Linear and Nonlinear Behaviors of the Photoreceptor Coupled Network.

Photoreceptors are electrically coupled to one another, and the spatiotemporal properties of electrical synapses in a two-dimensional retinal network are still not well studied, because of the limitation of the single electrode or pair recording techniques which do not allow simultaneously measuring responses of multiple photoreceptors at various locations in the retina. A multiple electrode recording system is needed. In this study, we investigate the network properties of the two-dimensional rod coupled array of the salamander retina (both sexes were used) by using the newly available multiple patch electrode system that allows simultaneous recordings from up to eight cells and to determine the electrical connectivity among multiple rods. We found direct evidence that voltage signal spread in the rod-rod coupling network in the absence of I h (mediated by HCN channels) is passive and follows the linear cable equation. Under physiological conditions, I h shapes the network signal by progressively shortening the response time-to-peak of distant rods, compensating the time loss of signal traveling from distant rods to bipolar cell somas and facilitating synchronization of rod output signals. Under voltage-clamp conditions, current flow within the coupled rods follows Ohm's law, supporting the idea that nonlinear behaviors of the rod network are dependent on membrane voltage. Rod-rod coupling is largely symmetrical in the 2D array, and voltage-clamp blocking the next neighboring rod largely suppresses rod signal spread into the second neighboring rod, suggesting that indirect coupling pathways play a minor role in rod-rod coupling.

The Lipid Intensive Drug Therapy for Sepsis Phase II Pilot Clinical Trial.

OBJECTIVES: Low cholesterol levels in early sepsis patients are associated with mortality. We sought to test if IV lipid emulsion administration to sepsis patients with low cholesterol levels would prevent a decline or increase total cholesterol levels at 48 hours. DESIGN: Phase II, adaptive, randomized pilot clinical trial powered for 48 patients. SETTING: Emergency department or ICU of an academic medical center. PATIENTS: Sepsis patients (first 24 hr) with Sequential Organ Failure Assessment greater than or equal to 4 or shock. INTERVENTIONS: Patients meeting study criteria, including screening total cholesterol levels less than or equal to 100 mg/dL or high-density lipoprotein cholesterol (HDL-C) + low-density lipoprotein cholesterol (LDL-C) less than or equal to 70 mg/dL, were randomized to receive one of three doses of lipid emulsion administered twice in 48 hours or no drug (controls). The primary endpoint was a change in serum total cholesterol (48 hr - enrollment) between groups. MEASUREMENTS AND MAIN RESULTS: Forty-nine patients were enrolled and randomized. Two patients randomized to lipid emulsion were withdrawn before drug administration. Data for 24 control patients and 23 lipid emulsion patients were analyzed. The mean change in total cholesterol from enrollment to 48 hours was not different between groups and was 5 mg/dL ( sd 20) for lipid emulsion patients, and 2 mg/dL ( sd 18) for control patients ( p = 0.62). The mean changes in HDL-C and LDL-C were similar between groups. Mean change in triglycerides was elevated in lipid emulsion patients (61 mg/dL, sd 87) compared with controls (20 mg/dL, sd 70, p = 0.086). The 48-hour change in SOFA score was -2 (interquartile range [IQR] -4, -1) for control patients and -2 (IQR -3, 0) for lipid emulsion patients ( p = 0.46). CONCLUSIONS: Administration of IV lipid emulsion to early sepsis patients with low cholesterol levels did not influence change in cholesterol levels from enrollment to 48 hours.

Comparison of Pocock and Simon's covariate-adaptive randomization procedures in clinical trials.

When multiple influential covariates need to be balanced during a clinical trial, stratified blocked randomization and covariate-adaptive randomization procedures are frequently used in trials to prevent bias and enhance the validity of data analysis results. The latter approach is increasingly used in practice for a study with multiple covariates and limited sample sizes. Among a group of these approaches, the covariate-adaptive procedures proposed by Pocock and Simon are straightforward to be utilized in practice. We aim to investigate the optimal design parameters for the patient treatment assignment probability of their developed three methods. In addition, we seek to answer the question related to the randomization performance when additional covariates are added to the existing randomization procedure. We conducted extensive simulation studies to address these practically important questions.

Learning from vertically distributed data across multiple sites: An efficient privacy-preserving algorithm for Cox proportional hazards model with variable selection.

OBJECTIVE: To develop a lossless distributed algorithm for regularized Cox proportional hazards model with variable selection to support federated learning for vertically distributed data. METHODS: We propose a novel distributed algorithm for fitting regularized Cox proportional hazards model when data sharing among different data providers is restricted. Based on cyclical coordinate descent, the proposed algorithm computes intermediary statistics by each site and then exchanges them to update the model parameters in other sites without accessing individual patient-level data. We evaluate the performance of the proposed algorithm with (1) a simulation study and (2) a real-world data analysis predicting the risk of Alzheimer's dementia from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Moreover, we compared the performance of our method with existing privacy-preserving models. RESULTS: Our algorithm achieves privacy-preserving variable selection for time-to-event data in the vertically distributed setting, without degradation of accuracy compared with a centralized approach. Simulation demonstrates that our algorithm is highly efficient in analyzing high-dimensional datasets. Real-world data analysis reveals that our distributed Cox model yields higher accuracy in predicting the risk of Alzheimer's dementia than the conventional Cox model built by each data provider without data sharing. Moreover, our algorithm is computationally more efficient compared with existing privacy-preserving Cox models with or without regularization term. CONCLUSION: The proposed algorithm is lossless, privacy-preserving and highly efficient to fit regularized Cox model for vertically distributed data. It provides a suitable and convenient approach for modeling time-to-event data in a distributed manner.

Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism.

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared with controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANCE STATEMENT Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential "hypo-priors" theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.

Functional Neural Correlates of a Useful Field of View (UFOV)-Based fMRI Task in Older Adults.

Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. Despite its efficacy, little is known about the neural correlates of this task. Within the current study, 233 healthy older adults completed a UFOV-based task while undergoing functional magnetic resonance imaging (fMRI). During the "stimulus" portion of this task, participants must identify a target in the center of the screen and the location of a target in the periphery, among distractors. During the "probe" portion, participants must decide if the object in the center and the location of the target in the periphery were identical to the "stimulus" screen. Widespread bilateral whole-brain activation was observed when activation patterns of the "probe" contrast were subtracted from the "stimulus" contrast. Conversely, the subtraction of "stimulus" from "probe" was associated with discrete activation patterns consisting of 13 clusters. Additionally, when evaluating the variance associated with task accuracy, specific subregions were identified that may be critical for task performance. Our data elucidate the functional neural correlates of a UFOV-based task, a task used in both cognitive training paradigms and assessment of function.

Trends in Residency Academic Productivity of Ophthalmic Plastic and Reconstructive Surgery Fellows Between 2012 and 2019.

PURPOSE: To characterize research productivity of ophthalmic plastic and reconstructive surgery (OPRS) fellows during residency. METHODS: A database was compiled of OPRS fellows listed on the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) Annual Fall Scientific Symposium program books who began their fellowship between 2012 and 2019. PubMed was searched for all publications published between July 1st of the year they began residency and September 30th of the year they began fellowship training. Bibliometric variables captured for each fellow included: the number of publications, first-author publications, and ophthalmology-related publications. RESULTS: A total of 197 OPRS fellows who began their fellowship training between 2012 and 2019 published a mean (± SD) of 2.42 ± 2.80 publications, 1.43 ± 1.85 first-author publications, and 2.33 ± 2.74 ophthalmology-related publications during residency. Linear regression revealed that the number of publications ( P < 0.001), first-author publications ( P < 0.001), and ophthalmology-related publications ( P < 0.001) that OPRS fellows published during residency have all significantly increased over the time assessed. CONCLUSIONS: The academic productivity of OPRS fellows during residency was quantified through bibliometric analysis to establish a national benchmark for the benefit of both prospective applicants and program directors. Residency research output of OPRS fellows has significantly increased between 2012 and 2019. Since ASOPRS program requirements necessitate academic productivity and thesis completion, publication records and involvement in research become valuable considerations when evaluating fellowship applicants. The knowledge of what accepted fellows have published provides the opportunity to make historical comparisons and may prove useful in the evaluation of the competitiveness of a given year's applicant pool.

Effects of Prefrontal Transcranial Direct Current Stimulation on Retention of Performance Gains on an Obstacle Negotiation Task in Older Adults.

OBJECTIVES: Complex walking in older adults can be improved with task practice and might be further enhanced by pairing transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex. We tested the hypothesis that a single session of practice of a complex obstacle negotiation task paired with active tDCS in older adults would produce greater within-session improvements in walking performance and retention of gains, compared to sham tDCS and no tDCS conditions. MATERIALS AND METHODS: A total of 50 older adults (mean age = 74.46 years ± 6.49) with self-reported walking difficulty were randomized to receive either active tDCS (active-tDCS group) or sham tDCS (sham-tDCS group) bilaterally to the dorsolateral prefrontal cortex or no tDCS (no-tDCS group). Each group performed ten practice trials of an obstacle negotiation task at their fastest safe speed. Retention of gains in walking performance was assessed with three trials conducted one week later. Within-session effects of practice and between-session retention effects on obstacle negotiation speed were examined. RESULTS: At the practice session, all three groups exhibited significant within-session gains in walking speed (p ≤ 0.005). However, the gains were significantly greater in the sham-tDCS group than in the active-tDCS and no-tDCS groups (p ≤ 0.03) and were comparable between the active-tDCS and no-tDCS groups (p = 0.89). At one-week follow-up, the active-tDCS group exhibited significant between-session retention of gains and continued "offline" improvement in walking speed (p = 0.005). The active-tDCS group showed significantly greater retention of gains than the no-tDCS (p = 0.02) but not the sham-tDCS group (p = 0.24). CONCLUSIONS: Pairing prefrontal active tDCS with a single session of obstacle negotiation practice may enhance one-week retention of gains in walking performance compared to no tDCS. However, the evidence is insufficient to suggest a benefit of active tDCS over sham tDCS for enhancing the gains in walking performance. Additional studies with a multisession intervention design and larger sample size are needed to further investigate these findings. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03122236.

Nr2f1 heterozygous knockout mice recapitulate neurological phenotypes of Bosch-Boonstra-Schaaf optic atrophy syndrome and show impaired hippocampal synaptic plasticity.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein's role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model and found that this model recapitulates some of the neurological phenotypes of BBSOAS, including altered learning/memory, hearing defects, neonatal hypotonia and decreased hippocampal volume. The mice showed altered fear memory, and further electrophysiological investigation in hippocampal slices revealed significantly reduced long-term potentiation and long-term depression. These results suggest that a deficit or alteration in hippocampal synaptic plasticity may contribute to the intellectual disability frequently seen in BBSOAS. RNA-sequencing (RNA-Seq) analysis revealed significant differential gene expression in the adult Nr2f1+/- hippocampus, including the up-regulation of multiple matrix metalloproteases, which are known to be critical for the development and the plasticity of the nervous system. Taken together, our studies highlight the important role of Nr2f1 in neurodevelopment. The discovery of impaired hippocampal synaptic plasticity in the heterozygous mouse model sheds light on the pathophysiology of altered memory and cognitive function in BBSOAS.

Diffusion Magnetic Resonance Imaging Detects Progression in Parkinson's Disease: A Placebo-Controlled Trial of Rasagiline.

BACKGROUND: Rasagiline has received attention as a potential disease-modifying therapy for Parkinson's disease (PD). Whether rasagiline is disease modifying remains in question. OBJECTIVE: The main objective of this study was to determine whether rasagiline has disease-modifying effects in PD over 1 year. Secondarily we evaluated two diffusion magnetic resonance imaging pulse sequences to determine the best sequence to measure disease progression. METHODS: This prospective, randomized, double-blind, placebo-controlled trial assessed the effects of rasagiline administered at 1 mg/day over 12 months in early-stage PD. The primary outcome was 1-year change in free-water accumulation in posterior substantia nigra (pSN) measured using two diffusion magnetic resonance imaging pulse sequences, one with a repetition time (TR) of 2500 ms (short TR; n = 90) and one with a TR of 6400 ms (long TR; n = 75). Secondary clinical outcomes also were assessed. RESULTS: Absolute change in pSN free-water accumulation was not significantly different between groups (short TR: P = 0.346; long TR: P = 0.228). No significant differences were found in any secondary clinical outcomes between groups. Long TR, but not short TR, data show pSN free-water increased significantly over 1 year (P = 0.025). Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III increased significantly over 1 year (P = 0.009), and baseline free-water in the pSN correlated with the 1-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III (P = 0.004) and 1-year change in bradykinesia score (P = 0.044). CONCLUSIONS: We found no evidence that 1 mg/day rasagiline has a disease-modifying effect in PD over 1 year. We found pSN free-water increased over 1 year, and baseline free-water relates to clinical motor progression, demonstrating the importance of diffusion imaging parameters for detecting and predicting PD progression. © 2021 International Parkinson and Movement Disorder Society.

Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults.

Age-related differences in dorsolateral prefrontal cortex (DLPFC) structure and function have each been linked to working memory. However, few studies have integrated multimodal imaging to simultaneously investigate relationships among structure, function, and cognition. We aimed to clarify how specifically DLPFC structure and function contribute to working memory in healthy older adults. In total, 138 participants aged 65-88 underwent 3 T neuroimaging and were divided into higher and lower groups based on a median split of in-scanner n-back task performance. Three a priori spherical DLPFC regions of interest (ROIs) were used to quantify blood-oxygen-level-dependent (BOLD) signal and FreeSurfer-derived surface area, cortical thickness, and white matter volume. Binary logistic regressions adjusting for age, sex, education, and scanner type revealed that greater left and right DLPFC BOLD signal predicted the probability of higher performing group membership (P values<.05). Binary logistic regressions also adjusting for total intracranial volume revealed left DLPFC surface area that significantly predicted the probability of being in the higher performing group (P = 0.017). The left DLPFC BOLD signal and surface area were not significantly associated and did not significantly interact to predict group membership (P values>.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.

Rehabilitation with accurate adaptability walking tasks or steady state walking: A randomized clinical trial in adults post-stroke.

OBJECTIVE: To assess changes in walking function and walking-related prefrontal cortical activity following two post-stroke rehabilitation interventions: an accurate adaptability (ACC) walking intervention and a steady state (SS) walking intervention. DESIGN: Randomized, single blind, parallel group clinical trial. SETTING: Hospital research setting. SUBJECTS: Adults with chronic post-stroke hemiparesis and walking deficits. INTERVENTIONS: ACC emphasized stepping accuracy and walking adaptability, while SS emphasized steady state, symmetrical stepping. Both included 36 sessions led by a licensed physical therapist. ACC walking tasks recruit cortical regions that increase corticospinal tract activation, while SS walking activates the corticospinal tract less intensely. MAIN MEASURES: The primary functional outcome measure was preferred steady state walking speed. Prefrontal brain activity during walking was measured with functional near infrared spectroscopy to assess executive control demands. Assessments were conducted at baseline, post-intervention (three months), and follow-up (six months). RESULTS: Thirty-eight participants were randomized to the study interventions (mean age 59.6 ± 9.1 years; mean months post-stroke 18.0 ± 10.5). Preferred walking speed increased from baseline to post-intervention by 0.13 ± 0.11 m/s in the ACC group and by 0.14 ± 0.13 m/s in the SS group. The Time × Group interaction was not statistically significant (P = 0.86). Prefrontal fNIRS during walking decreased from baseline to post-intervention, with a marginally larger effect in the ACC group (P = 0.05). CONCLUSIONS: The ACC and SS interventions produced similar changes in walking function. fNIRS suggested a potential benefit of ACC training for reducing demand on prefrontal (executive) resources during walking.

Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation.

STUDY DESIGN: This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation. OBJECTIVES: 1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation. MATERIALS AND METHODS: Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury. CONCLUSIONS: Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as "placebo" require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.

Combining Frontal Transcranial Direct Current Stimulation With Walking Rehabilitation to Enhance Mobility and Executive Function: A Pilot Clinical Trial.

OBJECTIVES: This pilot study assessed whether frontal lobe transcranial direct current stimulation (tDCS) combined with complex walking rehabilitation is feasible, safe, and shows preliminary efficacy for improving walking and executive function. MATERIALS AND METHODS: Participants were randomized to one of the following 18-session interventions: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Active tDCS was delivered over F3 (cathode) and F4 (anode) scalp locations for 20 min at 2 mA intensity. Outcome measures included tests of walking function, executive function, and prefrontal activity measured by functional near infrared spectroscopy. RESULTS: Ninety percent of participants completed the intervention protocol successfully. tDCS side effects of tingling or burning sensations were low (average rating less than two out of 10). All groups demonstrated gains in walking performance based on within-group effect sizes (d ≥ 0.50) for one or more assessments. The Sham/Typical group showed the greatest gains for walking based on between-group effect sizes. For executive function, the Active/Complex group showed the greatest gains based on moderate to large between-group effect sizes (d = 0.52-1.11). Functional near-infrared spectroscopy (fNIRS) findings suggest improved prefrontal cortical activity during walking. CONCLUSIONS: Eighteen sessions of walking rehabilitation combined with tDCS is a feasible and safe intervention for older adults. Preliminary effects size data indicate a potential improvement in executive function by adding frontal tDCS to walking rehabilitation. This study justifies future larger clinical trials to better understand the benefits of combining tDCS with walking rehabilitation.

Mild Intraocular Pressure Elevation in Mice Reveals Distinct Retinal Ganglion Cell Functional Thresholds and Pressure-Dependent Properties.

Elevation of intraocular pressure (IOP) causes retinal ganglion cell (RGC) dysfunction and death and is a major risk factor for glaucoma. We used a bead injection technique to increase IOP in mice of both genders by an average of ∼3 mmHg for 2 weeks. This level of IOP elevation was lower than that achieved in other studies, which allowed for the study of subtle IOP effects. We used multielectrode array recordings to determine the cellular responses of RGCs exposed to this mild degree of IOP elevation. We found that RGC photopic receptive field (RF) center size and whole-field RGC firing rates were unaffected by IOP elevation. In contrast, we found that the temporal properties of RGC photopic responses in the RF center were accelerated, particularly in ON sustained cells. We also detected a loss of antagonistic surround in several RGC subtypes. Finally, spontaneous firing rate, interspike interval variance, and contrast sensitivity were altered according to the magnitude of IOP exposure and also displayed an IOP-dependent effect. Together, these results suggest that individual RGC physiologic parameters have unique IOP-related functional thresholds that exist concurrently and change following IOP elevation according to specific patterns. Furthermore, even subtle IOP elevation can impart profound changes in RGC function, which in some cases may occur in an IOP-dependent manner. This system of overlapping functional thresholds likely underlies the complex effects of elevated IOP on the retina.SIGNIFICANCE STATEMENT Retinal ganglion cells (RGCs) are the obligate output neurons of the retina and are injured by elevated intraocular pressure (IOP) in diseases such as glaucoma. In this study, a subtle elevation of IOP in mice for 2 weeks revealed distinct IOP-related functional thresholds for specific RGC physiologic parameters and sometimes showed an IOP-dependent effect. These data suggest that overlapping IOP-related thresholds and response profiles exist simultaneously in RGCs and throughout the retina. These overlapping thresholds likely explain the range of RGC responses that occur following IOP elevation and highlight the wide capacity of neurons to respond in a diseased state.

Two-stage adaptive enrichment design for testing an active factor.

We propose an adaptive enrichment approach to test an active factor, which is a factor whose effect is non-zero in at least one subpopulation. We implement a two-stage play-the-winner design where all subjects in the second stage are enrolled from the subpopulation that has the highest observed effect in the first stage. We recommend a weighted Fisher's combination of the most powerful test for each stage, respectively: the first stage Hotelling's test and the second stage noncentral chi-square test. The test is further extended to cover binary outcomes and time-to-event outcomes.

Spatial distribution of tuberculosis and its association with meteorological factors in mainland China.

BACKGROUND: The incidence of tuberculosis (TB) remains high worldwide. Current strategies will not eradicate TB by 2035; instead, by 2182 is more likely. Therefore, it is urgent that new risk factors be identified. METHODS: An ecological study was conducted in 340 prefectures in China from 2005 to 2015. The spatial distribution of TB incidence was shown by clustering and hotspot analysis. The relationship between the distribution patterns and six meteorological factors was evaluated by the geographically weighted regression (GWR) model. RESULTS: During the 11 years of the study period, TB incidence was persistently low in the east and high in the west. Local coefficients from the GWR model showed a positive correlation between TB incidence and yearly average rainfall (AR) but a negative correlation with other meteorological factors. Average relative humidity (ARH) was negatively correlated with the incidence of TB in all prefectures (p < 0.05). CONCLUSION: Meteorological factors may play an important role in the prevention and control of TB.

Progression marker of Parkinson's disease: a 4-year multi-site imaging study.

Progression markers of Parkinson's disease are crucial for successful therapeutic development. Recently, a diffusion magnetic resonance imaging analysis technique using a bitensor model was introduced allowing the estimation of the fractional volume of free water within a voxel, which is expected to increase in neurodegenerative disorders such as Parkinson's disease. Prior work demonstrated that free water in the posterior substantia nigra was elevated in Parkinson's disease compared to controls across single- and multi-site cohorts, and increased over 1 year in Parkinson's disease but not in controls at a single site. Here, the goal was to validate free water in the posterior substantia nigra as a progression marker in Parkinson's disease, and describe the pattern of progression of free water in patients with a 4-year follow-up tested in a multicentre international longitudinal study of de novo Parkinson's disease (http://www.ppmi-info.org/). The analyses examined: (i) 1-year changes in free water in 103 de novo patients with Parkinson's disease and 49 controls; (ii) 2- and 4-year changes in free water in a subset of 46 patients with Parkinson's disease imaged at baseline, 12, 24, and 48 months; (iii) whether 1- and 2-year changes in free water predict 4-year changes in the Hoehn and Yahr scale; and (iv) the relationship between 4-year changes in free water and striatal binding ratio in a subgroup of Parkinson's disease who had undergone both diffusion and dopamine transporter imaging. Results demonstrated that: (i) free water level in the posterior substantia nigra increased over 1 year in de novo Parkinson's disease but not in controls; (ii) free water kept increasing over 4 years in Parkinson's disease; (iii) sex and baseline free water predicted 4-year changes in free water; (iv) free water increases over 1 and 2 years were related to worsening on the Hoehn and Yahr scale over 4 years; and (v) the 4-year increase in free water was associated with the 4-year decrease in striatal binding ratio in the putamen. Importantly, all longitudinal results were consistent across sites. In summary, this study demonstrates an increase over 1 year in free water in the posterior substantia nigra in a large cohort of de novo patients with Parkinson's disease from a multi-site cohort study and no change in healthy controls, and further demonstrates an increase of free water in Parkinson's disease over the course of 4 years. A key finding was that results are consistent across sites and the 1-year and 2-year increase in free water in the posterior substantia nigra predicts subsequent long-term progression on the Hoehn and Yahr staging system. Collectively, these findings demonstrate that free water in the posterior substantia nigra is a valid, progression imaging marker of Parkinson's disease, which may be used in clinical trials of disease-modifying therapies.

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice.

Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3-7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.

Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina.

Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are severe hereditary diseases that causes visual impairment in infants and children. SPATA7 has recently been identified as the LCA3 and juvenile RP gene in humans, whose function in the retina remains elusive. Here, we show that SPATA7 localizes at the primary cilium of cells and at the connecting cilium (CC) of photoreceptor cells, indicating that SPATA7 is a ciliary protein. In addition, SPATA7 directly interacts with the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), a key connecting cilium protein that has also been linked to LCA. In the retina of Spata7 null mutant mice, a substantial reduction of RPGRIP1 levels at the CC of photoreceptor cells is observed, suggesting that SPATA7 is required for the stable assembly and localization of the ciliary RPGRIP1 protein complex. Furthermore, our results pinpoint a role of this complex in protein trafficking across the CC to the outer segments, as we identified that rhodopsin accumulates in the inner segments and around the nucleus of photoreceptors. This accumulation then likely triggers the apoptosis of rod photoreceptors that was observed. Loss of Spata7 function in mice indeed results in a juvenile RP-like phenotype, characterized by progressive degeneration of photoreceptor cells and a strongly decreased light response. Together, these results indicate that SPATA7 functions as a key member of a retinal ciliopathy-associated protein complex, and that apoptosis of rod photoreceptor cells triggered by protein mislocalization is likely the mechanism of disease progression in LCA3/ juvenile RP patients.