussion/mTBl are briefly described here.
Saccadic Latency3
This refers to the reaction time to initiate a saccade in response to a rapid, stepwise change in target position. This parameter has been demonstrated to be useful to detect for the presence of a “very” recent (e.g., minutes, hours, days after the initial insult) concussion/mTBI. Latency is immediately abnormal and significantly elevated following the insult in many such cases (~75%), with gradual return to normalcy in 12 days. In long-term concussion, this is not typically the case, as latency is normal.24 Similarly, increased horizontal saccadic latency was present in military personnel with blast-induced mTBI (n = 51) compared with the control group (n = 26) using the Neuro-Kinetics I-Portal Neuro-Otologic Test Center.211 Pursuit6
Version Simulated Reading Saccadic Ratio11,18,19
This is a pure “oculomotor” test free of any linguistic and higher level cognitive demands (Fig. 1). The individual sim ply follows a “single” dot moving horizontally and stepwise across an otherwise blank computer monitor to simulate the eyes rapidly shifting (i.e., saccading) from one word to another, either as a single repetitive line of print or across and down a single page of print. The ratio of the total number of saccades executed to the total number of target displace ments is calculated. A ratio of 1.00 is ideal; in this case, a single and accurate saccade would have been used to track each positional change of the target. In contrast, a high ratio (e.g., 3.0) demonstrates that many more saccades (i.e., three times more) were executed than ideally required, thus suggesting marked saccadic dysmetria (i.e., saccadic inaccu racy).11,18'19 Markedly elevated saccade ratios have been found in those with chronic mTBI.11'18,19 This finding of saccadic dysmetria and an overall excessive number of saccades for predictable tracking is consistent with several earlier studies in the civilian population,16,20-23 as well as in the military population including those with blastinduced injury.17
FIGURE 1.
This refers to the eye’s ability to track a smoothly moving target.26 The goal is for eye velocity to match target velocity. Disruption of smooth pursuit eye movement has been charac terized in military personnel with blast-induced mTBI using computerized screening4,27 and specific diagnostic tools,25 as well as the civilian population.6 Vergence Peak Velocity28,29
This refers to the maximum velocity of a vergence response to a target change in depth in an attempt to fuse sensorily, and binocularly fixate motorically, an object of interest. In chronic mTBI, this parameter is significantly reduced (i.e., slowed). Thus, the vergence system response time is increased up to three-fold (i.e., to approximately 3 seconds). This finding is consistent with the pilot work of Alvarez et al30 in which this objectively based vergence deficit correlated with functional magnetic resonance imaging-based regions of interest in the mTBI brain. Near Point of Convergence28’29
This refers to the closest point of binocular motor fixation and sensory fusion, with maximal effort exerted by the individual,
Simulated reading test stimuli. Full-screen, multiple lines stimulus pattern (left). Single-line, stimulus pattern (right).
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in response to inward movement of a very near target (e.g., 5 cm) along the midline. In mTBI, this parameter is signifi cantly receded per clinical studies in both civilian31,32 and military blast-induced4,27 populations. This key clinical parameter has not yet been assessed objectively in a labora tory setting, but it would be a simple and rapid test to perform (i.e., approximately 1 minute). A c c o m m o d a tio n
Peak Velocity33'34
This refers to the maximum velocity of an accommodative response to a target change in depth to produce in-focus retinal imagery. In mTBI, this parameter is significantly reduced (i.e., slowed). Thus, the accommodative system response time would be increased by up to three-fold (i.e., to approximately 3 seconds). This finding of reduced peak velocity is consistent with the overall slowed dynamics of accommodation found in the civilian31 and military27 mTBI clinic populations.
to a brief, stepwise increase in the light stimulus level. In a military population that experienced subacute concussion/ mTBI, this parameter was significantly increased (i.e., delayed)5; however, in chronic nonmilitary individuals with concussion/mTBI, latency was normal.35 The above findings regarding dynamic pupillary responses in mTBI are consistent with recent findings of the Kardon group. In a basic science investigation in rodents,36 they found that following a blast-induced brain injury, pupil responses were reduced for red and blue light stimuli, but not for white light. This implicated the melanopsin receptor system. This testing was later extended, in part, to the normal human population,37 with future directions for the mTBI population as an objective test for concussion/mTBI. Thus, the preliminary findings from our laboratory as well as Kardon,37 Capo-Aponte,5 and others38,39 present compelling data that the objectively based and “reflexive” pupillary response has a high likelihood of being a vision-based “biomarker”39 for detecting mTBI/concussion in the acute, subacute, and chronic phases of mTBI.
Amplitude o f Accommodation33 34
This refers to the maximum amount of accommodation in response to inward movement of a very near target (e.g., 5 10 cm), with maximal effort exerted by the individual, to obtain and sustain target clarity. In mTBI, this parameter is significantly receded (i.e., reduced dioptrically) when com pared with age-based, normative data.33,34 Similarly, another study showed a statistically significant decrease in monocular amplitude of accommodation in Soldiers with blast-induced mTBI.27 It has not yet been assessed objectively in a labora tory setting, but this would be a simple and rapid test to perform (i.e., approximately 1 minute). P u p il
Peak Velocity5,35
This refers to the maximum response velocity to a brief (e.g., 500 milliseconds), stepwise increase in the light stimulus level. In mTBI, this parameter is significantly reduced (i.e., slowed). This has been found in both civilian35 and blast-induced mili tary5 populations. For example, military personnel with sub acute, blast-induced mTBI have slower average constriction velocity than controls, when measured objectively with a dig ital infrared pupillometer.5 Similarly, the average dilation velocity after the initial stimulation was reduced by nearly 22% in the mTBI population versus controls. Amplitude5 '35
This refers to the maximum response amplitude to a brief, stepwise increase in the light intensity level. In mTBI, this parameter is significantly reduced. Latency
This refers to the reaction time (i.e., time difference between the onset of the stimulus and the initiation of the response)
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Amplitude With Binasal Occlusion40
This refers to the visual-cortical response amplitude found with the addition of binasal occluders in place over an individual’s spectacle lens prescription (Fig. 2). The technique of binasal occlusion (BNO) is helpful in many of those with mTBI having symptomatic visual motion sensitivity (VMS), as it reduces some of the excessive and bothersome visual motion in the temporal-peripheral visual fields. In mTBI, the visual-evoked potential (VEP) amplitude is significantly “increased” from the baseline value “with” the BNO added. Our present findings are consistent with the earlier results of Padula et a l41 regarding the high diagnostic value of the BNO test in TBI, especially in those with VMS as well as with other more general studies in the VEP-mTBI domain.42,43 DISCUSSION Currently, there is a lack of objective biomarkers, or diagnostic tools, to accurately diagnose mTBI, especially those in the acute phase. This is particularly important for military health care providers caring for Warfighters in the battlefield, who have to make a determination of either to RTD or to evacuate from theater to receive additional care. The ideal biomarker test would be objective, noninvasive, easy to administer by first responders, portable, and with high sensitivity and specificity.14,15 Several vision parameters have been proposed here as potential, objectively based biomarkers for the detection of a new concussion/mTBI. Preliminary evidence exists regarding the use of these visual functions and specific tests to accu rately diagnose mTBI in military personnel.27 Moreover, a recent Delphi study44 completed by scientists and clinicians caring for Veterans at a Veterans Affairs treatment facility
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Biomarkers for Mild Traumatic Brain Injury gated and differentiated 10 out of 10 cases (100%) of medi cally documented mTBI from a matched, visually normal control group (n = 10). In a more detailed and related study in our laboratory (N.K. Yadav, K.J. Ciuffreda, unpublished data, 2014), the detection rate with the BNO-VEP was 90%. These two recent studies confirmed and extended the earlier work of Padula et al41 with his high (80%) detection rate. Lastly, one may also elect to use either, or the combined, parameters of vergence peak velocity and accommodative peak velocity, with each having a very high rate of detection of >90%28'29,33,34; in combination, it would be even higher (approaching 99%).
Pre-/Postdeployment
recommended measuring the oculomotor functions discussed earlier, since they are commonly adversely affected in mTBI patients.25 These proposed test protocols are not meant to replace the basic vision and neurological examinations conducted in the military and civilian sectors. They function as a very impor tant and objectively based “adjunct.” For example, from the basic neurological examination, one cannot detect/resolve an abnormal 40 milliseconds increase in saccadic latency, as found in acutely concussed boxers.3 The same would be true for reduced peak velocity of either vergence28-30 or accom modation,3334 although these too are targeted, high-yield parameters for detection of concussion/mTBI. How might this research-based information and documen tation be translated into the military clinical environment for improved diagnostic and therapeutic care in the future? There are several possible routes.
Objective Assessment for Detection of Concussion/mTBI Any one, or combination, of the aforementioned vision-based parameters has the potential to be a biomarker to detect for the presence of concussion/mTBI. Incorporating more than 1 parameter would increase the likelihood of detection. For example, the BNO-VEP test alone would have a very high probability of detection. In a recent study,40 this test segre
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As described above, use of any one, or combination, of these objectively documented parameters could be employed as part of the predeployment general medical health component of the Soldier Readiness Processing testing.45 This would establish one’s predeployment medical health status, including the presence of a prior concussion/mTBI. Similarly, it could also be used for postdeployment, namely as part of the Postdeployment Health Assessment Process,46 for the detection of a brain injury (e.g., concussion/TBI) that may be attribut able to one’s subsequent combat/military-related activities, with direct comparison to the predeployment findings for the purposes of documentation and disability assessment. For example, a test station for objective assessment of the highyield, vergence peak velocity parameter could be established having a total test time of only 2 minutes, with automated data processing of the dynamic vergence response to obtain its peak velocity immediately, which would then be entered directly into the Armed Forces Health Longitudinal Technology Appli cation electronic health records. The same would be true for many of the other specified, high-yield parameters.
Pre-/Postvision Rehabilitation It has been documented in several recent laboratory-based studies that vision rehabilitation, especially oculomotorbased, can be used successfully to remediate to a significant extent, and in as little as 9 hours,11' 19’20’24'30'31'34 a full range of oculomotor dysfunctions, with objective recording and automated analysis of the targeted parameter value. This could be performed before and after vision rehabilitation to assess the therapeutic efficacy of a visual intervention objec tively. Furthermore, detailed oculomotor protocols have been established18'29'34'47 and tested with a high degree of suc cess19’20'29’34’47 in this population.
Battlefield and Far-Forward Medical Facilities Per the above discussions, testing could be performed directly and in an automated manner on the battlefield (e.g., hand-held dynamic pupillometry)5’35 and/or in the far-forward medical facilities, for new concussion/mTBI detection. Testing in the visual domain may be combined with
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assessment in the neuropsychological domain in the subacute phase. This would include the Automated Neuropsychological Assessment Metrics48 and/or Immediate Postconcussion Assessment and Cognitive Test,49 for confirmation and exten sion to a broader skill set critical for an appropriate RTD time table. Additional nonvision-based objective tests could also be incorporated, such as blood biomarkers50 and newer imaging techniques (e.g., diffusion tension imaging).51 Lastly, lack of concussion/mTBI detection and persistence of the visual abnormalities (e.g., blur and diplopia), in conjunction with the typical attentional deficits 4 could adversely affect one’s military performance in a number of practical and critical ways. For example, residual visual deficits may result in slowed visual acquisition and visual processing of one’s war fare environment, especially under the stress of the battle field, where unnecessary time and confusion could result in a life-threating situation.4
STUDY LIMITATIONS There are some potential study limitations. First, sample sizes for most studies were relatively small. This may limit gener ality of the findings and proposed tests at present. Thus, future large-scale studies are needed. Second, nearly all of the studies involved mTBI. Testing should be extended to the moderate and severe TBI populations. Third, the robust BNO-VEP findings as a key diagnostic test in those with VMS should be tested in those without VMS to assess its generality and wider appeal. Fourth, there is a volitional component to some of the oculomotor testing (e.g., saccadic tracking). That is, a malingerer may decide not to track the target with a saccade, although we have never encountered this. However, if they can be enticed to track, they cannot volitionally execute a purposefully abnormally slowed response (e.g., reduced peak velocity). Fifth, for the dynamic pupillary testing, steady fixation on the central light source is required over the 5 seconds or so required recording time. Recording systems should be developed that track the pupil during testing to maintain optical alignment for attainment of artifact-free responses.
ACKNOWLEDGMENTS We thank LTC James Truong for his helpful comments during manuscript preparation. Our studies were supported from the following sources: Depart ment of Defense (DoD grants (W81XWH-12-1-0240 and W81XWH-10-10141), Langeloth Foundation, College of Optometrists in Vision Development (COVD), and the William C. Ezell Fellowship.
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