Evaluation of the Video Ocular Counter-Roll (vOCR) as a New Clinical Test of Otolith Function in Peripheral Vestibulopathy.

Importance: Video-oculography (VOG) goggles have been integrated into the assessment of semicircular canal function in patients with vestibular disorders. However, a similar bedside VOG method for testing otolith function is lacking. Objective: To evaluate the use of VOG-based measurement of ocular counter-roll (vOCR) as a clinical test of otolith function. Design, Setting, and Participants: A case-control study was conducted to compare vOCR measurement among patients at various stages of unilateral loss of vestibular function with healthy controls. The receiver operating characteristic curve method was used to determine the diagnostic accuracy of the vOCR test in detecting loss of otolith function. Participants were recruited at a tertiary center including the Johns Hopkins outpatient clinic and Johns Hopkins Hospital, Baltimore, Maryland. Participants included 56 individuals with acute (≤4 weeks after surgery), subacute (4 weeks-6 months after surgery), and chronic (>6 months after surgery) unilateral vestibular loss as well as healthy controls. A simple bedside maneuver with en bloc, 30° lateral tilt of the head and trunk was used for vOCR measurement. The study was conducted from February 2, 2017, to March 10, 2019. Intervention: In each participant vOCR was measured during static tilts of the head and trunk en bloc. Main Outcomes and Measures: The vOCR measurements and diagnostic accuracy of vOCR in detecting patients with loss of vestibular function from healthy controls. Results: Of the 56 participants, 28 (50.0%) were men; mean (SD) age was 53.5 (11.4) years. The mean (SD) time of acute unilateral vestibular loss was 9 (7) days (range, 2-17 days) in the acute group, 61 (39) days (range, 28-172 days) in the subacute group, and 985 (1066) days (range 185-4200 days) in the chronic group. The vOCR test showed reduction on the side of vestibular loss, and the deficit was greater in patients with acute and subacute vestibular loss than in patients with chronic loss and healthy controls (acute vs chronic: -1.81°; 95% CI, -3.45° to -0.17°; acute vs control: -3.18°; 95% CI, -4.83° to -1.54°; subacute vs chronic: -0.63°; 95% CI, -2.28° to 1.01°; subacute vs control: -2.01°; 95% CI, -3.65° to -0.36°; acute vs subacute: -1.17°; 95% CI, -2.88° to 0.52°; and chronic vs control: -1.37°; 95% CI, -2.96° to 0.21°). The asymmetry in vOCR between the side of vestibular loss and healthy side was significantly higher in patients with acute vs chronic loss (0.28; 95% CI, 0.06-0.51). Overall, the performance of the vOCR test in discriminating between patients with vestibular loss and healthy controls was 0.83 (area under the receiver operating characteristic curve). The best vOCR threshold to detect vestibular loss at the 30° tilt was 4.5°, with a sensitivity of 80% (95% CI, 0.62%-0.88%) and specificity of 82% (95% CI, 0.57%-1.00%). Conclusions and Relevance: The findings of this case-control study suggest that the vOCR test can be performed with a simple bedside maneuver and may be used to detect or track loss of otolith function.

Torsional component of microsaccades during fixation and quick phases during optokinetic stimulation.

While many studies have characterized the eye movements during visual fixation, includ-ing microsaccades, in most cases only horizontal and vertical components have been rec-orded and analyzed. Thus, little is known about the torsional component of microsaccades. We took advantage of a newly developed software and hardware to record eye movements around the three axes of rotation during fixation and torsional optokinetic stimulus. We found that the average amplitude of the torsional component of microsaccades during fixation was 0.34 ± 0.07 degrees with velocities following a main sequence with a slope comparable to the horizontal and vertical components. We also found the size of the tor-sional displacement during microsaccades was correlated with the horizontal but not the vertical component. In the presence of an optokinetic stimulus a nystagmus was induced producing a more frequent and larger torsional quick phases compared to microsaccades produced during fixation with a stationary stimulus. The torsional component and the vertical vergence component of quick phases grew larger with higher velocities. Addition-ally, our results validate and show the feasibility of recording torsional eye movements using video eye tracking in a desktop mounted setup.

Optogenetically transduced human ES cell-derived neural progenitors and their neuronal progenies: Phenotypic characterization and responses to optical stimulation.

Optogenetically engineered human neural progenitors (hNPs) are viewed as promising tools in regenerative neuroscience because they allow the testing of the ability of hNPs to integrate within nervous system of an appropriate host not only structurally, but also functionally based on the responses of their differentiated progenies to light. Here, we transduced H9 embryonic stem cell-derived hNPs with a lentivirus harboring human channelrhodopsin (hChR2) and differentiated them into a forebrain lineage. We extensively characterized the fate and optogenetic functionality of hChR2-hNPs in vitro with electrophysiology and immunocytochemistry. We also explored whether the in vivo phenotype of ChR2-hNPs conforms to in vitro observations by grafting them into the frontal neocortex of rodents and analyzing their survival and neuronal differentiation. Human ChR2-hNPs acquired neuronal phenotypes (TUJ1, MAP2, SMI-312, and synapsin 1 immunoreactivity) in vitro after an average of 70 days of coculturing with CD1 astrocytes and progressively displayed both inhibitory and excitatory neurotransmitter signatures by immunocytochemistry and whole-cell patch clamp recording. Three months after transplantation into motor cortex of naïve or injured mice, 60-70% of hChR2-hNPs at the transplantation site expressed TUJ1 and had neuronal cytologies, whereas 60% of cells also expressed ChR2. Transplant-derived neurons extended axons through major commissural and descending tracts and issued synaptophysin+ terminals in the claustrum, endopiriform area, and corresponding insular and piriform cortices. There was no apparent difference in engraftment, differentiation, or connectivity patterns between injured and sham subjects. Same trends were observed in a second rodent host, i.e. rat, where we employed longer survival times and found that the majority of grafted hChR2-hNPs differentiated into GABAergic neurons that established dense terminal fields and innervated mostly dendritic profiles in host cortical neurons. In physiological experiments, human ChR2+ neurons in culture generated spontaneous action potentials (APs) 100-170 days into differentiation and their firing activity was consistently driven by optical stimulation. Stimulation generated glutamatergic and GABAergic postsynaptic activity in neighboring ChR2- cells, evidence that hChR2-hNP-derived neurons had established functional synaptic connections with other neurons in culture. Light stimulation of hChR2-hNP transplants in vivo generated complicated results, in part because of the variable response of the transplants themselves. Our findings show that we can successfully derive hNPs with optogenetic properties that are fully transferrable to their differentiated neuronal progenies. We also show that these progenies have substantial neurotransmitter plasticity in vitro, whereas in vivo they mostly differentiate into inhibitory GABAergic neurons. Furthermore, neurons derived from hNPs have the capacity of establishing functional synapses with postsynaptic neurons in vitro, but this outcome is technically challenging to explore in vivo. We propose that optogenetically endowed hNPs hold great promise as tools to explore de novo circuit formation in the brain and, in the future, perhaps launch a new generation of neuromodulatory therapies.

No handedness effect on spatial orientation or ocular counter-roll during lateral head tilts.

Although vestibular inputs are bilaterally represented within the cerebral hemispheres, the higher level vestibular functions exhibit hemispheric asymmetries. Previous studies have suggested that such asymmetries are associated with handedness. Here, we studied the impact of handedness (i.e., hemispheric lateralization) on spatial orientation using a subjective visual vertical (SVV) task. We tested 22 right-handed and 22 left-handed subjects in upright position, during prolonged lateral head tilts of 20° (~15 min), and after the head returned to upright position. The corresponding changes in torsional eye position were measured simultaneously using video-oculography. During lateral head tilts, both right- and left-handers had initial SVV biases in the opposite direction of the head tilt (right-handers: left tilt 3.0 ± 1.3°, right tilt -4.7 ± 1.5°; left-handers: left tilt 3.4 ± 1.1°, right tilt -4.1 ± 1.0°). The SVV subsequently drifted in the direction of the head tilt, and there was an aftereffect in the same direction when the head was brought back upright. The ocular torsion initially changed in the opposite direction of the head tilt (right-handers: left tilt 3.8 ± 0.4°, right tilt -3.8 ± 0.4°; left-handers: left tilt 4.2 ± 0.5°, right tilt -4.5 ± 0.5°), and there were also drift and aftereffect in the same direction as the head tilt. The changes in upright perception and ocular torsion did not differ between right- and left-handers. These findings show no functional laterality, neither in the higher level neural mechanisms that maintain spatial orientation, nor in the lower level mechanisms that generate the ocular torsion response during lateral head tilt.

Clinical applications of control systems models: The neural integrators for eye movements.

The first models that were proposed to account for the neural control of eye movements applied a classic control systems approach, including feedback, and measured system responses to sinusoidal and transient stimuli. Although such models provided many insights, their limitations were quickly recognized, such as their inability to account for anticipatory responses. Another question was whether models with lumped transfer functions could usefully represent a population of neurons, in which individual units were shown to encode a spectrum of different signals, including resting discharge rates and noise. Recent trends have been towards neural network models and Bayesian operators, which account for observed properties such as the variability of responses and predictive behavior, but often puzzle clinicians by their complexity and non-intuitive operations. We propose that, since all models are incomplete, it makes sense to select the simplest model that can address the topic of interest. We examine two aspects of abnormal ocular motor control, affecting the common integrator for eye movements, and the vestibular velocity storage mechanism. In both cases, we show how classic control systems provided substantial insights into clinical disorders-such as gaze-evoked nystagmus and periodic alternating nystagmus-as well as suggesting new questions, experiments, and potential treatments.

Errors of Upright Perception in Patients With Vestibular Migraine.

Patients with vestibular migraine (VM) often report dizziness with changes in the head or body position. Such symptoms raise the possibility of dysfunction in neural mechanisms underlying spatial orientation in these patients. Here we addressed this issue by investigating the effect of static head tilts on errors of upright perception in a group of 27 VM patients in comparison with a group of 27 healthy controls. Perception of upright was measured in a dark room using a subjective visual vertical (SVV) paradigm at three head tilt positions (upright, ±20°). VM patients were also surveyed about the quality of their dizziness and spatial symptoms during daily activities. In the upright head position, SVV errors were within the normal range for VM patients and healthy controls (within 2° from true vertical). During the static head tilts of 20° to the right, VM patients showed larger SVV errors consistent with overestimation of the tilt magnitude (i.e., as if they felt further tilted toward the right side) (VM: -3.21° ± 0.93 vs. Control: 0.52° ± 0.70; p = 0.002). During the head tilt to the left, SVV errors in VM patients did not differ significantly from controls (VM: 0.77° ± 1.05 vs. Control: -0.04° ± 0.68; p = 0.52). There was no significant difference in SVV precision between the VM patients and healthy controls at any head tilt position. Consistent with the direction of the SVV errors in VM patients, they largely reported spatial symptoms toward the right side. These findings suggest an abnormal sensory integration for spatial orientation in vestibular migraine, related to daily dizziness in these patients.

Irritable Bowel Syndrome in Iran: SEPAHAN Systematic Review No. 1.

OBJECTIVES: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Due to its high prevalence and absence of curative therapy, IBS has the potential to create tremendous burden on the health care system. Herein, we systematically reviewed the published literature to investigate the epidemiology of IBS in Iran. METHODS: Studies that were reviewed in this article were primarily identified through four online bibliographic databases including PubMed, Google Scholar, Iran Medex, and Scientific Information Database. Manual search of reference lists was carried out to identify any additional studies such as relevant abstracts and also recent review articles which may have been missed. Potentially related studies were retrieved and the selection criteria were applied. Eligible articles were reviewed. RESULTS: From 4176 studies identified, 18 eligible studies were included. It was reported that in Iran, the prevalence of IBS was in the range of 1.1% to 25% and was more common in women. In addition, the difference in frequency of different age groups was minimal. There was a minimal difference in IBS prevalence within different age groups. CONCLUSIONS: In Iran, the incidence of IBS was in the wide range. Since there are not enough population-based studies, researchers should focus on developing well-designed population-based studies to determine the epidemiology of IBS in Iran. Moreover, cohort studies should be conducted in order to investigate the natural history of IBS. Investigating the etiology of IBS and attempt to organize health promotion programs are highly suggested.

Bloating in Iran: SEPAHAN Systematic Review No. 4.

OBJECTIVES: Bloating is a common and bothersome gastrointestinal symptom. Despite its high prevalence, associated costs, and effects on the quality of life, very few studies have reported the epidemiology of bloating in Iran. Through this systematic review, findings and limitations of the current research will be discussed. METHODS: In March 2012, we searched PubMed, Google Scholar, Scientific Information Database, IranMedex, and Magiran to find articles for inclusion in the study. Two of the authors screened the articles on the basis of titles and abstracts. The full manuscripts of these publications were then evaluated according to the predefined criteria. RESULTS: Fifteen articles were included in the study, and data regarding the prevalence of bloating were extracted. The studies depict a prevalence of 1.5% to 8.8% for bloating in the Iranian population. Two studies reported the prevalence of functional bloating to be 1.5% and 10% according to the Rome III and Rome II criteria, respectively. Female to male ratio remains ≥1 for most of the studies criteria. CONCLUSIONS: In Iran, data on the prevalence of bloating are limited, and have mostly been gathered from a highly selective population. The results of the present study advocate the necessity to perform further studies on the general population, which may help health policy makers in the allocation of the appropriate resources.

Constipation in Iran: SEPAHAN Systematic Review No. 5.

BACKGROUND: Constipation is physically and mentally troublesome for many patients and has adverse effects on their quality of life. The aim of the present study was to systematically review previous studies on the epidemiology of constipation in Iran. METHODS: Bibliographic databases including PubMed, Google Scholar, and Iranian databases including Scientific Information Database, Iran Medex, and Magiran were searched to select studies that reported the prevalence of constipation in Iran. RESULTS: Overall, 10 articles met the inclusion criteria of the current study. The prevalence of constipation in Iran ranged from 1.4-37%, and the prevalence of functional constipation was reported to be 2.4-11.2%. Gender, age, socioeconomic status and educational level seem to have major effects on this condition. CONCLUSION: The prevalence of constipation is high in Iran. There are very few data available regarding the natural history, quality of life and risk factors of constipation in our country. Conducting population-based studies is necessary to explore different epidemiological aspects of constipation in Iran.

Edentulism and Tooth Loss in Iran: SEPAHAN Systematic Review No. 6.

OBJECTIVES: Tooth loss appears to have an important role in the loss of mastication and esthetics. The aim of this systematic review was to investigate the prevalence of tooth loss and edentulism in the Iranian population. METHODS: Studies reviewed in this article were primarily identified via search of the online bibliographic databases including PubMed and Iranian Biomedical Journals, by using "tooth loss", "edentulism", "epidemiology", and "Iran" as keywords. Studies potentially related to this topic were retrieved and the selection criteria applied. From the chosen studies the eligible articles were reviewed. RESULTS: Of the studies identified after conducting the search, 10 eligible studies were extracted. The prevalence of tooth loss ranges between 0.3% in 3 to 5-year-old children to 70.7% in adults over 65. There is a lack of well-designed epidemiological studies on edentulism and tooth loss in Iran. The prevalence of tooth loss is high and it increases by aging. CONCLUSIONS: It seems that the prevalence of tooth loss is high among adults in Iran. It is highly suggested that population-based studies should be established to investigate the epidemiology and risk factors of tooth loss in Iran. The results of such studies will be useful in the adoption of appropriate preventive strategies.