Search

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis., Competing Interests: Declaration of interests E.R.G. received an honorarium from the journal Circulation Research of the American Heart Association as a member of the Editorial Board. S.M. is a co-founder and holds stock in Seonix Pty Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Continuum robots (CR) have been recently shown capable of micron-scale motion resolutions. Such motions are achieved through equilibrium modulation using indirect actuation for altering either internal preload forces or changing the cross-sectional stiffness along the length of a continuum robot. Previously reported, but unexplained, turning point behavior is modeled using two approaches. An energy minimization approach is first used to explain the source of this behavior. Subsequently, a kinematic model using internal constraints in multi-backbone CRs is used to replicate this turning point behavior. An approach for modeling the micro-motion differential kinematics is presented using experimental data based on the solution of a system of linear matrix equations. This approach provides a closed-form approximation of the empirical micro-motion kinematics and could be easily used for real-time control. A motivating application of image-based biopsy using 3D optical coherence tomography (OCT) is envisioned and demonstrated in this paper. A system integration for generating OCT volumes by sweeping a custom B-mode OCT probe is presented. Results showing high accuracy in obtaining 3D OCT measurements are shown using a commercial OCT probe. Qualitative results using a miniature probe integrated within the robot are also shown. Finally, closed-loop visual servoing using OCT data is demonstrated for guiding a needle into an agar channel. Results of this paper present what we believe is the first embodiment of a continuum robot capable of micro and macro motion control for 3D OCT imaging. This approach can support the development of new technologies for CRs capable of surgical intervention and micro-motion for ultra-precision tasks.

Objective: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure., Methods: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure., Results: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene ( CHRNA3 ). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex., Conclusions: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure., (© 2021 American Academy of Neurology.)

Background: In this study we are using source localized neurofeedback to moderate tinnitus related distress by influencing neural activity of the target region as well as the connectivity within the default network., Hypothesis: We hypothesize that up-training alpha and down-training beta and gamma activity in the posterior cingulate cortex has a moderating effect on tinnitus related distress by influencing neural activity of the target region as well as the connectivity within the default network and other functionally connected brain areas., Methods: Fifty-eight patients with chronic tinnitus were included in the study. Twenty-three tinnitus patients received neurofeedback training of the posterior cingulate cortex with the aim of up-training alpha and down-training beta and gamma activity, while 17 patients underwent training of the lingual gyrus as a control situation. A second control group consisted of 18 tinnitus patients on a waiting list for future tinnitus treatment., Results: This study revealed that neurofeedback training of the posterior cingulate cortex results in a significant decrease of tinnitus related distress. No significant effect on neural activity of the target region could be obtained. However, functional and effectivity connectivity changes were demonstrated between remote brain regions or functional networks as well as by altering cross frequency coupling of the posterior cingulate cortex., Conclusion: This suggests that neurofeedback could remove the information, processed in beta and gamma, from the carrier wave, alpha, which transports the high frequency information and influences the salience attributed to the tinnitus sound. Based on the observation that much pathology is the result of an abnormal functional connectivity within and between neural networks various pathologies should be considered eligible candidates for the application of source localized EEG based neurofeedback training.

Tinnitus can be distressful, and tinnitus distress has been linked to increased beta oscillatory activity in the dorsal anterior cingulate cortex (dACC). The amount of distress is linked to alpha activity in the medial temporal lobe (amygdala and parahippocampal area), as well as the subgenual (sg)ACC and insula, and the functional connectivity between the parahippocampal area and the sgACC at 10 and 11.5 Hz. The authors describe 2 patients with very severely distressing intractable tinnitus who underwent transcranial magnetic stimulation (TMS) with a double-cone coil targeting the dACC and subsequent implantation of electrodes on the dACC. One of the patients responded to the implant and one did not, even though phenomenologically they both expressed the same tinnitus loudness and distress. The responder has remained dramatically improved for more than 2 years with 6-Hz burst stimulation of the dACC. The 2 patients differed in functional connectivity between the area of the implant and a tinnitus network consisting of the parahippocampal area as well as the sgACC and insula; that is, the responder had increased functional connectivity between these areas, whereas the nonresponder had decreased functional connectivity between these areas. Only the patient with increased functional connectivity linked to the target area of repetitive TMS or implantation might transmit the stimulation current to the entire tinnitus network and thus clinically improve.

Background: Fibromyalgia is a disorder distinguished by pervasive musculoskeletal pain that has pervasive effects on affected individuals magnifying the importance of finding a safe and viable treatment option., Objective: The goal of this study is to investigate if transcranial direct current stimulation (tDCS) treatment can predict the outcome of occipital nerve field stimulation (ONFS) via a subcutaneous electrode., Methods: Nine patients with fibromyalgia were selected fulfilling the American College of Rheumatology-90 criteria. The patients were implanted with a subcutaneous trial-lead in the C2 dermatome innervated by the occipital nerve. After the treatment phase of ONFS using a C2 implant, each patient participated in three sessions of tDCS. Stimulation outcomes for pain suppression were examined between the two methods to determine possible correlations., Results: Positive correlation of stimulation effect was noted between the numeric rating scale changes for pain obtained by tDCS treatments and short-term measures of ONFS, but no correlation was noted between tDCS and long-term ONFS outcomes. A correlation also was noted between short-term ONS C2 implant pain suppression and long-term ONS C2 implant treatment success., Conclusions: This pilot study suggests that tDCS is a predictive measure for success of OFNS in short-term but cannot be used as a predictive measure for success of long-term OFNS. Our data confirm previous findings that ONFS via an implanted electrode can improve fibromyalgia pain in a placebo-controlled way and exert a long-term pain suppression effect for ONFS via an implanted electrode., (© 2015 International Neuromodulation Society.)

Tinnitus is the sensation of a ringing, buzzing, roaring or hissing sound in the absence of an external sound. As tinnitus has been related to hyperactivity and synaptic plasticity changes in the central auditory system, invasive and noninvasive neuromodulation methods have been used to interfere with this underlying mechanism to reduce tinnitus loudness and distress. Recently, transcranial random noise stimulation applied over the auditory cortex induced a more pronounced effect on tinnitus loudness than transcranial direct current and alternating current stimulation. We performed tRNS over the temporoparietal cortex in 154 patients with non-pulsatile tinnitus. A total of 119 patients received low-frequency tRNS (lf-tRNS), 19 high-frequency tRNS (hf-tRNS) and 16 whole frequency spectrum tRNS (wf-tRNS). The effect was evaluated by using the numeric rating scale loudness and distress pre- and post-stimulation. This study revealed a significant reduction in tinnitus loudness when lf-tRNS and hf-tRNS were applied as well as a reduction in tinnitus-related distress with lf-tRNS. Moreover, we observed a significantly more pronounced reduction in loudness and distress in pure tone (PT) tinnitus compared to narrow band noise (NBN) tinnitus when hf-tRNS was applied, a difference that could not be obtained with lf-tRNS. Based on these results, tRNS might be a promising treatment option for non-pulsatile tinnitus; however, we cannot yet provide a clear mechanistic explanation for the different results obtained with different types of stimulation, i.e., lf-tRNS, hf-tRNS and wf-tRNS, or with different types of tinnitus, i.e., PT and NBN tinnitus.

Tinnitus, a phantom sensation experienced by people around the world, currently is endured without a known cure. Some find the condition tolerable, while others are tortured on a daily basis from the incessant phantom noises. For those who seek treatment, oftentimes, they have a comorbid condition (e.g., depression, anxiety, insomnia), which is treated pharmaceutically. These products aim to reduce the comorbities associated with tinnitus thereby minimizing the overall burden present. Because of the phantom nature of tinnitus, it is often compared to neurologic pain. Since pain can be managed with pharmaceutical options, it is reasonable to assume that similar agents might work to alleviate tinnitus. The effects of antidepressants, benzodiazepines, anticonvulsants, and glutamate antagonists are reviewed in this paper. Table 1 summarizes the pharmaceutical products discussed. Due to the variety of comorbid factors and potential causes of tinnitus, there may not be one pharmaceutical treatment that will combat every type of tinnitus. Nevertheless, a product that finally addresses the true cause of tinnitus, and not just its comorbidities, will benefit millions of people worldwide.