Phasic, Event-Related Transcutaneous Auricular Vagus Nerve Stimulation Modifies Behavioral, Pupillary, and Low-Frequency Oscillatory Power Responses.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications.SIGNIFICANCE STATEMENT taVNS has gained increasing attention as a noninvasive neuromodulation technique and is widely used in clinical and nonclinical research. Nevertheless, the exact mechanism of action of taVNS is not yet fully understood. By assessing physiology and behavior in a response conflict task in healthy humans, we demonstrate the first successful application of a phasic, noninvasive vagus nerve stimulation to improve cognitive control and to systematically modulate pupillary and electrophysiological markers of the noradrenergic system. Understanding the mechanisms of action of taVNS could optimize future clinical applications and lead to better treatments for mental disorders associated with noradrenergic dysfunction. In addition, we present a new taVNS-sensitive pupillary measure representing an easy-to-use biomarker for future taVNS studies.

Assessment of sedation by automated pupillometry in critically ill patients: a prospective observational study.

BACKGROUND: Quantitative measurement of pupil change has not been assessed against the Richmond Agitation and Sedation Scale (RASS) and spectral edge frequency (SEF) during sedation. The aim of this study was to evaluate pupillometry against these measures in sedated critically ill adult patients. METHODS: In ventilated and sedated patients, pupillary variables were measured by automated pupillometry at each RASS level from -5 to 0 after discontinuation of hypnotics, while processed electroencephalogram variables were displayed continuously and SEF was recorded at each RASS level. Correlations were made between percentage pupillary light reflex (%PLR) and RASS, and between %PLR and SEF. The ability of %PLR to differentiate light sedation (RASS ≥-2), moderate (RASS =-3), and deep sedation (RASS ≤-4) was assessed by areas under receiver operating characteristic (ROC) curves. RESULTS: A total of 163 paired measurements were recorded in 38 patients. With decreasing sedation depth, median %PLR increased progressively from 20% (interquartile range 17-25%) to 36% (interquartile range 33-40%) (P<0.001). Strong correlations were found between %PLR and RASS (Rho=0.635) and between %PLR and SEF (R=0.641). Area under the curve (AUC) of 0.87 with a %PLR threshold of 28% differentiated moderate/light sedation from deep sedation with sensitivity of 83% and specificity of 83%. An AUC of 0.82 with a threshold of 31% distinguished light sedation from moderate/deep sedation with a sensitivity of 81% and a specificity of 75%. CONCLUSIONS: Quantitative assessment of %PLR correlates with other indicators of sedation depth in critically ill patients.

The use of quantitative pupillometry in brain death determination: preliminary findings.

PURPOSE: Quantitative pupillometry (QP) has been increasingly applied in neurocritical care as an easy-to-use and reliable technique for evaluating the pupillary light reflex (PLR). Here, we report our preliminary findings on using QP for clinical brain death (BD) determination. MATERIALS: This retrospective study included 17 patients ≥ 18 years (mean age, 57.3 years; standard deviation, 15.8 years) with confirmed BD, as defined by German Guidelines for the determination of BD. The PLR was tested using the NPi®-200 Pupillometer (Neuroptics, Laguna Hill, USA), a handheld infrared device automatically tracking and analyzing pupil dynamics over 3 s. In addition, pupil diameter and neurological pupil index (NPi) were also evaluated. RESULTS: Intracerebral bleeding, subarachnoid hemorrhage, and hypoxic encephalopathy were the most prevalent causes of BD. In all patients, the NPi was 0 for both eyes, indicating the cessation of mid-brain function. The mean diameter was 4.9 mm (± 1.3) for the right pupil and 5.2 mm (±1.2) for the left pupil. CONCLUSIONS: QP is a valuable tool for the BD certification process to assess the loss of PLR due to the cessation of brain stem function. Furthermore, implementing QP before the withdrawal of life-sustaining therapy in brain-injured patients may reduce the rate of missed organ donation opportunities. Further studies are warranted to substantiate the feasibility and potential of this technique in treating patients and identify suitable candidates for this technique during the BD certification process.

The value of pupillary diameter in evaluating pain perception after awakening in patients undergoing general anesthesia during orthopedic surgery.

BACKGROUND: The pupillary response to tetanic electrical stimulation reflects the balance between nociceptive stimulation and analgesia. Although pupillary pain index (PPI) was utilized to predict postoperative pain, it depended on tetanic stimulation and was complex. We aim to describe the potential relationship between PD in the presence of surgical stimulation and pain levels after awakening. METHODS: According to the Verbal Rating Scale (VRS) score after extubation, the patients were divided into painless group (VRS = 0) and pain group (VRS ≥ 1). Pupillary diameter (PD) and pupillary light reflex velocity (PLRV) were compared between two groups when patients entered the operating room (T1), before incision (T2), 10 s after incision (T3), 30 s after incision (T4), 1 h after incision (T5), at the end of surgery (T6), shortly after extubation (T7), and when patients expressed pain clearly (T8). The magnitude of PD change (ΔPD) compared to the baseline value after anesthesia induction (T2) was calculated. The correlations between pupillary parameters and pain after awakening were calculated. RESULTS: Patients with VRS ≥ 1 had greater PD than painless patients at T3-7 (P = 0.04, 0.04, 0.003, <0.001, <0.001), and it was positively correlated with VRS score after awakening at T4-7 (r = 0.188, 0.217, 0.684, 0.721). The ability of T6ΔPD to predict VRS ≥ 1 was strong [threshold: 20.53%, area under the curve (AUC): 0.93, 95% confidence interval (CI): 0.89-0.97 ]. CONCLUSION: Our study indicates that PD is a useful index to direct the individualized analgesics used during operation, to better avoid the occurrence of pain during the postoperative emergence period. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000040908, registration date: 15/12/2020).

Feasibility of USG-Guided Objective Initial Assessment of Pupillary Size and Pupillary Reflexes Versus Clinical Examination in Patients With Altered Mental Status: A Cross-Sectional Study.

BACKGROUND: Pupillary assessment is an important part of the neurological assessment which provides vital information in critically ill patients. However, clinical pupillary assessment is subjective. The ultrasound-guided pupillary examination is objective. There are limited pieces of literature regarding its use in assessing patients with altered mental status. So, we studied the extent of agreement of B-mode ultrasound with clinical examination for assessment of the pupillary size and reflex in patients with altered mental status. OBJECTIVES: The primary objective was to determine the extent of agreement between clinical examination and ultrasound-based examination for assessing pupillary reflex and size in patients with altered mental status in two settings (trauma and non-trauma patients). METHODS: Exactly 200 subjects (158 males, mean [range] age 43.56 [18-92 years]) with no history of partial globe rupture or dementia were included in this cross-sectional study from March 2019 to March 2020. B-mode ultrasound was performed with the subject's eyes closed using a 7-12 MHz linear probe and a standardized light stimulus. ICC score, paired t-test, kappa, Wilcoxon signed-rank test, and Bland-Altman plots were used for statistical analysis. RESULTS: The clinical-USG agreement for pupillary light reflex examination (Pupillary Diameter [PD] at rest, after direct light stimulation [Dstim ] and consensual light stimulation [Cstim ]) was excellent (ICC, 0.93-0.96). The Kappa coefficient (0.74 ± 0.07) showed an agreement of 87.36% between clinical and USG examination for pupillary reflex (reactive or non-reactive). CONCLUSION: USG-guided pupillary examination proves to be a better adjunct to neurological assessment in patients with altered mental status.

Pupillary Light Reflex Detected by Ophthalmic Ultrasonography in Critically Ill Children With Difficult to Assess Pupils.

Direct visualization of the eye can be difficult or impossible when there is significant facial burns, trauma, or edema. We present 4 nonresponsive, critically ill children whose pupils could not be directly visualized. Ophthalmic ultrasound revealed pupillary reactivity at presentation and throughout their recovery. Determining pupillary reactivity in these nonresponsive patients impacted their initial triage, resuscitation, and medical management. We propose that ophthalmic point-of-care ultrasonography can assess the pupillary light reflex in critically ill children whose pupils cannot be directly visualized.

Anisocoria After Direct Light Stimulus is Associated with Poor Outcomes Following Acute Brain Injury.

BACKGROUND: Assessing pupil size and reactivity is the standard of care in neurocritically ill patients. Anisocoria observed in critically ill patients often prompts further investigation and treatment. This study explores anisocoria at rest and after light stimulus determined using quantitative pupillometry as a predictor of discharge modified Rankin Scale (mRS) scores. METHODS: This analysis includes data from an international registry and includes patients with paired (left and right eye) quantitative pupillometry readings linked to discharge mRS scores. Anisocoria was defined as the absolute difference in pupil size using three common cut points (> 0.5 mm, > 1 mm, and > 2 mm). Nonparametric models were constructed to explore patient outcome using three predictors: the presence of anisocoria at rest (in ambient light); the presence of anisocoria after light stimulus; and persistent anisocoria (present both at rest and after light). The primary outcome was discharge mRS score associated with the presence of anisocoria at rest versus after light stimulus using the three commonly defined cut points. RESULTS: This analysis included 152,905 paired observations from 6,654 patients with a mean age of 57.0 (standard deviation 17.9) years, and a median hospital stay of 5 (interquartile range 3-12) days. The mean admission Glasgow Coma Scale score was 12.7 (standard deviation 3.5), and the median discharge mRS score was 2 (interquartile range 0-4). The ranges for absolute differences in pupil diameters were 0-5.76 mm at rest and 0-6.84 mm after light. Using an anisocoria cut point of > 0.5 mm, patients with anisocoria after light had worse median mRS scores (2 [interquartile range 0-4]) than patients with anisocoria at rest (1 [interquartile range 0-3]; P < .0001). Patients with persistent anisocoria had worse median mRS scores (3 [interquartile range 1-4]) than those without persistent anisocoria (1 [interquartile range 0-3]; P < .0001). Similar findings were observed using a cut point for anisocoria of > 1 mm and > 2 mm. CONCLUSIONS: Anisocoria after light is a new biomarker that portends worse outcome than anisocoria at rest. After further validation, anisocoria after light should be considered for inclusion as a reported and trended assessment value.

Smartphone pupillometry for detection of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment.

Light triggers numerous non-image-forming, or non-visual, biological effects. The brain correlates of these non-image-forming effects have been investigated, notably using magnetic resonance imaging and short light exposures varying in irradiance and spectral quality. However, it is not clear whether non-image-forming responses estimation may be biased by having light in sequential blocks, for example, through a potential carryover effect of one light onto the next. We reasoned that pupil light reflex was an easy readout of one of the non-image-forming effects of light that could be used to address this issue. We characterised the sustained pupil light reflex in 13-16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light (0.16 melanopic equivalent daylight illuminance lux) and polychromatic blue-enriched white light of three different levels (37, 92, 190 melanopic equivalent daylight illuminance lux). As expected, higher melanopic irradiance was associated with larger sustained pupil light reflex in each cognitive domain. This result was stable over the light sequence under higher melanopic irradiance levels compared with lower ones. Exploratory frequency-domain analyses further revealed that sustained pupil light reflex was more variable under lower melanopic irradiance levels. Importantly, sustained pupil light reflex varied across tasks independently of the light condition, pointing to a potential impact of light history and/or cognitive context on sustained pupil light reflex. Together, our results emphasise that the distinct contribution and adaptation of the different retinal photoreceptors influence the non-image-forming effects of light and therefore potentially their brain correlates.

Central retina plays a decisive role in the suppression of pupillary escape.

PURPOSE: To explore the pupil redilation during persistent light exposure (pupillary escape phenomenon) at the macula and periphery with monochromatic light stimuli. METHODS: Forty healthy subjects aged 18-64 years (24 females) were examined by chromatic pupil campimetry (CPC) using red and blue 4-s stimuli of 10° radius at the center and 20°-peripheral locations one per quadrant. One glaucoma patient and one achromatopsia patient served as disease models. For statistical analyses, linear mixed-effects models were performed followed by post hoc t-tests. RESULTS: A distinct pupillary escape could be demonstrated peripherally (blue 0.099%*s, red 0.153%*s); at the central healthy retina, there was no relevant escape, neither for blue nor red stimulation. Comparing central versus peripheral stimulation revealed highly significant differences in the escape (difference blue 0.100 ± 0.013, red 0.144 ± 0.013, < 0.0001, respectively). In the periphery, the escape was significantly more pronounced for red compared with blue stimulation (difference 0.054 ± 0.013; p = 0.0001). Enhanced pupillary escape outside of the 95% confidence interval of the linear mixed-effects model of the healthy population could be exemplarily shown in a patient with glaucomatous ganglion cell damage. In the achromatopsia example, no relevant escape was found for blue stimulation, but for red stimulation in the periphery in a comparable range to healthy controls. CONCLUSION: The results emphasize that an intact inner retinal network of nerve fibers arising from the central macular region is necessary for maintaining pupillary constriction during a bright 4-s light stimulus and preventing increase of pupillary escape. Increasing receptive field sizes towards the periphery on the level of retinal ganglion cells and less input from central 1:1 connections could be one of the driving mechanisms for pupillary escape.

Comparison of effects of volatile and intravenous anesthetics on pupillary function during general anesthesia in children: A prospective observational study.

BACKGROUND: The light reflex, which reflects central nervous system dysfunction, can also be affected by anesthetic agents. AIMS: We evaluated whether these effects differed according to the anesthetic agent in pediatric patients. METHODS: Twenty children aged 3-12 years who were scheduled to undergo elective surgery under general anesthesia were randomly allocated to propofol and sevoflurane groups and underwent pupillometric assessments at five points during anesthesia: T1, after confirming loss of consciousness; T2, after endotracheal intubation; T3, at the time of skin incision; T4, 1 h after skin incision; and T5, before endotracheal extubation. The primary outcome was the Neurological Pupil index at T4, and the secondary outcomes were other pupillometric parameters, including pupil diameter, percentage of change in pupil diameter, dilation velocity, and constriction velocity. RESULTS: At T4, the Neurological Pupil index was significantly lower in the sevoflurane group (median difference, 0.30; 95% CI, 0.00 to 0.70; p = .036). Furthermore, the Neurological Pupil index at all time points was lower in the sevoflurane group. The time-and-group interaction effects on constriction velocity and dilation velocity were significantly different [F(1, 4) = 16.68, p = .002; F(1, 4) = 14.78, p = .008, respectively] but were not different on the Neurological Pupil index, pupil diameter, and percentage of change in pupil diameter. No intergroup differences were observed in the baseline characteristics, the flow rate of remifentanil at each time point, and total infused remifentanil. CONCLUSION: The Neurological Pupil index value in pediatric patients under general anesthesia is affected by the anesthetic agent used; this factor requires consideration in evaluations of the Neurological Pupil index during general anesthesia.

Neurological Pupil Index and Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: A Retrospective Multicentric Study.

BACKGROUND: Delayed cerebral ischemia (DCI) occurs in around 30% of patients suffering from nontraumatic subarachnoid hemorrhage (SAH) and is associated with poor neurological outcome. Whether the Neurological Pupil index (NPi) derived from the automated pupillometry could help to diagnose the occurrence of DCI remains unknown. The aim of this study was to investigate the association of NPi with the occurrence of DCI in patients with SAH. METHODS: This was a multicenter, retrospective cohort study of consecutive patients with SAH admitted to the intensive care units of five hospitals between January 2018 and December 2020 who underwent daily NPi recordings (every 8 h) during the first 10 days of admission. DCI was diagnosed according to standard definitions (in awake patients) or based on neuroimaging and neuromonitoring (in sedated or unconscious patients). An NPi < 3 was defined as abnormal. The primary outcome of the study was to assess the time course of daily NPi between patients with DCI and patients without DCI. Secondary outcome included the number of patients who had an NPi < 3 before DCI. RESULTS: A total of 210 patients were eligible for the final analysis; DCI occurred in 85 (41%) patients. Patients who developed DCI had similar values of mean and worst daily NPi over time when compared with patients without DCI. Patients with DCI had a higher proportion of at least one NPi < 3 at any moment before DCI when compared with others (39/85, 46% vs. 35/125, 38%, p = 0.009). Similarly, the worst NPi before DCI diagnosis was lower in the DCI group when compared with others (3.1 [2.5-3.8] vs. 3.7 [2.7-4.1], p = 0.05). In the multivariable logistic regression analysis, the presence of NPi < 3 was not independently associated with the development of DCI (odds ratio 1.52 [95% confidence interval 0.80-2.88]). CONCLUSIONS: In this study, NPi measured three times a day and derived from the automated pupillometry had a limited value for the diagnosis of DCI in patients with SAH.

A smartphone pupillometry tool for detection of acute large vessel occlusion.

OBJECTIVES: Pupillary light reflex (PLR) parameters can be used as quantitative biomarkers of neurological function. Since digital infrared pupillometry is expensive, we sought to examine alterations in PLR parameters using a smartphone quantitative pupillometry platform in subjects with acute ischemic stroke (AIS). MATERIALS AND METHODS: Patients were enrolled if they presented to the emergency department as a stroke code activation and had evidence of a large vessel occlusion (LVO) on computed tomography angiography. Controls were enrolled from hospital staff. A smartphone pupillometer was used in AIS patients with LVO pre-mechanical thrombectomy, immediately post-thrombectomy, and at 24 h post-thrombectomy. Clinical and demographic data were collected, along with the proprietary Neurological Pupil index (NPi) score from the NPi-200 digital infrared pupillometer. PLR parameters were compared using mean differences. The absolute and non-absolute inter-eye difference in each parameter for each subject were also analyzed by measuring 1 - (R:L) to determine alteration in the equilibrium between subject pupils. The NPi was analyzed for mean differences between cohorts. RESULTS: Healthy controls (n = 132) and AIS patients (n = 31) were enrolled. Significant differences were observed in PLR parameters for healthy subjects when compared to pre-thrombectomy subjects in both mean and absolute inter-eye differences after post hoc Bonferroni correction. The proprietary NPi score was not significantly different for all groups and comparisons. CONCLUSIONS: Significant alterations in the PLR were observed in AIS patients with LVO before thrombectomy, indicating the potential use of smartphone pupillometry for detection of LVO.

Trpm1: Novel function at the intersection of light and pain response in the iris.

In mammals, the retina is the photosensitive tissue that is responsible for the capture of light and the transduction of the light-initiated signals to the brain. These visual signals help to drive image and non-image forming behaviors. The pupillary light reflex (PLR) is an involuntary non-image forming behavior which involves the constriction of the iris muscle tissue in response to ambient light intensity. A subset of photosensitive retinal ganglion cells provides the principal pathway for all light input to the olivary pretectal nucleus which directs the neuronal input to drive iris constriction. Transient receptor potential melastatin 1 (Trpm1) knockout mice have a severe defect in PLR, but it remains unclear how the Trpm1 channel contributes to this behavior. We have demonstrated that the reduced PLR in Trpm1-/- mice at scotopic and photopic intensities is due to a functional loss of Trpm1 in the retina as well as the iris sphincter muscle. We have also tested constriction in isolated eyes and have shown that light-driven constriction independent of signaling from the brain also requires Trpm1 expression. In both the in vivo PLR and the iris photomechanical response, melanopsin is required for the light-dependent activation. Finally, pharmacological experiments using capsaicin to activate pain afferents in the eye demonstrate that Trpm1 expression is required for all sensory driven iris constriction. Our results demonstrate for the first time that Trpm1 has a novel and necessary role in iridial cells and is required for all sensory-driven constriction in the iris.

Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia.

BACKGROUND: Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions. METHODS: We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5 months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome-wide polygenic scores (GPSs). RESULTS: Univariate twin modelling showed high heritability at 5 months for both pupil size (h2 = .64) and constriction in response to light (h2 = .62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (rG = .38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (ß = .15, p = .024), while there was no significant association with the GPS for autism or any other GPSs. CONCLUSIONS: This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life.

A differential of the left eye and right eye neurological pupil index is associated with discharge modified Rankin scores in neurologically injured patients.

BACKGROUND: Automated infrared pupillometry (AIP) and the Neurological Pupil index (NPi) provide an objective means of assessing and trending the pupillary light reflex (PLR) across a broad spectrum of neurological diseases. NPi quantifies the PLR and ranges from 0 to 5; in healthy individuals, the NPi of both eyes is expected to be ≥ 3.0 and symmetric. AIP values demonstrate emerging value as a prognostic tool with predictive properties that could allow practitioners to anticipate neurological deterioration and recovery. The presence of an NPi differential (a difference ≥ 0.7 between the left and right eye) is a potential sign of neurological abnormality. METHODS: We explored NPi differential by considering the modified Rankin Score at discharge (DC mRS) among patients admitted to neuroscience intensive care units (NSICU) of 4 U.S. and 1 Japanese hospitals and for two cohorts of brain injuries: stroke (including subarachnoid hemorrhage, intracerebral hemorrhage, acute ischemic stroke, and aneurysm, 1,200 total patients) and 185 traumatic brain injury (TBI) patients for a total of more than 54,000 pupillary measurements. RESULTS: Stroke patients with at least 1 occurrence of an NPi differential during their NSICU stay have higher DC mRS scores (3.9) compared to those without an NPi differential (2.7; P < .001). Patients with TBI and at least 1 occurrence of an NPi differential during their NSICU stay have higher discharge modified Rankin Scale scores (4.1) compared to those without an NPi differential (2.9; P < .001). When patients experience both abnormalities, abnormal (NPi < 3.0) and an NPi differential, the latter has an anticipatory relationship with respect to the former (P < .001 for z-score skewness analysis). Finally, our analysis confirmed ≥ 0.7 as the optimal cutoff value for the NPi differential (AUC = 0.71, P < .001). CONCLUSION: The NPi differential is an important factor that clinicians should consider when managing critically ill neurological injured patients admitted to the neurocritical care units. TRIAL REGISTRATION: NCT02804438 , Date of Registration: June 17, 2016.

Pupillary responses to differences in luminance, color and set size.

The pupil responds to a salient stimulus appearing in the environment, in addition to its modulation by global luminance. These pupillary responses can be evoked by visual or auditory stimuli, scaled with stimulus salience, and enhanced by multisensory presentation. In addition, pupil size is modulated by various visual stimulus attributes, such as color, area, and motion. However, research that concurrently examines the influence of different factors on pupillary responses is limited. To explore how presentation of multiple visual stimuli influences human pupillary responses, we presented arrays of visual stimuli and systematically varied their luminance, color, and set size. Saliency level, computed by the saliency model, systematically changed with set size across all conditions, with higher saliency levels in larger set sizes. Pupillary constriction responses were evoked by the appearance of visual stimuli, with larger pupillary responses observed in larger set size. These effects were pronounced even though the global luminance level was unchanged using isoluminant chromatic stimuli. Furthermore, larger pupillary constriction responses were obtained in the blue, compared to other color conditions. Together, we argue that both cortical and subcortical areas contribute to the observed pupillary constriction modulated by set size and color.

Development of Autonomic Nervous System Assays as Point-of-Care Tests to Supplement Clinical Judgment in Risk Assessment for Suicidal Behavior: A Review.

PURPOSE OF REVIEW: A biomarker point-of-care (POC) test that supplements the psychiatric interview and improves detection of patients at risk for suicide would be of value, and assays of autonomic nervous system (ANS) activity would satisfy the logistical requirements for a POC test. We performed a selective review of the available literature of ANS assays related to risk for suicide. RECENT FINDINGS: We searched PubMed and Web of Science with the strategy: "suicide OR suicidal" AND "electrodermal OR heart rate variability OR pupillometry OR pupillography." The search produced 119 items, 21 of which provided original data regarding ANS methods and suicide. These 21 studies included 6 for electrodermal activity, 14 for heart rate variability, and 1 for the pupillary light reflex. The 21 papers showed associations between ANS assays and suicide risk in a direction suggesting underlying hyperarousal in patients at risk for suicide. ANS assays show promise for future development as POC tests to supplement clinical decision making in estimating risk for suicide.

Early quantitative infrared pupillometry for prediction of neurological outcome in patients admitted to intensive care after out-of-hospital cardiac arrest.

BACKGROUND: Quantitative pupillometry is recommended for neuroprognostication after out-of-hospital cardiac arrest 72 h or more after ICU admission, but the feasibility and utility of earlier assessment is unknown. METHODS: This was a study of the utility of an early quantitative pupillometry index in predicting neurological outcome in patients with reduced consciousness after out-of-hospital cardiac arrest. Quantitative infrared pupillometry index was measured at 0, 6, 24, 48, and 72 h from admission. Acceptable predictive utility was defined as a positive predictive value of >95% and false positive rate of zero, with a narrow 95% confidence interval (95% CI). RESULTS: At least one quantitative pupillometry index measurement was available from within the first 6 h for all 77 patients who met inclusion criteria. A quantitative pupillometry index ≤2.4 at baseline and ≤2.3 within the first 6 h met the criteria for utility. The positive predictive value of the baseline cut-off (≤2.4) for poor neurological outcome was 1.00 (95% CI, 0.54-1.00) with an estimated false positive rate of 0% (95% CI, 0-9%). The positive predictive value of the 6 h cut-off (≤2.3) for poor neurological outcome was 1.00 (95% CI, 0.59-1.00) with an estimated false positive rate of 0% (95% CI, 0-8%). Sensitivities of these cut-offs for ruling out poor neurological outcomes at 0 and 6 h were 19% and 22%, respectively. Of seven patients with a quantitative pupillometry index ≤2.3 within 6 h of ICU admission, none survived. Analyses that used quantitative pupillometry index measurements from 24 to 72 h, but excluded baseline and 6 h values, were not predictive by the utility criteria. CONCLUSIONS: Quantitative pupillometry within 6 h of ICU admission after out-of-hospital cardiac arrest may identify patients with a very low chance of neurologically intact survival. Further studies of early quantitative pupillometry in this population are warranted.

Sensitivity and specificity of pupillary light reflex measures for ASD using monocular pupillometry.

INTRODUCTION: Automated hand-held pupillometry demonstrates precision accuracy, offering promise for augmenting ASD screening. METHODS: Monocular pupillometry was examined in children and adolescents (36 ASD; 24 TD). Multiple logistic regression and receiver operating characteristic analysis assessed PLR metrics and diagnostic status. RESULTS: Constriction time (Ct1) (ASD: M = 0.69, SD = 0.21; TD: M = 0.82, SD = 0.18; t(58 = 2.37; p = 0.02) and return to baseline (RTB T75) (ASD: M = 2.93, SD = 1.21; TD: M = 2.32, SD = 1.08; t(58) = - 2.03; p = 0.04) predicted ASD (ß = - 1.31, OR = 0.27; RTB T75, ß = 0.156, OR = 1.162). Sensitivity = 74.8%, when RTB ≥ 1.83 s and 69.4% when Ct1 = 0.785 s. CONCLUSION: Findings suggest monocular pupillometry captures differences detecting ASD.