• Mild Traumatic Brain Injury (mTBI) and Photosensitivity: Objective Pupillometric Findings

      Truong, James Q. (2016-06)
      Background Given the extensive neural network of the human, binocular, pupillary system including its sympathetic and parasympathetic innervation, it is plausible that a mild traumatic brain injury (mTBI) could compromise pupillary control, thus causing pupillary asymmetry and dysfunction. Furthermore, presence of such pupillary abnormalities could exacerbate mTBI-related visual symptomatology, such as photosensitivity. There have only been two studies in the area, and they both used monocular pupillometry with only one test condition; hence they were limited. Furthermore, their results were in part equivocal. There remain many unanswered questions (i.e., gaps) in this important field of study including: 1) does mTBI affect the pupillary light reflex (PLR)?, 2) is there an increase in inter-ocular pupillary asymmetry (IOPA) in mTBI?, and 3) are there PLR differences related to one of the most prominent and prevalent dysfunctions resulting from mTBI, namely photosensitivity? Aim The overall aim of the present dissertation was twofold. First, to evaluate comprehensively the effect of mTBI on the human pupillary system, and furthermore to determine if pupillometry could be used as an objective visual biomarker for mTBI. Second, to evaluate comprehensively the effect of photosensitivity on the human pupillary system, and furthermore to determine if pupillometry could be used as an objective biomarker for photosensitivity. Methods The binocular pupillary light reflex was evaluated in mTBI, and it was compared to normal individuals, with and without photosensitivity, under a range of test conditions. Nine pupillary parameters (maximum, minimum, and final pupillary diameter; latency; amplitude; and peak and average constriction and dilation velocities) and 6 stimulus conditions (dim pulse, dim step, bright pulse, bright step, bright red step, and bright blue step) were assessed in 32 adults with mTBI (21-60 years of age) and compared to 40 normals (22-56 years of age). The Neuroptics, infrared, DP-2000 binocular pupillometer was used (30Hz sampling rate; 0.05mm resolution) with binocular stimulation and recording. Results and Discussion 1. Inter-ocular pupillary asymmetry: There were no statistical differences in either static or dynamic inter-ocular pupillary asymmetry (IOPA) between the normal and mTBI groups. Thus, the pupillary effects of mTBI appear to be symmetrical rather than asymmetrical in nature, which suggests post-chiasmal involvement. The mean average (across groups) static IOPA was 0.26 + 0.20mm or 4.17 + 3.29%. The mean average dynamic IOPA was dependent on the light stimulus condition, with the average across all test conditions and groups being 0.11 + 0.10mm or 1.84 + 1.70%. 2. Pupillometry in mTBI: mTBI has been reported to cause the pupillary light reflex (PLR) to be globally attenuated (i.e., slower in onset and more sluggish in response dynamics). The present results showed that there were many statistically significant differences (p < 0.05) in the PLR parameters between the mTBI and normal groups. Furthermore, different test conditions allowed for discrimination of different parameters between the two groups. For any of the given six test conditions, 5 to 8 of the 9 pupillary parameters were statistically different (p < 0.05) between the two groups. The overall trends revealed that the mTBI cohort had longer constriction latency, slower constriction and dilation velocities, and smaller pupillary diameters (baseline, minimum, and 6PSPD). The most consistent and robust pupillary parameters that differentiated between the two groups were the pupillary diameters (maximum, minimum, and 6SPSD; p < 0.01 under all 6 test conditions), and peak dilation velocity (p < 0.02, under all applicable conditions). This suggests that mTBI adversely affects both the sympathetic and parasympathetic systems, however, the effect appears to be greater on the sympathetic system. 3. Pupillometry in photosensitivity: There were statistically significant differences (p < 0.05) in the PLR parameters of those with versus without photosensitivity in both groups. Interestingly, these differences depended upon whether the photosensitivity was mTBI related. Those with mTBI and photosensitivity manifested six significant differences (p < 0.05) as compared with those with mTBI cohort without photosensitivity: larger baseline diameter, larger minimum diameter, faster peak dilation velocity, faster T50 and T75 recovery times, and a larger pupil diameter at 6 seconds post-stimulus. Normal (non-mTBI) subjects with photosensitivity exhibited four significant differences (p < 0.05) as compared with their normal cohort without photosensitivity: larger constriction amplitude, faster average constriction
    • Objective Assessment of Retinal Ganglion Cell Function in Glaucoma

      Joshi, Nabin (2017-09-25)
      Glaucoma refers to a group of diseases causing progressive degeneration of the retinal ganglion cells. It is a clinical diagnosis based on the evidence of structural damage of the optic nerve head with corresponding visual field loss. Structural damage is assessed by visualization of the optic nerve head (ONH) through various imaging and observational techniques, while the behavioral loss of sensitivity is assessed with an automated perimeter. However, given the subjective nature of visual field assessment in patients, visual function examination suffers from high variability as well as patient and operator- related biases. To overcome these drawbacks, past research has focused on the use of objective methods of quantifying retinal function in patients with glaucoma such as electroretinograms, visually evoked potentials, pupillometry etc. Electroretinograms are objective, non-invasive method of assessing retinal function, and careful manipulation of the visual input or stimulus can result in extraction of signals particular to select classes of the retinal cells, and photopic negative response (PhNR) is a component of ERG that reflects primarily the retinal ganglion cell function. On the other hand, pupillary response to light, measured objectively with a pupillometer, also indicates the functional state of the retina and the pupillary pathway. Hence, the study of both ERGs and pupillary response to light provide an objective avenue of research towards understanding the mechanisms of neurodegeneration in glaucoma, possibly affecting the clinical care of the patients in the long run.
    • Objective assessment of visual dysfunction in the acquired brain injury (ABI) population using the visual-evoked potential (VEP)

      Yadav, Naveen K. (2014-07-09)
      Purpose: To assess quantitatively and objectively selected visual dysfunctions in patients with mild traumatic brain injury (mTBI) (i.e., increased abnormal visual motion sensitivity (VMS), attentional deficits) and stroke (i.e., hemianopic visual field defects) by using empirically-derived, optimized pattern visual evoked potential (VEP) parameters derived from our laboratory. Furthermore, the goal was to develop simple and reliable clinical VEP protocols to assess the aforementioned visual dysfunctions in acquired brain injury. Methods: Four experiments were performed binocularly with full refractive correction using an objective, pattern VEP technique. Experiments #1-3 included both visually-normal (VN) adults and adults with mTBI, all ages 18-70 years. Experiment #4 included adult patients with stroke and hemianopic visual field defects, all ages 18-70 years. The following tests and stimulus conditions were used in Experiments #1-4: Experiment #1 – central field VEP with 10, 20, and 40 min arc check sizes at low (20%) and high (85%) contrast levels; Experiment #2 – central field VEP (baseline), binasal occlusion only (BNO), base-in prism (BI) only (4 pd total), and BNO with 4 pd BI; Experiment #3 – central field VEP (eyes open (EO), baseline), eyes-closed (EC, “relaxed”), and eyes-closed number counting (ECNC, “increased attentional state”); Experiment #4 – central field VEP, intact hemi-field only, and hemianopic field only. Results: The followings results were found: Experiment #1 – The 20 min arc check size provided the largest VEP amplitude and normative latency values at both contrast levels in both the VN and mTBI groups. These optimal parameters were then used to measure VEP responses in Experiments #2-4. Experiment #2 – With BNO alone, the VEP amplitude was larger in individuals with mTBI (90%) and smaller in the VN (100%) groups, as compared to other two test conditions and baseline. In addition, with BNO only, those with mTBI demonstrated improvement in their visual impressions and in performing specific sensorimotor tasks. Experiment #3 – Objectively-based alpha attenuation ratio (AR = EC ÷ EO, ECNC ÷ EC) was able to detect, assess, and differentiate between mTBI with versus without an attentional deficits, as well as between VNs. These objective AR findings were correlated with the subjective Adult ADHD Self-Report Scale (ASRS) questionnaire scores. Experiment #4 – The group and individual VEP findings showed that the central field and the intact hemi-field VEP amplitudes were larger than found in the hemianopic field. Moreover, these objective findings were correlated with the subjective clinical perimetric results. Conclusions: The optimized VEP parameters provided quantitative, rapid, reliable, and repeatable responsivity in all experiments. These findings demonstrated that the conventional pattern VEP could be beneficial for researchers in general, as well as clinicians to differentiate between mTBI versus the VN group with a high probability, and also between mTBI with versus without an attentional deficit. In addition, the VEP could be used clinically to detect and assess hemianopic visual field defects in patients with stroke. Based on these findings, the VEP has the potential to be used as an objective visual system biomarker for the diagnosis of mTBI/concussion, and also as an objective adjunct clinical tool to detect visual field defects in patients with stroke.
    • Oculomotor rehabilitation for reading dysfunction in mild traumatic brain injury

      Thiagarajan, Preethi (2013-06-04)
      Abstract: Aim Considering the extensive neural network of the oculomotor subsystems, global damage as a result of traumatic brain injury could compromise precise oculomotor control, thus causing reading dysfunction. The aim of the present thesis was to evaluate comprehensively the effect of oculomotor-based vision rehabilitation in symptomatic individuals with respect to nearwork and reading and having a mild traumatic brain injury (mTBI). A wide range of laboratory and clinical parameters related to reading involving vergence, accommodation, and version were tested. Methods Twelve subjects with documented mTBI and nearvision-related symptoms participated in the study. A cross-over, interventional experimental design was used involving true “oculomotor” training and “SHAM” training. Each training protocol was performed for 6 weeks, 2 sessions a week, 45 minutes of actual training per session. During each training session, all three oculomotor subsystems (vergence/accommodation/version) were trained for 15 minutes each in a randomized order. All laboratory and clinical parameters were measured before (baseline) and after true oculomotor (post-OMT) and SHAM (post-SHAM) training. In addition, nearvision-related symptoms were assessed using the Convergence Insufficiency Symptom Survey (CISS) scale. Lastly, subjective attention was measured using the Visual Search and Attention Test (VSAT). iv Results Following true oculomotor training, there was a marked improvement in various laboratory and clinical parameters assessed. Over 80% of the abnormal parameters found at baseline testing were found to significantly improve with training. Dynamics of vergence and accommodation, along with clinically assessed maximum amplitudes, improved markedly. Versional saccadic eye movements demonstrated improved rhythmicity and accuracy. These results together had a significant positive impact on overall reading ability. The improved reading-related oculomotor behavior was reflected in reduction of symptoms. In addition, subjective attention was found to also improve with true oculomotor training. In contrast, none of the aforementioned parameters changed with SHAM training. Conclusions Oculomotor-based vision rehabilitation had a strong positive effect on reading-related oculomotor control. This oculomotor learning effect is suggestive of intact neuroplasticity mechanisms in a compromised brain following TBI.
    • Roles of Calcium Signaling and Protein Kinase C Activation in Mediating Receptor Control of Corneal Epithelial Renewal

      Zhang, Fan (2007-06-26)
      Epidermal growth factor, EGF, is one of the essential growth factors that stimulates injury-induced corneal epithelial healing rates. Cell signaling contributors mediating this response include capacitative calcium entry (CCE) activation and protein kinase C (PKC) isoform stimulation. This study shows in human corneal epithelial cells, HCEC, that CCE is preferentially activated by the PKC isoforms  and . Moreover such activation requires increases in plasma membrane Ca2+ influx through store-operated channels. Therefore, EGF-induced stimulation of cell proliferation and migration may depend on unique effects mediated by six different PKC isoforms identified in HCEC. TRPV1 is a vanilloid subtype of the transient receptor potential protein superfamily. This isoform is a subunit of a non-selective cation channel mediating downstream responses to heat, low pH, or noxious stimuli. TRPV1 expression has been recently described in some epithelial tissues and induces proinflammatory cytokine release through mitogen-activated protein kinase (MAPK) superfamily stimulation. This study describes in HCEC the signaling pathways mediating TRPV1-induced increases in proinflammatory cytokine release. It suggests that epithelial TRPV1 receptor activation by noxious stimuli contributes in-vivo to mounting proinflammatory reactions.