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Consumer-grade EEG devices, such as the InteraXon Muse 2 headband, present a promising opportunity to enhance the accessibility and inclusivity of neuroscience research. However, their effectiveness in capturing language-related ERP components, such as the N400, remains underexplored. This study thus aimed to investigate the feasibility of using the Muse 2 to measure the N400 effect in a semantic relatedness judgment task. Thirty-seven participants evaluated the semantic relatedness of word pairs while their EEG was recorded using the Muse 2. Single-trial ERPs were analyzed using robust Yuen t -tests and hierarchical linear modeling (HLM) to assess the N400 difference between semantically related and unrelated target words. ERP analyses indicated a significantly larger N400 effect in response to unrelated word pairs over the right frontal electrode. Additionally, dependability estimates suggested acceptable internal consistency for the N400 data. Overall, these findings illustrate the capability of the Muse 2 to reliably measure the N400 effect, reinforcing its potential as a valuable tool for language research. This study highlights the potential of affordable, wearable EEG technology to expand access to brain research by offering an affordable and portable way to study language and cognition in diverse populations and settings.

Background Aims: Chimeric antigen receptor (CAR) T cells have demonstrated remarkable efficacy against hematological malignancies; however, they have not experienced the same success against solid tumors such as glioblastoma (GBM). There is a growing need for high-throughput functional screening platforms to measure CAR T-cell potency against solid tumor cells., Methods: We used real-time, label-free cellular impedance sensing to evaluate the potency of anti-disialoganglioside (GD2) targeting CAR T-cell products against GD2+ patient-derived GBM stem cells over a period of 2 days and 7 days in vitro. We compared CAR T products using two different modes of gene transfer: retroviral transduction and virus-free CRISPR-editing. Endpoint flow cytometry, cytokine analysis and metabolomics data were acquired and integrated to create a predictive model of CAR T-cell potency., Results: Results indicated faster cytolysis by virus-free CRISPR-edited CAR T cells compared with retrovirally transduced CAR T cells, accompanied by increased inflammatory cytokine release, CD8+ CAR T-cell presence in co-culture conditions and CAR T-cell infiltration into three-dimensional GBM spheroids. Computational modeling identified increased tumor necrosis factor α concentrations with decreased glutamine, lactate and formate as being most predictive of short-term (2 days) and long-term (7 days) CAR T cell potency against GBM stem cells., Conclusions: These studies establish impedance sensing as a high-throughput, label-free assay for preclinical potency testing of CAR T cells against solid tumors., Competing Interests: Declaration of Competing Interest KS is a member of the scientific advisory boards of Andson Biotech and Notch Therapeutics and receives research support from Synthego Corporation, Spotlight Therapeutics, and the Center for Cell Manufacturing Technologies. LK received in-kind contributions of assay consumables from Axion Biosystems Inc., and research support from the Center for Cell Manufacturing Technologies. SC is employed by Axion Biosystems Inc. TK is owner and employee of Evolved Analytics LLC., licensor of DataModelor., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Restoring community walking remains a highly valued goal for persons recovering from traumatic incomplete spinal cord injury (SCI). Recently, studies report that brief episodes of low-oxygen breathing (acute intermittent hypoxia, AIH) may serve as an effective plasticity-inducing primer that enhances the effects of walking therapy in persons with chronic (> 1 year) SCI. More persistent walking recovery may occur following repetitive (weeks) AIH treatment involving persons with more acute SCI, but this possibility remains unknown. Here we present our clinical trial protocol, designed to examine the distinct influences of repetitive AIH, with and without walking practice, on walking recovery in persons with sub-acute SCI (< 12 months) SCI. Our overarching hypothesis is that daily exposure (10 sessions, 2 weeks) to AIH will enhance walking recovery in ambulatory and non-ambulatory persons with subacute (< 12 months) SCI, presumably by harnessing endogenous mechanisms of plasticity that occur soon after injury., Methods: To test our hypothesis, we are conducting a randomized, placebo-controlled clinical trial on 85 study participants who we stratify into two groups according to walking ability; those unable to walk (non-ambulatory group) and those able to walk (ambulatory group). The non-ambulatory group receives either daily AIH (15, 90s episodes at 10.0% O 2 with 60s intervals at 20.9% O 2 ) or daily SHAM (15, 90s episodes at 20.9% O 2 with 60s intervals at 20.9% O 2 ) intervention. The ambulatory group receives either 60-min walking practice (WALK), daily AIH + WALK, or daily SHAM+WALK intervention. Our primary outcome measures assess overground walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up & Go Test). For safety, we also measure levels of pain, spasticity, systemic hypertension, and autonomic dysreflexia. We record outcome measures at baseline, days 5 and 10, and follow-ups at 1 week, 1 month, 6 months, and 12 months post-treatment., Discussion: The goal of this clinical trial is to reveal the extent to which daily AIH, alone or in combination with task-specific walking practice, safely promotes persistent recovery of walking in persons with traumatic, subacute SCI. Outcomes from this study may provide new insight into ways to enhance walking recovery in persons with SCI., Trial Registration: ClinicalTrials.gov, NCT02632422 . Registered 16 December 2015.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biology and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphology of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphology changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphology from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.

Alzheimer's disease is marked by the presence of amyloid-beta (Aβ) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aβ in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aβ accumulation. Hippocampal Aβ was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aβ, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aβ, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aβ, and restore hippocampal BDNF expression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Incomplete spinal cord injury (iSCI) often leads to partial disruption of spinal pathways that are important for motor control of walking. Persons with iSCI present with deficits in walking ability in part because of inconsistent leg kinematics during stepping. Although kinematic variability is important for normal walking, growing evidence indicates that excessive variability may limit walking ability and increase reliance on assistive devices (AD) after iSCI. The purpose of this study was to assess the effects of iSCI-induced impairments on kinematic variability during overground walking. We hypothesized that iSCI results in greater variability of foot and joint displacement during overground walking compared with controls. We further hypothesized that variability is larger in persons with limited walking speed and greater reliance on ADs. To test these hypotheses, iSCI and control subjects walked overground. Kinematic variability was quantified as step-to-step foot placement variability (end-point), and variability in hip-knee, hip-ankle, and knee-ankle joint space (angular coefficient of correspondence [ACC]). We characterized sensitivity of kinematic variability to cadence, auditory cue, and AD. Supporting our hypothesis, persons with iSCI exhibited greater kinematic variability than controls, which scaled with deficits in overground walking speed (p < 0.01). Significant correlation between ACC and end-point variability, and with walking speed, indicates that both are markers of walking performance. Moreover, hip-knee and hip-ankle ACC discriminated AD use, indicating that ACC may capture AD-specific control strategies. We conclude that increased variability of foot and joint displacement are indicative of motor impairment severity and may serve as therapeutic targets to restore walking after iSCI.

Persons with incomplete spinal cord injury (iSCI) face ongoing struggles with walking, including reduced speed and increased reliance on assistive devices (ADs). The forces underlying body weight support and gait, as measured by ground reaction forces (GRFs), are likely altered after iSCI because of weakness and AD dependence but have not been studied. The purpose of this study was to examine GRF production during overground walking after iSCI, because greater insight into GRF constraints is important for refining therapeutic interventions. Because of reduced and discoordinated motor output after iSCI, we hypothesized that persons with iSCI would exert smaller GRFs and altered GRF modifications to increased cadence compared with able-bodied (AB) persons, especially when using an AD. Fifteen persons with chronic iSCI, stratified into no AD (n = 7) and AD (n = 8) groups, walked across an instrumented walkway at self-selected and fast (115% self-selected) cadences. Fifteen age-matched AB controls walked at their own cadences and iSCI-matched conditions (cadence and AD). Results showed fore-aft GRFs are reduced in persons with iSCI compared with AB controls, with reductions greatest in persons dependent on an AD. When controlling for cadence and AD, propulsive forces were still lower in persons with iSCI. Compared with AB controls, persons with iSCI demonstrated altered GRF modifications to increased cadence. Persons with iSCI exhibit different stance-phase forces compared with AB controls, which are impacted further by AD use and slower walking speed. Minimizing AD use and/or providing propulsive biofeedback during walking could enhance GRF production after iSCI.

Objective: To test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury., Methods: Six participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo 2 ] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo 2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG., Results: Daily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants ( p = 0.057) and vs sham + hand opening practice in all 6 participants ( p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (-7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice ( p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline ( p = 0.018) and sham + hand opening practice ( p = 0.030). In 5 participants, daily AIH-induced changes in hand opening were accompanied by improved EMG coactivity ( p = 0.029)., Conclusions: This report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence., Clinicaltrialsgov Identifier: NCT01272336., (© 2017 American Academy of Neurology.)

Alzheimer's disease is marked by the accumulation of the amyloid-beta (Aβ) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aβ, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aβ and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aβ was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aβ levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aβ disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer's-like pathology., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The intact neuromotor system prepares for object grasp by first opening the hand to an aperture that is scaled according to object size and then closing the hand around the object. After cervical spinal cord injury (SCI), hand function is significantly impaired, but the degree to which object-specific hand aperture scaling is affected remains unknown. Here, we hypothesized that persons with incomplete cervical SCI have a reduced maximum hand opening capacity but exhibit novel neuromuscular coordination strategies that permit object-specific hand aperture scaling during reaching. To test this hypothesis, we measured hand kinematics and surface electromyography from seven muscles of the hand and wrist during attempts at maximum hand opening as well as reaching for four balls of different diameters. Our results showed that persons with SCI exhibited significantly reduced maximum hand aperture compared to able-bodied (AB) controls. However, persons with SCI preserved the ability to scale peak hand aperture with ball size during reaching. Persons with SCI also used distinct muscle coordination patterns that included increased co-activity of flexors and extensors at the wrist and hand compared to AB controls. These results suggest that motor planning for aperture modulation is preserved even though execution is limited by constraints on hand opening capacity and altered muscle co-activity. Thus, persons with incomplete cervical SCI may benefit from rehabilitation aimed at increasing hand opening capacity and reducing flexor-extensor co-activity at the wrist and hand.

Objective: Incomplete spinal cord injury (iSCI) disrupts motor control and limits the ability to coordinate muscles for overground walking. Inappropriate muscle activity has been proposed as a source of clinically observed walking deficits after iSCI. We hypothesized that persons with iSCI exhibit lower locomotor complexity compared to able-body (AB) controls as reflected by fewer motor modules, as well as, altered module composition and activation., Methods: Eight persons with iSCI and eight age-matched AB controls walked overground at prescribed cadences. Electromyograms of fourteen single leg muscles were recorded. Non-negative matrix factorization was used to identify the composition and activation of motor modules, which represent groups of consistently co-activated muscles that accounted for 90% of variability in muscle activity., Results: Motor module number, composition, and activation were significantly altered in persons with iSCI as compared to AB controls during overground walking at self-selected cadences. However, there was no significant difference in module number between persons with iSCI and AB controls when cadence and assistive device were matched., Conclusions: Muscle coordination during overground walking is impaired after chronic iSCI., Significance: Our results are indicative of neuromuscular constraints on muscle coordination after iSCI. Altered muscle coordination contributes to person-specific gait deficits during overground walking., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To test the hypothesis that daily acute intermittent hypoxia (dAIH) and dAIH combined with overground walking improve walking speed and endurance in persons with chronic incomplete spinal cord injury (iSCI)., Methods: Nineteen subjects completed the randomized, double-blind, placebo-controlled, crossover study. Participants received 15, 90-second hypoxic exposures (dAIH, fraction of inspired oxygen [Fio2] = 0.09) or daily normoxia (dSHAM, Fio2 = 0.21) at 60-second normoxic intervals on 5 consecutive days; dAIH was given alone or combined with 30 minutes of overground walking 1 hour later. Walking speed and endurance were quantified using 10-Meter and 6-Minute Walk Tests. The trial is registered at ClinicalTrials.gov (NCT01272349)., Results: dAIH improved walking speed and endurance. Ten-Meter Walk time improved with dAIH vs dSHAM after 1 day (mean difference [MD] 3.8 seconds, 95% confidence interval [CI] 1.1-6.5 seconds, p = 0.006) and 2 weeks (MD 3.8 seconds, 95% CI 0.9-6.7 seconds, p = 0.010). Six-Minute Walk distance increased with combined dAIH + walking vs dSHAM + walking after 5 days (MD 94.4 m, 95% CI 17.5-171.3 m, p = 0.017) and 1-week follow-up (MD 97.0 m, 95% CI 20.1-173.9 m, p = 0.014). dAIH + walking increased walking distance more than dAIH after 1 day (MD 67.7 m, 95% CI 1.3-134.1 m, p = 0.046), 5 days (MD 107.0 m, 95% CI 40.6-173.4 m, p = 0.002), and 1-week follow-up (MD 136.0 m, 95% CI 65.3-206.6 m, p < 0.001)., Conclusions: dAIH ± walking improved walking speed and distance in persons with chronic iSCI. The impact of dAIH is enhanced by combination with walking, demonstrating that combinatorial therapies may promote greater functional benefits in persons with iSCI., Classification of Evidence: This study provides Class I evidence that transient hypoxia (through measured breathing treatments), along with overground walking training, improves walking speed and endurance after iSCI.

Afferent feedback alters muscle activity during locomotion and must be tightly controlled. As primary afferent depolarization-induced presynaptic inhibition (PAD-PSI) regulates afferent signaling, we investigated hindlimb PAD-PSI during locomotion in an in vitro rat spinal cord-hindlimb preparation. We compared the relation of PAD-PSI, measured as dorsal root potentials (DRPs), to observed ipsilateral and contralateral limb endpoint forces. Afferents activated during stance-phase force strongly and proportionately influenced DRP magnitude in the swinging limb. Responses increased with locomotor frequency. Electrical stimulation of contralateral afferents also preferentially evoked DRPs in the opposite limb during swing (flexion). Nerve lesioning, in conjunction with kinematic results, support a prominent contribution from toe Golgi tendon organ afferents. Thus, force-dependent afferent feedback during stance binds interlimb sensorimotor state to a proportional PAD-PSI in the swinging limb, presumably to optimize interlimb coordination. These results complement known actions of ipsilateral afferents on PAD-PSI during locomotion., (© 2013 New York Academy of Sciences.)

Presynaptic inhibition is a powerful mechanism for selectively and dynamically gating sensory inputs entering the spinal cord. We investigated how hindlimb mechanics influence presynaptic inhibition during locomotion using pioneering approaches in an in vitro spinal cord-hindlimb preparation. We recorded lumbar dorsal root potentials to measure primary afferent depolarization-mediated presynaptic inhibition and compared their dependence on hindlimb endpoint forces, motor output, and joint kinematics. We found that stance-phase force on the opposite limb, particularly at toe contact, strongly influenced the magnitude and timing of afferent presynaptic inhibition in the swinging limb. Presynaptic inhibition increased in proportion to opposite limb force, as well as locomotor frequency. This form of presynaptic inhibition binds the sensorimotor states of the two limbs, adjusting sensory inflow to the swing limb based on forces generated by the stance limb. Functionally, it may serve to adjust swing-phase sensory transmission based on locomotor task, speed, and step-to-step environmental perturbations.

The neonatal rodent spinal cord maintained in vitro is a powerful model system to understand the central properties of spinal circuits generating mammalian locomotion. We describe three enabling approaches that incorporate afferent input and attached hindlimbs. (i) Sacral dorsal column stimulation recruits and strengthens ongoing locomotor-like activity, and implementation of a closed positive-feedback paradigm is shown to support its stimulation as an untapped therapeutic site for locomotor modulation. (ii) The spinal cord hindlimbs-restrained preparation allows suction electrode electromyographic recordings from many muscles. Inducible complex motor patterns resemble natural locomotion, and insights into circuit organization are demonstrated during spontaneous motor burst 'deletions', or following sensory stimuli such as tail and paw pinch. (iii) The spinal cord hindlimbs-pendant preparation produces unrestrained hindlimb stepping. It incorporates mechanical limb perturbations, kinematic analyses, ground reaction force monitoring, and the use of treadmills to study spinal circuit operation with movement-related patterns of sensory feedback while providing for stable whole-cell recordings from spinal neurons. Such techniques promise to provide important additional insights into locomotor circuit organization.

Although the spinal cord contains the pattern-generating circuitry for producing locomotion, sensory feedback reinforces and refines the spatiotemporal features of motor output to match environmental demands. In vitro preparations, such as the isolated rodent spinal cord, offer many advantages for investigating locomotor circuitry, but they lack the natural afferent feedback provided by ongoing locomotor movements. We developed a novel preparation consisting of an isolated in vitro neonatal rat spinal cord oriented dorsal-up with intact hindlimbs free to step on a custom-built treadmill. This preparation combines the neural accessibility of in vitro preparations with the modulatory influence of sensory feedback from physiological hindlimb movement. Locomotion induced by N-methyl D-aspartate and serotonin showed kinematics similar to that of normal adult rat locomotion. Changing orientation and ground interaction (dorsal-up locomotion vs ventral-up air-stepping) resulted in significant kinematic and electromyographic changes that were comparable to those reported under similar mechanical conditions in vivo. We then used two mechanosensory perturbations to demonstrate the influence of sensory feedback on in vitro motor output patterns. First, swing assistive forces induced more regular, robust muscle activation patterns. Second, altering treadmill speed induced corresponding changes in stride frequency, confirming that changes in sensory feedback can alter stride timing in vitro. In summary, intact hindlimbs in vitro can generate behaviorally appropriate locomotor kinematics and responses to sensory perturbations. Future studies combining the neural and chemical accessibility of the in vitro spinal cord with the influence of behaviorally appropriate hindlimb movements will provide further insight into the operation of spinal motor pattern-generating circuits.