Symptom reduction in mal de débarquement syndrome with attenuation of the velocity storage contribution in the central vestibular pathways.

Background: The velocity storage mechanism of the central vestibular system is closely associated with the vestibulo-ocular reflex (VOR), but also contributes to the sense of orientation in space and the perception of self-motion. We postulate that mal de débarquement syndrome (MdDS) is a consequence of inappropriate sensory adaptation of velocity storage. The premise that a maladapted velocity storage may be corrected by spatial readaptation of the VOR has recently been translated into the development of the first effective treatment for MdDS. However, this treatment's initial impact may be reversed by subsequent re-triggering events. Presently, we hypothesized that MdDS symptoms could alternatively be reduced by attenuating the velocity storage contribution in the central vestibular pathways. Methods: Forty-three patients with MdDS (aged 47 ± 14 yo; 36 women) were randomly assigned to two treatment groups and followed for 6 months. The horizontal VOR was tested with chair rotation during laboratory visits, and the strength of velocity storage was quantified with model-based parameters-the time constant (Tc) and the gain of coupling from the vestibular primary afferent signals (g0). To attenuate velocity storage, Group 1 underwent a progressively intensifying series of low-frequency earth-vertical oscillatory rotation coupled to conflicting visual stimuli. Group 2 underwent an established protocol combining head tilts and visual stimulation, designed to correct maladapted spatial orientation but not change the velocity storage strength. The symptom severity was self-rated on an 11-point scale and reported before and up to 6 months after the treatment. Results: In Group 1, velocity storage was modified through reduction of g0 (p < 0.001) but not Tc. The symptom rating was at least halved initially in 43% of Group 1 (p = 0.04), the majority of whom retained a similar level of improvement during the 6-month follow-up period. In Group 2, no systematic change was induced in the parameters of velocity storage strength, as expected. The symptom rating was at least halved initially in 80% of Group 2 (p < 0.001), but paralleling previous findings, symptoms often returned subsequently. Conclusion: Attenuation of velocity storage shows promise as a lasting remedy for MdDS that can complement the VOR readaptation approach.

Lasting alteration of spatial orientation induced by passive motion in rabbits and its possible relevance to mal de débarquement syndrome.

Background: Mal de débarquement syndrome (MdDS) is a chronic disorder of spatial orientation with a persistent false sensation of self-motion, whose onset typically follows prolonged exposure to passive motion of a transport vehicle. Development of similar but transient after-sensations mimicking the exposed motion and associated postural instability, indicative of central vestibular adaptation, are common. The cause of MdDS is thought to be a subsequent failure to readapt to a stationary environment. However, vestibular plasticity pertinent to this illness has not been studied sufficiently. Because the rabbit's eye movement is sensitive to three-dimensional spatial orientation, characterizing maladaptation of the vestibulo-ocular reflex (VOR) induced in the animal may open an approach to understanding MdDS. Methods: Three rabbits underwent a series of 2-h conditioning with an unnatural repetitive motion that involved a complex combination of roll, pitch, and yaw movements in a head-based reference frame, consisting of periodic rolling in darkness in a frame of reference that rotated about an earth-vertical axis. Eye movement in three dimensions was sampled during the conditioning stimulus as well as during test stimuli before and up to several days after conditioning. Results: During roll-while-rotating conditioning, the roll component of the VOR was compensatory to the oscillation about the corresponding axis, but the pitch component was not, initially prominently phase-leading the head pitch motion but subsequently becoming patently phase-delayed. Unidirectional yaw nystagmus, weak but directionally compensatory to the earth-vertical axis rotation, was seen throughout the period of conditioning. After conditioning, simple side-to-side rolling induced an abnormal yaw ocular drift in the direction that opposed the nystagmus seen during conditioning, indicating a maladaptive change in spatial orientation. The impact of conditioning appeared to be partially retained even after 1 week and could be partially reversed or cumulated depending on the rotation direction in the subsequent conditioning. Conclusion: The observed reversible long-term maladaptation of spatial orientation as well as the depth of knowledge available in relation to the vestibular cerebellar circuits in this species support the potential utility of a rabbit model in MdDS research.

Visuomotor Synchronization: Military Normative Performance.

INTRODUCTION: Cognitive processes such as perception and reasoning are preceded and dependent on attention. Because of the close overlap between neural circuits of attention and eye movement, attention may be objectively quantified with recording of eye movements during an attention-dependent task. Our previous work demonstrated that performance scores on a circular visual tracking task that requires dynamic synchronization of the gaze with the target motion can be impacted by concussion, sleep deprivation, and attention deficit/hyperactivity disorder. The current study examined the characteristics of performance on a standardized predictive visual tracking task in a large sample from a U.S. Military population to provide military normative data. MATERIALS AND METHODS: The sample consisted of 1,594 active duty military service members of either sex aged 18-29 years old who were stationed at Fort Hood Army Base. The protocol was reviewed and approved by the U.S. Army Medical Research and Materiel Command Institutional Review Board. Demographic, medical, and military history data were collected using questionnaires, and performance-based data were collected using a circular visual tracking test and Trail Making Test. Differences in visual tracking performance by demographic characteristics were examined with a multivariate analysis of variance, as well as a Kolmogorov-Smirnov test and a rank-sum test. Associations with other measures were examined with a rank-sum test or Spearman correlations. RESULTS: Robust sex differences in visual tracking performance were found across the various statistical models, as well as age differences in several isolated comparisons. Accordingly, norms of performance scores, described in terms of percentile standings, were developed adjusting for age and sex. The effects of other measures on visual tracking performance were small or statistically non-significant. An examination of the score distributions of various metrics suggested that strategies preferred by men and women may optimize different aspects of visual tracking performance. CONCLUSION: This large-scale quantification of attention, using dynamic visuomotor synchronization performance, provides rigorously characterized age- and sex-based military population norms. This study establishes analytics for assessing normal and impaired attention and detecting changes within individuals over time. Practical applications for combat readiness and surveillance of attention impairment from sleep insufficiency, concussion, medication, or attention disorders will be enhanced with portable, easily accessible, fast, and reliable dynamic eye-tracking technologies.

Dual statistical models link baseline visual attention measure to risk for significant symptomatic concussion in sports.

Aim: Athletic pre-season testing can establish functional baseline for comparison following concussion. Whether impacts of future concussions may be foretold by such testing is little known. Materials & methods: Two sets of models for a significant burden of concussion were generated: a traditional approach using a series of logistic regressions, and a penalized regression approach using elastic net. Results: 3091 youth and adult athletes were baseline-assessed. 90 subsequently experienced concussion and 35 were still experiencing a significant burden of concussion when tested within two weeks. Both models associated prior history of head injury and visual attention-related metrics with a significant burden of concussion. Conclusion: Pre-season testing of visual attention may identify athletes who are at risk for significant sports-related concussion.

Athletic pre-season testing can establish functional baseline for comparison following concussion and may predict impacts of future concussions. In this study, 3,091 youth and adult athletes were baseline-assessed. 90 subsequently experienced concussion and 35 were still experiencing a significant burden of concussion when tested within two weeks. A statistical model and a machine-learning model both associated prior history of head injury and visual attention-related metrics with a significant burden of concussion. Pre-season testing of visual attention may identify athletes who are at risk for significant sports-related concussion.

Concussion Disrupts Normal Brain White Matter Microstructural Symmetry.

Injuries and illnesses can alter the normal bilateral symmetry of the brain, and determining the extent of this disruption may be useful in characterizing the pathology. One way of quantifying brain symmetry is in terms of bilateral correlation of diffusion tensor metrics between homologous white matter tracts. With this approach, we hypothesized that the brains of patients with a concussion are more asymmetrical than those of healthy individuals without a history of a concussion. We scanned the brains of 35 normal individuals and 15 emergency department patients with a recent concussion. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were determined for regions of interest (ROI) defined by a standard white-matter atlas that included 21 bilateral ROIs. For each ROI pair, bilateral correlation coefficients were calculated and compared between the two subject groups. A symmetry index, defined as the ratio between the difference and the sum of bilateral measures, was also calculated for each ROI pair and compared between the groups. We found that in normal subjects, the extent of symmetry varied among regions and individuals, and at least subtle forms of structural lateralization were common across regions. In patients, higher asymmetry was found overall as well as in the corticospinal tract specifically. Results indicate that a concussion can manifest in brain asymmetry that deviates from a normal state. The clinical utility of characterizing post-concussion pathology as abnormal brain asymmetry merits further exploration.

The Scientific Contributions of Bernard Cohen (1929-2019).

Throughout Bernard Cohen's active career at Mount Sinai that lasted over a half century, he was involved in research on vestibular control of the oculomotor, body postural, and autonomic systems in animals and humans, contributing to our understanding of such maladies as motion sickness, mal de débarquement syndrome, and orthostatic syncope. This review is an attempt to trace and connect Cohen's varied research interests and his approaches to them. His influence was vast. His scientific contributions will continue to drive research directions for many years to come.

Disrupted White Matter Microstructure of the Cerebellar Peduncles in Scholastic Athletes After Concussion.

Concussion, or mild traumatic brain injury (mTBI), is a major public health concern, linked with persistent post-concussive syndrome, and chronic traumatic encephalopathy. At present, standard clinical imaging fails to reliably detect traumatic axonal injury associated with concussion and post-concussive symptoms. Diffusion tensor imaging (DTI) is an MR imaging technique that is sensitive to changes in white matter microstructure. Prior studies using DTI did not jointly investigate white matter microstructure in athletes, a population at high risk for concussive and subconcussive head traumas, with those in typical emergency room (ER) patients. In this study, we determine DTI scalar metrics in both ER patients and scholastic athletes who suffered concussions and compared them to those in age-matched healthy controls. In the early subacute post-concussion period, athletes demonstrated an elevated rate of regional decreases in axial diffusivity (AD) compared to controls. These regional decreases of AD were especially pronounced in the cerebellar peduncles, and were more frequent in athletes compared to the ER patient sample. The group differences may indicate differences in the mechanisms of the concussive impacts as well as possible compound effects of cumulative subconcussive impacts in athletes. The prevalence of white matter abnormality in cerebellar tracts lends credence to the hypothesis that post-concussive symptoms are caused by shearing of axons within an attention network mediated by the cerebellum, and warrant further study of the correlation between cerebellar DTI findings and clinical, neurocognitive, oculomotor, and vestibular outcomes in mTBI patients.

Concussion Subtype Identification With the Rivermead Post-concussion Symptoms Questionnaire.

Classifying concussion in key subtypes according to presenting symptomatology at an early post-injury stage is an emerging approach that may allow prediction of clinical trajectories and delivery of targeted treatments. The Rivermead Post-concussion Symptoms Questionnaire (RPQ) is a simple, freely available, and widely used tool for assessment of the presence and severity of various post-concussion symptoms. We aimed to probe the prevalence among athletes of symptom classes associated with identified concussion phenotypes using the RPQ at baseline and acutely after a concussion. Participants of organized sports aged 12-30 years were baseline-assessed with the expectation that some would experience a concussion during the study period. Concussed athletes were re-assessed within 2 weeks of their injuries. The RPQ was supplemented with three specific questions and reworded for baseline assessment. A binomial test was used to contrast the prevalence of an attribute in the concussed cohort against the probability established by the baseline observation. Three thousand and eighty-eight athletes were baseline-assessed and eighty-nine were re-assessed post-concussion. All concussed athletes endorsed having some elevated symptoms in the RPQ, and such endorsements were more prevalent than those among normal athletes. Moderate-to-severe post-concussion symptoms of specific classes tended to be endorsed with few additional symptoms of other classes of similar intensities. Elevated symptoms detected with the RPQ within as short as 2 weeks after a concussion may help delineate patients' clinical subtypes and guide their treatment. Further refinement of symptom questionnaires and use of objective measures will be needed to properly populate the concussion subtype classification.

Association of Visual Tracking Metrics With Post-concussion Symptomatology.

Attention impairment may provide a cohesive neurobiological explanation for clusters of clinical symptoms that occur after a concussion; therefore, objective quantification of attention is needed. Visually tracking a moving target is an attention-dependent sensorimotor function, and eye movement can be recorded easily and objectively to quantify performance. Our previous work suggested the utility of gaze-target synchronization metrics of a predictive visual tracking task in concussion screening and recovery monitoring. Another objectively quantifiable performance measure frequently suggested for concussion screening is simple visuo-manual reaction time (simple reaction time, SRT). Here, we used visual tracking and SRT tasks to assess changes between pre- and within-2-week post-concussion performances and explore their relationships to post-concussion symptomatology. Athletes participating in organized competitive sports were recruited. Visual tracking and SRT records were collected from the recruited athlete pool as baseline measures over a 4-year period. When athletes experienced a concussion, they were re-assessed within 2 weeks of their injury. We present the data from a total of 29 concussed athletes. Post-concussion symptom burden was assessed with the Rivermead Post-Concussion Symptoms Questionnaire and subscales of the Brain Injury Screening Questionnaire. Post-concussion changes in visual tracking and SRT performance were examined using a paired t-test. Correlations of changes in visual tracking and SRT performance to symptom burden were examined using Pearson's coefficients. Post-concussion changes in visual tracking performance were not consistent among the athletes. However, changes in several visual tracking metrics had moderate to strong correlations to symptom scales (r up to 0.68). On the other hand, while post-concussion SRT performance was reduced (p < 0.01), the changes in the performance metrics were not meaningfully correlated to symptomatology (r ≤ 0.33). Results suggest that visual tracking performance metrics reflect clinical symptoms when assessed within 2 weeks of concussion. Evaluation of concussion requires assessments in multiple domains because the clinical profiles are heterogeneous. While most individuals show recovery within a week of injury, others experience prolonged recovery periods. Visual tracking performance metrics may serve as a biomarker of debilitating symptoms of concussion implicating attention as a root cause of such pathologies.

Visual Tracking in Development and Aging.

A moving target is visually tracked with a combination of smooth pursuit and saccades. Human visual tracking eye movement develops through early childhood and adolescence, and declines in senescence. However, the knowledge regarding performance changes over the life course is based on data from distinct age groups in isolation using different procedures, and thus is fragmented. We sought to describe the age-dependence of visual tracking performance across a wide age range and compare it to that of simple visuo-manual reaction time. We studied a cross-sectional sample of 143 subjects aged 7-82 years old (37% male). Eye movements were recorded using video-oculography, while subjects viewed a computer screen and tracked a small target moving along a circular trajectory at a constant speed. For simple reaction time (SRT) measures, series of key presses that subjects made in reaction to cue presentation on a computer monitor were recorded using a standard software. The positional precision and smooth pursuit velocity gain of visual tracking followed a U-shaped trend over age, with best performances achieved between the ages of 20 and 50 years old. A U-shaped trend was also found for mean reaction time in agreement with the existing literature. Inter-individual variability was evident at any age in both visual tracking and reaction time metrics. Despite the similarity in the overall developmental and aging trend, correlations were not found between visual tracking and reaction time performances after subtracting the effects of age. Furthermore, while a statistically significant difference between the sexes was found for mean SRT in the sample, a similar difference was not found for any of the visual tracking metrics. Therefore, the cognitive constructs and their neural substrates supporting visual tracking and reaction time performances appear largely independent. In summary, age is an important covariate for visual tracking performance, especially for a pediatric population. Since visual tracking performance metrics may provide signatures of abnormal neurological or cognitive states independent of reaction time-based metrics, further understanding of age-dependent variations in normal visual tracking behavior is necessary.

Frequency Responses to Visual Tracking Stimuli May Be Affected by Concussion.

Human visual tracking performance is known to be reduced with an increase of the target's speed and oscillation frequency, but changes in brain states following a concussion may alter these frequency responses. The goal of this study was to characterize and compare frequency-dependent smooth pursuit velocity degradation in normal subjects and patients who had chronic postconcussion symptoms, and also examine cases of acutely concussed patients. Eye movements were recorded while subjects tracked a target that moved along a circular trajectory of 10° radius at 0.33, 0.40, or 0.67 Hz. Performance was characterized by the gain of smooth pursuit velocity, with reduced gain indicating reduced performance. The difference between normal and chronic patient groups in the pattern of decrease in the gain of horizontal smooth pursuit velocity as a function of the stimulus frequency reflected patients performing more poorly than normal subjects at 0.4 Hz while both groups performing similarly at 0.33 or 0.67 Hz. The performance of acute patients may represent yet another type of frequency response. The findings suggest that there may be ranges of stimulus frequencies that differentiate the effects of concussion from normal individuals.

Possible Medication-Resistant Deficits in Adult ADHD.

OBJECTIVE: The nature of ADHD, especially in adulthood, is not well-understood. Therefore, we explored subcomponents of attention in adult ADHD. METHOD: Twenty-three adults with ADHD were tested on neurocognitive and visual tracking performance both while on their regular prescription stimulant medication and while abstaining from the medication for 1 day. Pairwise comparisons to 46 two-for-one matched normal controls were made to detect medication-resistant effects of ADHD, and within-participant comparisons were made to detect medication-sensitive effects in patients. RESULTS: Even when on medication, patients performed more poorly than controls on a spatial working memory task, and on visual tracking and simple reaction time tasks immediately following other attention-demanding tasks. Patients' visual tracking performance degraded while off-medication in a manner consistent with reduced vigilance. CONCLUSION: There may be persistent cognitive impairments in adult ADHD despite medication. In addition, the benefit of stimulants seems reduced under cognitive fatigue.

Degradation of Binocular Coordination during Sleep Deprivation.

To aid a clear and unified visual perception while tracking a moving target, both eyes must be coordinated, so the image of the target falls on approximately corresponding areas of the fovea of each eye. The movements of the two eyes are decoupled during sleep, suggesting a role of arousal in regulating binocular coordination. While the absence of visual input during sleep may also contribute to binocular decoupling, sleepiness is a state of reduced arousal that still allows for visual input, providing a context within which the role of arousal in binocular coordination can be studied. We examined the effects of sleep deprivation on binocular coordination using a test paradigm that we previously showed to be sensitive to sleep deprivation. We quantified binocular coordination with the SD of the distance between left and right gaze positions on the screen. We also quantified the stability of conjugate gaze on the target, i.e., gaze-target synchronization, with the SD of the distance between the binocular average gaze and the target. Sleep deprivation degraded the stability of both binocular coordination and gaze-target synchronization, but between these two forms of gaze control the horizontal and vertical components were affected differently, suggesting that disconjugate and conjugate eye movements are under different regulation of attentional arousal. The prominent association found between sleep deprivation and degradation of binocular coordination in the horizontal direction may be used for a fit-for-duty assessment.

Chronic Post-Concussion Neurocognitive Deficits. II. Relationship with Persistent Symptoms.

Individuals who sustain a concussion may continue to experience problems long after their injury. However, it has been postulated in the literature that the relationship between a concussive injury and persistent complaints attributed to it is mediated largely by the development of symptoms associated with posttraumatic stress disorder (PTSD) and depression. We sought to characterize cognitive deficits of adult patients who had persistent symptoms after a concussion and determine whether the original injury retains associations with these deficits after accounting for the developed symptoms that overlap with PTSD and depression. We compared the results of neurocognitive testing from 33 patients of both genders aged 18-55 at 3 months to 5 years post-injury with those from 140 control subjects. Statistical comparisons revealed that patients generally produced accurate responses on reaction time-based tests, but with reduced efficiency. On visual tracking, patients increased gaze position error variability following an attention demanding task, an effect that may reflect greater fatigability. When neurocognitive performance was examined in the context of demographic- and symptom-related variables, the original injury retained associations with reduced performance at a statistically significant level. For some patients, reduced cognitive efficiency and fatigability may represent key elements of interference when interacting with the environment, leading to varied paths of recovery after a concussion. Poor recovery may be better understood when these deficits are taken into consideration.

Chronic Post-Concussion Neurocognitive Deficits. I. Relationship with White Matter Integrity.

We previously identified visual tracking deficits and associated degradation of integrity in specific white matter tracts as characteristics of concussion. We re-explored these characteristics in adult patients with persistent post-concussive symptoms using independent new data acquired during 2009-2012. Thirty-two patients and 126 normal controls underwent cognitive assessments and MR-DTI. After data collection, a subset of control subjects was selected to be individually paired with patients based on gender and age. We identified patients' cognitive deficits through pairwise comparisons between patients and matched control subjects. Within the remaining 94 normal subjects, we identified white matter tracts whose integrity correlated with metrics that indicated performance degradation in patients. We then tested for reduced integrity in these white matter tracts in patients relative to matched controls. Most patients showed no abnormality in MR images unlike the previous study. Patients' visual tracking was generally normal. Patients' response times in an attention task were slowed, but could not be explained as reduced integrity of white matter tracts relating to normal response timing. In the present patient cohort, we did not observe behavioral or anatomical deficits that we previously identified as characteristic of concussion. The recent cohort likely represented those with milder injury compared to the earlier cohort. The discrepancy may be explained by a change in the patient recruitment pool circa 2007 associated with an increase in public awareness of concussion.

Visuo-vestibular information processing by unipolar brush cells in the rabbit flocculus.

The unipolar brush cell (UBC) is a glutamatergic granular layer interneuron that is predominantly located in the vestibulocerebellum and parts of the vermis. In rat and rabbit, we previously found using juxtacellular labeling combined with spontaneous activity recording that cells with highly regular spontaneous activity belong to the UBC category. Making use of this signature, we recorded from floccular UBCs in both anesthetized and awake rabbits while delivering visuo-vestibular stimulation by using sigmoidal rotation of the whole animal. In the anesthetized rabbit, the activity of the presumed UBC units displayed a wide variety of modulation profiles that could be related to aspects of head velocity or acceleration. These modulation profiles could also be found in the awake rabbit where, in addition, they could also carry an eye position signal. Furthermore, units in the awake rabbit could demonstrate rather long response latencies of up to 0.5 s. We suggest that the UBCs recorded in this study mostly belong to the type I UBC category (calretinin-positive) and that they can play diverse roles in floccular visuo-vestibular information processing, such as transformation of velocity-related signals to acceleration-related signals.

Ocular disconjugacy cannot be measured without establishing a solid spatial reference.

This correspondence points out a need for clarification concerning the methodology utilized in the study "Eye tracking detects disconjugate eye movements associated with structural traumatic brain injury and concussion", recently published in Journal of Neurotrauma. The authors of the paper state that binocular eye movements were recorded using a single-camera video-oculography technique and that binocular disconjugate characteristics were analyzed without calibration of eye orientation. It is claimed that a variance-based disconjugacy metric was found to be sensitive to the severity of a concussive brain injury and to the status of recovery after the original injury. However, the reproducibility of the paper's findings may be challenged simply by the paucity of details in the methodological description. More importantly, from the information supplied or cited in the paper, it is difficult to evaluate the validity of the potentially interesting conclusions of the paper.