Activation of endogenous retroviruses during brain development causes an inflammatory response.

Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for an inflammatory response, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9-based gene disruption of the epigenetic co-repressor protein Trim28, we found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo deletion of Trim28 in cortical NPCs during mouse brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain. Neuronal ERV expression was linked to activated microglia and the presence of ERV-derived proteins in aggregate-like structures. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in an inflammatory response.

Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders.

The etiology of most neurological disorders is poorly understood and current treatments are largely ineffective. New ideas and concepts are therefore vitally important for future research in this area. This review explores the concept that dysregulation of transposable elements (TEs) contributes to the appearance and pathology of neurodevelopmental and neurodegenerative disorders. Despite TEs making up at least half of the human genome, they are vastly understudied in relation to brain disorders. However, recent advances in sequencing technologies and gene editing approaches are now starting to unravel the pathological role of TEs. Aberrant activation of TEs has been found in many neurological disorders; the resulting pathogenic effects, which include alterations of gene expression, neuroinflammation, and direct neurotoxicity, are starting to be resolved. An increased understanding of the relationship between TEs and pathological processes in the brain improves the potential for novel diagnostics and interventions for brain disorders.

Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in ageing humans. To address this, we generated induced neurons through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. Huntington's disease induced neurons (HD-iNs) displayed profound deficits in autophagy, characterized by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in control induced neurons, highlighting the importance of wild-type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rationale for future development of autophagy activation therapies.

Human manual control precision depends on vestibular sensory precision and gravitational magnitude.

Precise motion control is critical to human survival on Earth and in space. Motion sensation is inherently imprecise, and the functional implications of this imprecision are not well understood. We studied a "vestibular" manual control task in which subjects attempted to keep themselves upright with a rotational hand controller (i.e., joystick) to null out pseudorandom, roll-tilt motion disturbances of their chair in the dark. Our first objective was to study the relationship between intersubject differences in manual control performance and sensory precision, determined by measuring vestibular perceptual thresholds. Our second objective was to examine the influence of altered gravity on manual control performance. Subjects performed the manual control task while supine during short-radius centrifugation, with roll tilts occurring relative to centripetal accelerations of 0.5, 1.0, and 1.33 GC (1 GC = 9.81 m/s2). Roll-tilt vestibular precision was quantified with roll-tilt vestibular direction-recognition perceptual thresholds, the minimum movement that one can reliably distinguish as leftward vs. rightward. A significant intersubject correlation was found between manual control performance (defined as the standard deviation of chair tilt) and thresholds, consistent with sensory imprecision negatively affecting functional precision. Furthermore, compared with 1.0 GC manual control was more precise in 1.33 GC (-18.3%, P = 0.005) and less precise in 0.5 GC (+39.6%, P < 0.001). The decrement in manual control performance observed in 0.5 GC and in subjects with high thresholds suggests potential risk factors for piloting and locomotion, both on Earth and during human exploration missions to the moon (0.16 G) and Mars (0.38 G). NEW & NOTEWORTHY The functional implications of imprecise motion sensation are not well understood. We found a significant correlation between subjects' vestibular perceptual thresholds and performance in a manual control task (using a joystick to keep their chair upright), consistent with sensory imprecision negatively affecting functional precision. Furthermore, using an altered-gravity centrifuge configuration, we found that manual control precision was improved in "hypergravity" and degraded in "hypogravity." These results have potential relevance for postural control, aviation, and spaceflight.

When uncertain, does human self-motion decision-making fully utilize complete information?

When forced to choose humans often feel uncertain. Investigations of human perceptual decision-making often employ signal detection theory, which assumes that even when uncertain all available information is fully utilized. However, other studies have suggested or assumed that, when uncertain, human subjects guess totally at random, ignoring available information. When uncertain, do humans simply guess totally at random? Or do humans fully utilize complete information? Or does behavior fall between these two extremes yielding "above chance" performance without fully utilizing complete information? While it is often assumed complete information is fully utilized, even when uncertain, to our knowledge this has never been experimentally confirmed. To answer this question, we combined numerical simulations, theoretical analyses, and human studies performed using a self-motion direction-recognition perceptual decision-making task (did I rotate left or right?). Subjects were instructed to make forced-choice binary (left/right) and trinary (left/right/uncertain) decisions when cued following each stimulus. Our results show that humans 1) do not guess at random when uncertain and 2) make binary and trinary decisions equally well. These findings show that humans fully utilize complete information when uncertain for our perceptual decision-making task. This helps unify signal detection theory and other models of forced-choice decision-making which allow for uncertain responses. NEW & NOTEWORTHY Humans make many perceptual decisions every day. But what if we are uncertain? While many studies assume that humans fully utilize complete information, other studies have suggested and/or assumed that when we're uncertain and forced to decide, information is not fully utilized. While humans tend to perform above chance when uncertain, no earlier study has tested whether available information is fully utilized. Our results show that humans make fully informed decisions even when uncertain.

Human perception of whole body roll-tilt orientation in a hypogravity analog: underestimation and adaptation.

Overestimation of roll tilt in hypergravity ("G-excess" illusion) has been demonstrated, but corresponding sustained hypogravic conditions are impossible to create in ground laboratories. In this article we describe the first systematic experimental evidence that in a hypogravity analog, humans underestimate roll tilt. We studied perception of self-roll tilt in nine subjects, who were supine while spun on a centrifuge to create a hypogravity analog. By varying the centrifuge rotation rate, we modulated the centripetal acceleration (GC) at the subject's head location (0.5 or 1 GC) along the body axis. We measured orientation perception using a subjective visual vertical task in which subjects aligned an illuminated bar with their perceived centripetal acceleration direction during tilts (±11.5-28.5°). As hypothesized, based on the reduced utricular otolith shearing, subjects initially underestimated roll tilts in the 0.5 GC condition compared with the 1 GC condition (mean perceptual gain change = -0.27, P = 0.01). When visual feedback was given after each trial in 0.5 GC, subjects' perceptual gain increased in approximately exponential fashion over time (time constant = 16 tilts or 13 min), and after 45 min, the perceptual gain was not significantly different from the 1 GC baseline (mean gain difference between 1 GC initial and 0.5 GC final = 0.16, P = 0.3). Thus humans modified their interpretation of sensory cues to more correctly report orientation during this hypogravity analog. Quantifying the acute orientation perceptual learning in such an altered gravity environment may have implications for human space exploration on the moon or Mars. NEW & NOTEWORTHY Humans systematically overestimate roll tilt in hypergravity. However, human perception of orientation in hypogravity has not been quantified across a range of tilt angles. Using a centrifuge to create a hypogravity centripetal acceleration environment, we found initial underestimation of roll tilt. Providing static visual feedback, perceptual learning reduced underestimation during the hypogravity analog. These altered gravity orientation perceptual errors and adaptation may have implications for astronauts.

Intra-individual consistency of vestibular perceptual thresholds.

Vestibular perceptual thresholds quantify sensory noise associated with reliable perception of small self-motions. Previous studies have identified substantial variation between even healthy individuals' thresholds. However, it remains unclear if or how an individual's vestibular threshold varies over repeated measures across various time scales (repeated measurements on the same day, across days, weeks, or months). Here, we assessed yaw rotation and roll tilt thresholds in four individuals and compared this intra-individual variability to inter-individual variability of thresholds measured across a large age-matched cohort each measured only once. For analysis, we performed simulations of threshold measurements where there was no underlying variability (or it was manipulated) to compare to that observed empirically. We found remarkable consistency in vestibular thresholds within individuals, for both yaw rotation and roll tilt; this contrasts with substantial inter-individual differences. Thus, we conclude that vestibular perceptual thresholds are an innate characteristic, which validates pooling measures across sessions and potentially serves as a stable clinical diagnostic and/or biomarker.

Biomarkers for evaluating the clinical response to immune checkpoint inhibitors in renal cell carcinoma (Review).

Renal cell carcinoma (RCC) is a highly aggressive neoplastic disease of the renal parenchyma that is characterized by an intrinsic resistance to cytotoxic chemotherapy; for this reason, curative treatment is only achieved through surgical intervention in its early stages. The successful treatment of advanced or metastatic RCC will require the combined use of novel targeted therapies such as tyrosine kinase inhibitors, vascular endothelial growth factor blockers and immune checkpoint blockade therapies. Unfortunately, not all patients are candidates for such treatments, and at present, it is not possible to predict a patient's therapeutic response or likelihood to develop treatment­associated complications. The present review described the literature focusing on the use of biomarkers for predicting patients' responses to therapies that induce immune checkpoint blockade in RCC.

Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease.

SVA (SINE (short interspersed nuclear element)-VNTR (variable number of tandem repeats)-Alu) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized and how their regulatory impact is constrained by an innate epigenetic defense system.

DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor.

The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.

The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1.

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.

Protumoral lipid droplet-loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted.

Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet-loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O-acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.

Single-cell transcriptomics of human traumatic brain injury reveals activation of endogenous retroviruses in oligodendroglia.

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

Effectiveness of caffeine and blue-enriched light on cognitive performance and electroencephalography correlates of alertness in a spaceflight robotics simulation.

Human cognitive impairment associated with sleep loss, circadian misalignment and work overload is a major concern in any high stress occupation but has potentially catastrophic consequences during spaceflight human robotic interactions. Two safe, wake-promoting countermeasures, caffeine and blue-enriched white light have been studied on Earth and are available on the International Space Station. We therefore conducted a randomized, placebo-controlled, cross-over trial examining the impact of regularly timed low-dose caffeine (0.3 mg per kg per h) and moderate illuminance blue-enriched white light (~90 lux, ~88 melEDI lux, 6300 K) as countermeasures, separately and combined, in a multi-night simulation of sleep-wake shifts experienced during spaceflight among 16 participants (7 F, ages 26-55). We find that chronic administration of low-dose caffeine improves subjective and objective correlates of alertness and performance during an overnight work schedule involving chronic sleep loss and circadian misalignment, although we also find that caffeine disrupts subsequent sleep. We further find that 90 lux of blue-enriched light moderately reduces electroencephalogram (EEG) power in the theta and delta regions, which are associated with sleepiness. These findings support the use of low-dose caffeine and potentially blue-enriched white light to enhance alertness and performance among astronauts and shiftworking populations.

Effects of caffeine and blue-enriched light on spare visual attention during simulated space teleoperation.

Safe and successful operation of the International Space Station robotic arm is a complex task requiring difficult bimanual hand coordination and spatial reasoning skills, adherence to operating procedures and rules, and systems knowledge. These task attributes are all potentially affected by chronic sleep loss and circadian misalignment. In a randomized, placebo-controlled, cross-over trial examining the impact of regularly timed low-dose caffeine (0.3 mg kg-1 h-1) and moderate illuminance blue-enriched white light (~90 lux, ~88 melEDI lux, 6300 K), 16 participants performed 3 types of realistic robotic arm tasks using a high-fidelity desktop simulator overnight. Our goal was to determine how these countermeasures, separately and combined, impacted telerobotic task performance and the ability to allocate attention to an unrelated secondary visual task. We found that all participants maintained a similar level of robotic task performance throughout the primary task but the application of caffeine separately and with blue-enriched light significantly decreased response time to a secondary visual task by -9% to -13%, whereas blue-enriched light alone changed average response times between -4% and +2%. We conclude that, for sleep-restricted individuals, caffeine improved their ability to divide their visual attention, while the effect of blue-enriched light alone was limited. Light and caffeine together was most effective. Use of these countermeasures should improve the margin of safety if astronauts perform familiar tasks under degraded conditions or novel tasks where task workload is increased.

LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification.

The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element-1 (L1) retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type-specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPR interference silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.

Visual Vestibular Conflict Mitigation in Virtual Reality Using Galvanic Vestibular Stimulation.

BACKGROUND: Virtual reality (VR) is an effective technique to reduce cost and increase fidelity in training programs. In VR, visual and vestibular cues are often in conflict, which may result in simulator-induced motion sickness. The purpose of this study is to investigate the integration of Galvanic Vestibular Stimulation (GVS) with a VR flight training simulator by assessing flight performance, secondary task performance, simulator sickness and presence.METHODS: There were 20 participants who performed 2 separate VR flight simulation sessions, with and without GVS (control). Flight performance, secondary task performance, and electrogastrogram were measured during VR flight simulation. The standardized simulator sickness and presence questionnaires were administered.RESULTS: Electrogastrogram measures such as dominant power instability coefficient (DPIC) and percentages of bradygastric waves (%B) were lower in the GVS session than the control session in the flight simulation (DPIC: 0.44 vs. 0.54; %B: 21.2% vs. 30.5%) and postflight (DPIC: 0.38 vs. 0.53; %B: 22.8% vs. 31.4%) periods. Flight performance (#hit-gates) was improved in the GVS session compared to the control (GVS: 17, Control: 15.5). Secondary task performance (%hits) was improved with GVS for the Easy task (GVS: 55.5%, Control: 43.1%).DISCUSSION: This study demonstrates the potential of synchronizing GVS with visual stimuli in VR flight training to reduce visual-vestibular sensory conflict to improve fidelity and performance. These results provide initial evidence, but continued research is warranted to further understand the benefits and applications of GVS in VR simulator training.Pradhan GN, Galvan-Garza RC, Perez AM, Stepanek J, Cevette MJ. Visual vestibular conflict mitigation in virtual reality using galvanic vestibular stimulation. Aerosp Med Hum Perform. 2022; 93(5):406-414.

Generating Flight Illusions Using Galvanic Vestibular Stimulation in Virtual Reality Flight Simulations.

Background: Vestibular flight illusions remain a significant source of concern for aviation training. Most fixed-based simulation training environments, including new virtual reality (VR) technology, lack the ability to recreate vestibular flight illusions as vestibular cues cannot be provided without stimulating the vestibular end organs. Galvanic vestibular stimulation (GVS) has long been used to create vestibular perception. The purpose of this study is to evaluate the ability of GVS to simulate common flight illusions by intentionally providing mismatched GVS during flight simulation scenarios in VR. Methods: Nineteen participants performed two flight simulation tasks-take off and sustained turn-during two separate VR flight simulation sessions, with and without GVS (control). In the GVS session, specific multi-axis GVS stimulation (i.e., electric currents) was provided to induce approximate somatogravic and Coriolis illusions during the take-off and sustained turn tasks, respectively. The participants used the joystick to self-report their subjective motion perception. The angular joystick movement along the roll, yaw, and pitch axes was used to measure cumulative angular distance and peak angular velocity as continuous variables of motion perception across corresponding axes. Presence and Simulator Sickness Questionnaires were administered at the end of each session. Results: The magnitude and variability of perceived somatogravic illusion during take-off task in the form of cumulative angular distance (p < 0.001) and peak velocity (p < 0.001) along the pitch-up axis among participants were significantly larger in the GVS session than in the NO GVS session. Similarly, during the sustained turn task, perceived Coriolis illusion in the form of cumulative angular distances (roll: p = 0.005, yaw: p = 0.015, pitch: p = 0.007) and peak velocities (roll: p = 0.003, yaw: p = 0.01, pitch: p = 0.007) across all three axes were significantly larger in the GVS session than in the NO GVS session. Subjective nausea was low overall, but significantly higher in the GVS session than in the NO GVS session (p = 0.026). Discussion: Our findings demonstrated that intentionally mismatched GVS can significantly affect motion perception and create flight illusion perceptions during fixed-based VR flight simulation. This has the potential to enhance future training paradigms, providing pilots the ability to safely experience, identify, and learn to appropriately respond to flight illusions during ground training.

A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development.

The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population. Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution.

The Effect of Noisy Galvanic Vestibular Stimulation on Learning of Functional Mobility and Manual Control Nulling Sensorimotor Tasks.

Galvanic vestibular stimulation (GVS) is a non-invasive method of electrically stimulating the vestibular system. We investigated whether the application of GVS can alter the learning of new functional mobility and manual control tasks and whether learning can be retained following GVS application. In a between-subjects experiment design, 36 healthy subjects performed repeated trials, capturing the learning of either (a) a functional mobility task, navigating an obstacle course on a compliant surface with degraded visual cues or (b) a manual control task, using a joystick to null self-roll tilt against a pseudo-random disturbance while seated in the dark. In the "learning" phase of trials, bilateral, bipolar GVS was applied continuously. The GVS waveform also differed between subjects in each task group: (1) white noisy galvanic vestibular stimulation (nGVS) at 0.3 mA (2) high-level random GVS at 0.7 mA (selected from pilot testing as destabilizing, but not painful), or (3) with the absence of stimulation (i.e., sham). Following the "learning" trials, all subjects were blindly transitioned to sham GVS, upon which they immediately completed another series of trials to assess any aftereffects. In the functional mobility task, we found nGVS significantly improved task learning (p = 0.03, mean learning metric 171% more than the sham group). Further, improvements in learning the functional mobility task with nGVS were retained, even once the GVS application was stopped. The benefits in learning with nGVS were not observed in the manual control task. High level GVS tended to inhibit learning in both tasks, but not significantly so. Even once the high-level stimulation was stopped, the impaired performance remained. Improvements in learning with nGVS may be due to increased information throughput resulting from stochastic resonance. The benefit of nGVS for functional mobility, but not manual control nulling, may be due to the multisensory (e.g., visual and proprioceptive), strategic, motor coordination, or spatial awareness aspects of the former task. Learning improvements with nGVS have the potential to benefit individuals who perform functional mobility tasks, such as astronauts, firefighters, high performance athletes, and soldiers.