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Brain-computer interface (BCI) is a rapidly evolving technology that has the potential to widely influence research, clinical and recreational use. Non-invasive BCI approaches are particularly common as they can impact a large number of participants safely and at a relatively low cost. Where traditional non-invasive BCIs were used for simple computer cursor tasks, it is now increasingly common for these systems to control robotic devices for complex tasks that may be useful in daily life. In this review, we provide an overview of the general BCI framework as well as the various methods that can be used to record neural activity, extract signals of interest, and decode brain states. In this context, we summarize the current state-of-the-art of non-invasive BCI research, focusing on trends in both the application of BCIs for controlling external devices and algorithm development to optimize their use. We also discuss various open-source BCI toolboxes and software, and describe their impact on the field at large.

Introduction: Stereoelectroencephalography (sEEG) is a mesoscale intracranial monitoring method which records from the brain volumetrically with depth electrodes. Implementation of sEEG in BCI has not been well-described across a diverse patient cohort., Methods: Across eighteen subjects, channels with high frequency broadband (HFB, 65-115Hz) power increases during hand, tongue, or foot movements during a motor screening task were provided real-time feedback based on these HFB power changes to control a cursor on a screen., Results: Seventeen subjects established successful control of the overt motor BCI, but only nine were able to control imagery BCI with ≥ 80% accuracy. In successful imagery BCI, HFB power in the two target conditions separated into distinct subpopulations, which appear to engage unique subnetworks of the motor cortex compared to cued movement or imagery alone., Conclusion: sEEG-based motor BCI utilizing overt movement and kinesthetic imagery is robust across patient ages and cortical regions with substantial differences in learning proficiency between real or imagined movement.

Background: Intracranial electrodes are typically localized from post-implantation CT artifacts. Automatic algorithms localizing low signal-to-noise ratio artifacts and high-density electrode arrays are missing. Additionally, implantation of grids/strips introduces brain deformations, resulting in registration errors when fusing post-implantation CT and pre-implantation MR images. Brain-shift compensation methods project electrode coordinates to cortex, but either fail to produce smooth solutions or do not account for brain deformations., New Methods: We first introduce GridFit, a model-based fitting approach that simultaneously localizes all electrodes' CT artifacts in grids, strips, or depth arrays. Second, we present CEPA, a brain-shift compensation algorithm combining orthogonal-based projections, spring-mesh models, and spatial regularization constraints., Results: We tested GridFit on ∼6000 simulated scenarios. The localization of CT artifacts showed robust performance under difficult scenarios, such as noise, overlaps, and high-density implants (<1 mm errors). Validation with data from 20 challenging patients showed 99% accurate localization of the electrodes (3160/3192). We tested CEPA brain-shift compensation with data from 15 patients. Projections accounted for simple mechanical deformation principles with < 0.4 mm errors. The inter-electrode distances smoothly changed across neighbor electrodes, while changes in inter-electrode distances linearly increased with projection distance., Comparison With Existing Methods: GridFit succeeded in difficult scenarios that challenged available methods and outperformed visual localization by preserving the inter-electrode distance. CEPA registration errors were smaller than those obtained for well-established alternatives. Additionally, modeling resting-state high-frequency activity in five patients further supported CEPA., Conclusion: GridFit and CEPA are versatile tools for registering intracranial electrode coordinates, providing highly accurate results even in the most challenging implantation scenarios. The methods are implemented in the iElectrodes open-source toolbox., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH., Methods: In this PHYOX3 interim analysis, participants with PH1 who continued from a single-dose nedosiran trial (PHYOX1), with no previous kidney or liver transplantation, dialysis, or evidence of systemic oxalosis were eligible. The safety and efficacy of once-monthly nedosiran was assessed over 30 months., Results: Thirteen participants completed PHYOX1 and continued into PHYOX3. At baseline, the mean (SD) and median (range) age was 24.2 (6.6) years and 23.0 (14-39) years, respectively; 53.8% were female and 61.5% were White. Mean estimated glomerular filtration rate (eGFR) remained stable (62-84.2 mL/min per 1.73 m 2 ) to month 30. Mean 24-hour urinary oxalate (Uox) excretion showed a sustained reduction from baseline of ≥60% at every visit (months 2-30). From month 2, at least 10 of 13 (76.9%) participants achieved normal (<0.46 mmol/24h; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to <0.60 mmol/24h; ≥ULN to <1.3 × ULN) 24-hour Uox excretion. All participants experienced ≥1 adverse event (AE), mostly mild or moderate in severity (primarily, injection site events). Three serious, not treatment-related AEs were reported; there were no deaths or study discontinuations due to AEs., Conclusion: Nedosiran was well-tolerated in patients with PH1, and treatment resulted in a sustained, substantial reduction in Uox excretion for at least 30 months in this long-term study. No safety signals have been identified to date. The PHYOX3 study is ongoing., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Many studies over the past decades have provided exciting evidence that electrical signals recorded from the scalp (electroencephalogram, EEG) hold meaningful information about the brain's function or dysfunction. This information is used routinely in research laboratories to test specific hypotheses and in clinical settings to aid in diagnoses (such as during polysomnography evaluations). Unfortunately, with very few exceptions, such meaningful information about brain function has not yet led to valuable solutions that can address the needs of many people outside such research laboratories or clinics. One of the major hurdles to practical application of EEG-based neurotechnologies is the current predominant requirement to use electrodes that are placed in the hair, which greatly reduces practicality and cosmesis. While several studies reported results using one specific combination of signal/reference electrode outside the hair in one specific context (such as a brain-computer interface experiment), it has been unclear what information about brain function can be acquired using different signal/referencing locations placed outside the hair. To address this issue, in this study, we set out to determine to what extent EEG phenomena related to auditory, visual, cognitive, motor, and sleep function can be detected from different combinations of individual signal/referencing electrodes that are placed outside the hair. The results of our study from 15 subjects suggest that only a few EEG electrodes placed in locations on the forehead or around the ear can provide substantial task-related information in 6 of 7 tasks. Thus, the results of our study provide encouraging evidence and guidance that should invigorate and facilitate the translation of laboratory experiments into practical, useful, and valuable EEG-based neurotechnology solutions., (Creative Commons Attribution license.)

Making hand movements in response to visual cues is common in daily life. It has been well known that this process activates multiple areas in the brain, but how these neural activations progress across space and time remains largely unknown. Taking advantage of intracranial electroencephalographic (iEEG) recordings using depth and subdural electrodes from 36 human subjects using the same task, we applied single-trial and cross-trial analyses to high-frequency iEEG activity. The results show that the neural activation was widely distributed across the human brain both within and on the surface of the brain, and focused specifically on certain areas in the parietal, frontal, and occipital lobes, where parietal lobes present significant left lateralization on the activation. We also demonstrate temporal differences across these brain regions. Finally, we evaluated the degree to which the timing of activity within these regions was related to sensory or motor function. The findings of this study promote the understanding of task-related neural processing of the human brain, and may provide important insights for translational applications., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Music is core to human experience, yet the precise neural dynamics underlying music perception remain unknown. We analyzed a unique intracranial electroencephalography (iEEG) dataset of 29 patients who listened to a Pink Floyd song and applied a stimulus reconstruction approach previously used in the speech domain. We successfully reconstructed a recognizable song from direct neural recordings and quantified the impact of different factors on decoding accuracy. Combining encoding and decoding analyses, we found a right-hemisphere dominance for music perception with a primary role of the superior temporal gyrus (STG), evidenced a new STG subregion tuned to musical rhythm, and defined an anterior-posterior STG organization exhibiting sustained and onset responses to musical elements. Our findings show the feasibility of applying predictive modeling on short datasets acquired in single patients, paving the way for adding musical elements to brain-computer interface (BCI) applications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bellier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Context modulates sensory neural activations enhancing perceptual and behavioral performance and reducing prediction errors. However, the mechanism of when and where these high-level expectations act on sensory processing is unclear. Here, we isolate the effect of expectation absent of any auditory evoked activity by assessing the response to omitted expected sounds. Electrocorticographic signals were recorded directly from subdural electrode grids placed over the superior temporal gyrus (STG). Subjects listened to a predictable sequence of syllables, with some infrequently omitted. We found high-frequency band activity (HFA, 70-170 Hz) in response to omissions, which overlapped with a posterior subset of auditory-active electrodes in STG. Heard syllables could be distinguishable reliably from STG, but not the identity of the omitted stimulus. Both omission- and target-detection responses were also observed in the prefrontal cortex. We propose that the posterior STG is central for implementing predictions in the auditory environment. HFA omission responses in this region appear to index mismatch-signaling or salience detection processes., (© The Author(s) 2023. Published by Oxford University Press.)

Cells in the precentral gyrus directly send signals to the periphery to generate movement and are principally organized as a topological map of the body. We find that movement-induced electrophysiological responses from depth electrodes extend this map three-dimensionally throughout the gyrus. Unexpectedly, this organization is interrupted by a previously undescribed motor association area in the depths of the midlateral aspect of the central sulcus. This 'Rolandic motor association' (RMA) area is active during movements of different body parts from both sides of the body and may be important for coordinating complex behaviors., (© 2023. The Author(s).)

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate  ≥ 30 mL/min/1.73 m 2 . Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near-normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To investigate the feasibility of passive functional mapping in the receptive language cortex during general anesthesia using electrocorticographic (ECoG) signals., Methods: We used subdurally placed ECoG grids to record cortical responses to speech stimuli during awake and anesthesia conditions. We identified the cortical areas with significant responses to the stimuli using the spectro-temporal consistency of the brain signal in the broadband gamma (BBG) frequency band (70-170 Hz)., Results: We found that ECoG BBG responses during general anesthesia effectively identify cortical regions associated with receptive language function. Our analyses demonstrated that the ability to identify receptive language cortex varies across different states and depths of anesthesia. We confirmed these results by comparing them to receptive language areas identified during the awake condition. Quantification of these results demonstrated an average sensitivity and specificity of passive language mapping during general anesthesia to be 49±7.7% and 100%, respectively., Conclusion: Our results demonstrate that mapping receptive language cortex in patients during general anesthesia is feasible., Significance: Our proposed protocol could greatly expand the population of patients that can benefit from passive language mapping techniques, and could eliminate the risks associated with electrocortical stimulation during an awake craniotomy., (Copyright © 2022. Published by Elsevier B.V.)

Background: Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH., Methods: Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m 2 ) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint., Results: Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52, O. formigenes was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was - 3.80 μmol/L; 95% CI: - 7.83, 0.23; p-value = 0.064). Kidney function remained stable in both treatments., Conclusions: Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (p = 0.06). A subtle effect observed with Oxabact suggests that O. formigenes may aid in preventing kidney stones. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)

This article describes initial work toward an ecosystem for adaptive neuromodulation in humans by documenting the experience of implanting CorTec's BrainInterchange (BIC) device in a beagle canine and using the BCI2000 environment to interact with the BIC device. It begins with laying out the substantial opportunity presented by a useful, easy-to-use, and widely available hardware/software ecosystem in the current landscape of the field of adaptive neuromodulation, and then describes experience with implantation, software integration, and post-surgical validation of recording of brain signals and implant parameters. Initial experience suggests that the hardware capabilities of the BIC device are fully supported by BCI2000, and that the BIC/BCI2000 device can record and process brain signals during free behavior. With further development and validation, the BIC/BCI2000 ecosystem could become an important tool for research into new adaptive neuromodulation protocols in humans., Competing Interests: GW declares intellectual property disclosures related to behavioral state and seizure classification algorithms licensed to Cadence Neuroscience Inc. GW has licensed intellectual property to NeuroOne, Inc. GS has provided consulting services to CorTec and JR is employed by CorTec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schalk, Worrell, Mivalt, Belsten, Kim, Morris, Hermes, Klassen, Staff, Messina, Kaufmann, Rickert, Brunner, Worrell and Miller.)

Background: IgA vasculitis (IgAV) is the most common form of systemic vasculitis in childhood and frequently involves the kidney. A minority of patients with IgA vasculitis nephritis (IgAVN), especially those presenting with heavy proteinuria and/or kidney failure at onset, are at risk of chronic end-stage kidney disease. For deciding upon treatment intensity, knowledge of the short-term clinical course of IgAVN is needed to improve treatment algorithms., Methods: For this retrospective multicenter study, the medical records of 66 children with biopsy-proven IgAVN were reviewed. Age, gender, medical history and therapeutic interventions were recorded. Laboratory data included serum creatinine, albumin, urinary protein excretion (UPE) and glomerular filtration rate (eGFR). Threshold values were determined for each parameter, full remission was defined as no proteinuria and eGFR > 90 ml/min/1.73m 2 ., Results: Median age at onset of IgAVN was 8.9 years. 14.1% of the children presented with nephrotic syndrome, 50% had an eGFR below 90 ml/min/1.73 m 2 and 51.5% showed cellular crescents in renal histology. The treatment regimens varied notably. Forty-four patients were treated with immunosuppression; 17 patients with crescents or nephrotic syndrome were treated with corticosteroid (CS) pulse therapy. After 6 months, UPE had decreased from 3.7 to 0.3 g/g creatinine and the proportion of patients with a decreased eGFR had fallen from 50.0% to 35.5%. Thirteen children (26.5%) achieved full remission within 6 months., Conclusions: In most patients with IgAVN proteinuria decreases slowly and kidney function improves, but full remission is reached only in a minority after 6 months. Persistent heavy proteinuria in the first two months rarely developed into long-term proteinuria. Therefore, decisions for more intense treatment should take into account the course of UPE over time. For a comparison of treatment effects, patient numbers were too small. Prospective, randomized controlled trials are necessary to clarify risk factors and the effect of immunosuppressive therapies., (© 2022. The Author(s).)

Objective . Accurate identification of functional cortical regions is essential in neurological resection. The central sulcus (CS) is an important landmark that delineates functional cortical regions. Median nerve stimulation (MNS) is a standard procedure to identify the position of the CS intraoperatively. In this paper, we introduce an automated procedure that uses MNS to rapidly localize the CS and create functional somatotopic maps. Approach . We recorded electrocorticographic signals from 13 patients who underwent MNS in the course of an awake craniotomy. We analyzed these signals to develop an automated procedure that determines the location of the CS and that also produces functional somatotopic maps. Main results . The comparison between our automated method and visual inspection performed by the neurosurgeon shows that our procedure has a high sensitivity (89%) in identifying the CS. Further, we found substantial concordance between the functional somatotopic maps generated by our method and passive functional mapping (92% sensitivity). Significance . Our automated MNS-based method can rapidly localize the CS and create functional somatotopic maps without imposing additional burden on the clinical procedure. With additional development and validation, our method may lead to a diagnostic tool that guides neurosurgeons and reduces postoperative morbidity in patients undergoing resective brain surgery., (Creative Commons Attribution license.)

How is music represented in the brain? While neuroimaging has revealed some spatial segregation between responses to music versus other sounds, little is known about the neural code for music itself. To address this question, we developed a method to infer canonical response components of human auditory cortex using intracranial responses to natural sounds, and further used the superior coverage of fMRI to map their spatial distribution. The inferred components replicated many prior findings, including distinct neural selectivity for speech and music, but also revealed a novel component that responded nearly exclusively to music with singing. Song selectivity was not explainable by standard acoustic features, was located near speech- and music-selective responses, and was also evident in individual electrodes. These results suggest that representations of music are fractionated into subpopulations selective for different types of music, one of which is specialized for the analysis of song., Competing Interests: Declaration of interests N.K. was recently on the Current Biology advisory board. The other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Recent computational models of perception conceptualize auditory oddball responses as signatures of a (Bayesian) learning process, in line with the influential view of the mismatch negativity (MMN) as a prediction error signal. Novel MMN experimental paradigms have put an emphasis on neurophysiological effects of manipulating regularity and predictability in sound sequences. This raises the question of the contextual adaptation of the learning process itself, which on the computational side speaks to the mechanisms of gain-modulated (or precision-weighted) prediction error. In this study using electrocorticographic (ECoG) signals, we manipulated the predictability of oddball sound sequences with two objectives: (i) Uncovering the computational process underlying trial-by-trial variations of the cortical responses. The fluctuations between trials, generally ignored by approaches based on averaged evoked responses, should reflect the learning involved. We used a general linear model (GLM) and Bayesian Model Reduction (BMR) to assess the respective contributions of experimental manipulations and learning mechanisms under probabilistic assumptions. (ii) To validate and expand on previous findings regarding the effect of changes in predictability using simultaneous EEG-MEG recordings. Our trial-by-trial analysis revealed only a few stimulus-responsive sensors but the measured effects appear to be consistent over subjects in both time and space. In time, they occur at the typical latency of the MMN (between 100 and 250 ms post-stimulus). In space, we found a dissociation between time-independent effects in more anterior temporal locations and time-dependent (learning) effects in more posterior locations. However, we could not observe any clear and reliable effect of our manipulation of predictability modulation onto the above learning process. Overall, these findings clearly demonstrate the potential of trial-to-trial modeling to unravel perceptual learning processes and their neurophysiological counterparts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lecaignard, Bertrand, Brunner, Caclin, Schalk and Mattout.)

Despite significant interest in the neural underpinnings of behavioral variability, little light has been shed on the cortical mechanism underlying the failure to respond to perceptual-level stimuli. We hypothesized that cortical activity resulting from perceptual-level stimuli is sensitive to the moment-to-moment fluctuations in cortical excitability, and thus may not suffice to produce a behavioral response. We tested this hypothesis using electrocorticographic recordings to follow the propagation of cortical activity in six human subjects that responded to perceptual-level auditory stimuli. Here we show that for presentations that did not result in a behavioral response, the likelihood of cortical activity decreased from auditory cortex to motor cortex, and was related to reduced local cortical excitability. Cortical excitability was quantified using instantaneous voltage during a short window prior to cortical activity onset. Therefore, when humans are presented with an auditory stimulus close to perceptual-level threshold, moment-by-moment fluctuations in cortical excitability determine whether cortical responses to sensory stimulation successfully connect auditory input to a resultant behavioral response., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Variations in reaction time are a ubiquitous characteristic of human behavior. Extensively documented, they have been successfully modeled using parameters of the subject or the task, but the neural basis of behavioral reaction time that varies within the same subject and the same task has been minimally studied. In this paper, we investigate behavioral reaction time variance using 28 datasets of direct cortical recordings in humans who engaged in four different types of simple sensory-motor reaction time tasks. Using a previously described technique that can identify the onset of population-level cortical activity and a novel functional connectivity algorithm described herein, we show that the cumulative latency difference of population-level neural activity across the task-related cortical network can explain up to 41% of the trial-by-trial variance in reaction time. Furthermore, we show that reaction time variance may primarily be due to the latencies in specific brain regions and demonstrate that behavioral latency variance is accumulated across the whole task-related cortical network. Our results suggest that population-level neural activity monotonically increases prior to movement execution, and that trial-by-trial changes in that increase are, in part, accounted for by inhibitory activity indexed by low-frequency oscillations. This pre-movement neural activity explains 19% of the measured variance in neural latencies in our data. Thus, our study provides a mechanistic explanation for a sizable fraction of behavioral reaction time when the subject's task is the same from trial to trial., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase., Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6., Results: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients., Conclusions: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.)., (Copyright © 2021 Massachusetts Medical Society.)

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4-15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.

Objective: The precise localization of intracranial electrodes is a fundamental step relevant to the analysis of intracranial electroencephalography (iEEG) recordings in various fields. With the increasing development of iEEG studies in human neuroscience, higher requirements have been posed on the localization process, resulting in urgent demand for more integrated, easy-operation and versatile tools for electrode localization and visualization. With the aim of addressing this need, we develop an easy-to-use and multifunction toolbox called iEEGview, which can be used for the localization and visualization of human intracranial electrodes., Approach: iEEGview is written in Matlab scripts and implemented with a GUI. From the GUI, by taking only pre-implant MRI and post-implant CT images as input, users can directly run the full localization pipeline including brain segmentation, image co-registration, electrode reconstruction, anatomical information identification, activation map generation and electrode projection from native brain space into common brain space for group analysis. Additionally, iEEGview implements methods for brain shift correction, visual location inspection on MRI slices and computation of certainty index in anatomical label assignment., Main Results: All the introduced functions of iEEGview work reliably and successfully, and are tested by images from 28 human subjects implanted with depth and/or subdural electrodes., Significance: iEEGview is the first public Matlab GUI-based software for intracranial electrode localization and visualization that holds integrated capabilities together within one pipeline. iEEGview promotes convenience and efficiency for the localization process, provides rich localization information for further analysis and offers solutions for addressing raised technical challenges. Therefore, it can serve as a useful tool in facilitating iEEG studies.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro . In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

Background: Older age at organ transplantation is associated with increased risk of infection and malignancy but reduced risk of cellular rejection. De novo donor-specific anti-HLA antibodies ( dn DSA), are key biomarkers associated with reduced long-term allograft survival, yet there is a lack of data focusing on age-associated changes., Methods: Development of dn DSA was restrospectively analyzed in all subjects who received a kidney transplant at the University Hospital Zurich between 01/2006 and 02/2015. Follow up continued until 03/2016. The incidence of dn DSA in different age categories was compared with special focus on the extremes of age: children < 10 years ( n  = 19) and adults ≥60 years of age ( n  = 110)., Results: Incidence of dn DSA gradually decreased with age, with older recipients having a significantly lower risk (HR 0.21, p  = 0.0224) compared to pediatric recipients. Cumulative incidence of dn DSA at 2, 5 and 10 years was 6.2, 9.1 and 36% in the older recipients versus 5.3, 29.5 and 47.1% in pediatric recipients. Median time to development of dn DSA was similar (older 720 days, min 356, max 3646 days; children 1086 days, min 42, max 2474 days). Annual incidence was highest within the first two years after transplantation in the older recipients and peaked in years two to four in pediatric recipients. Dn DSA were predominantly class II. More dn DSA were observed with cyclosporine as compared to tacrolimus., Conclusion: Older kidney transplant recipients have a lower risk of developing dn DSA than pediatric recipients, pointing towards reduced humoral immune reactivity with increasing age. This observation raises the question of adjustment in immunosuppression., Competing Interests: The study was approved by the local ethics committee of Zurich (protocol number: KEK-ZH-Nr. 2017–00500).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Electrical stimulation of the cortex using subdurally implanted electrodes can causally reveal structural connectivity by eliciting cortico-cortical evoked potentials (CCEPs). While many studies have demonstrated the potential value of CCEPs, the methods to evaluate them were often relatively subjective, did not consider potential artifacts, and did not lend themselves to systematic scientific investigations., New Method: We developed an automated and quantitative method called SIGNI (Stimulation-Induced Gamma-based Network Identification) to evaluate cortical population-level responses to electrical stimulation that minimizes the impact of electrical artifacts. We applied SIGNI to electrocorticographic (ECoG) data from eight human subjects who were implanted with a total of 978 subdural electrodes. Across the eight subjects, we delivered 92 trains of approximately 200 discrete electrical stimuli each (amplitude 4-15 mA) to a total of 64 electrode pairs., Results: We verified SIGNI's efficacy by demonstrating a relationship between the magnitude of evoked cortical activity and stimulation amplitude, as well as between the latency of evoked cortical activity and the distance from the stimulated locations., Conclusions: SIGNI reveals the timing and amplitude of cortical responses to electrical stimulation as well as the structural connectivity supporting these responses. With these properties, it enables exploration of new and important questions about the neurophysiology of cortical communication and may also be useful for pre-surgical planning., (Copyright © 2018. Published by Elsevier B.V.)

The Seventh International Brain-Computer Interface (BCI) Meeting was held May 21-25th, 2018 at the Asilomar Conference Grounds, Pacific Grove, California, United States. The interactive nature of this conference was embodied by 25 workshops covering topics in BCI (also called brain-machine interface) research. Workshops covered foundational topics such as hardware development and signal analysis algorithms, new and imaginative topics such as BCI for virtual reality and multi-brain BCIs, and translational topics such as clinical applications and ethical assumptions of BCI development. BCI research is expanding in the diversity of applications and populations for whom those applications are being developed. BCI applications are moving toward clinical readiness as researchers struggle with the practical considerations to make sure that BCI translational efforts will be successful. This paper summarizes each workshop, providing an overview of the topic of discussion, references for additional information, and identifying future issues for research and development that resulted from the interactions and discussion at the workshop.

Stereo-electroencephalography (SEEG) is an intracranial recording technique in which depth electrodes are inserted in the brain as part of presurgical assessments for invasive brain surgery. SEEG recordings can tap into neural signals across the entire brain and thereby sample both cortical and subcortical sites. However, even though signal referencing is important for proper assessment of SEEG signals, no previous study has comprehensively evaluated the optimal referencing method for SEEG. In our study, we recorded SEEG data from 15 human subjects during a motor task, referencing them against the average of two white matter contacts (monopolar reference). We then subjected these signals to 5 different re-referencing approaches: common average reference (CAR), gray-white matter reference (GWR), electrode shaft reference (ESR), bipolar reference, and Laplacian reference. The results from three different signal quality metrics suggest the use of the Laplacian re-reference for study of local population-level activity and low-frequency oscillatory activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)