Hierarchical Bayesian estimation of motor-evoked potential recruitment curves yields accurate and robust estimates.

Electromagnetic stimulation probes and modulates the neural systems that control movement. Key to understanding their effects is the muscle recruitment curve, which maps evoked potential size against stimulation intensity. Current methods to estimate curve parameters require large samples; however, obtaining these is often impractical due to experimental constraints. Here, we present a hierarchical Bayesian framework that accounts for small samples, handles outliers, simulates high-fidelity data, and returns a posterior distribution over curve parameters that quantify estimation uncertainty. It uses a rectified-logistic function that estimates motor threshold and outperforms conventionally used sigmoidal alternatives in predictive performance, as demonstrated through cross-validation. In simulations, our method outperforms non-hierarchical models by reducing threshold estimation error on sparse data and requires fewer participants to detect shifts in threshold compared to frequentist testing. We present two common use cases involving electrical and electromagnetic stimulation data and provide an open-source library for Python, called hbMEP, for diverse applications.

Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Biomarkers predict the efficacy of closed-loop rTMS treatment for refractory depression.

Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients (i.e., less than 50%). Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders.

Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression.

Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.

Timing dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans it is not known whether dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses.

Although epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-six people undergoing clinically indicated cervical spine surgery consented to mapping of motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argue for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function.NEW & NOTEWORTHY A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline and revealed differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally, indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively.

Spatiospectral brain networks reflective of improvisational experience.

Musical improvisers are trained to categorize certain musical structures into functional classes, which is thought to facilitate improvisation. Using a novel auditory oddball paradigm (Goldman et al., 2020) which enables us to disassociate a deviant (i.e. musical chord inversion) from a consistent functional class, we recorded scalp EEG from a group of musicians who spanned a range of improvisational and classically trained experience. Using a spatiospectral based inter and intra network connectivity analysis, we found that improvisers showed a variety of differences in connectivity within and between large-scale cortical networks compared to classically trained musicians, as a function of deviant type. Inter-network connectivity in the alpha band, for a time window leading up to the behavioural response, was strongly linked to improvisation experience, with the default mode network acting as a hub. Spatiospectral networks post response were substantially different between improvisers and classically trained musicians, with greater inter-network connectivity (specific to the alpha and beta bands) seen in improvisers whereas those with more classical training had largely reduced inter-network activity (mostly in the gamma band). More generally, we interpret our findings in the context of network-level correlates of expectation violation as a function of subject expertise, and we discuss how these may generalize to other and more ecologically valid scenarios.

Targeting Sensory and Motor Integration for Recovery of Movement After CNS Injury.

The central nervous system (CNS) integrates sensory and motor information to acquire skilled movements, known as sensory-motor integration (SMI). The reciprocal interaction of the sensory and motor systems is a prerequisite for learning and performing skilled movement. Injury to various nodes of the sensorimotor network causes impairment in movement execution and learning. Stimulation methods have been developed to directly recruit the sensorimotor system and modulate neural networks to restore movement after CNS injury. Part 1 reviews the main processes and anatomical interactions responsible for SMI in health. Part 2 details the effects of injury on sites critical for SMI, including the spinal cord, cerebellum, and cerebral cortex. Finally, Part 3 reviews the application of activity-dependent plasticity in ways that specifically target integration of sensory and motor systems. Understanding of each of these components is needed to advance strategies targeting SMI to improve rehabilitation in humans after injury.

Ballistocardiogram Artifact Reduction in Simultaneous EEG-fMRI Using Deep Learning.

OBJECTIVE: The concurrent recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is a technique that has received much attention due to its potential for combined high temporal and spatial resolution. However, the ballistocardiogram (BCG), a large-amplitude artifact caused by cardiac induced movement contaminates the EEG during EEG-fMRI recordings. Removal of BCG in software has generally made use of linear decompositions of the corrupted EEG. This is not ideal as the BCG signal propagates in a manner which is non-linearly dependent on the electrocardiogram (ECG). In this paper, we present a novel method for BCG artifact suppression using recurrent neural networks (RNNs). METHODS: EEG signals were recovered by training RNNs on the nonlinear mappings between ECG and the BCG corrupted EEG. We evaluated our model's performance against the commonly used Optimal Basis Set (OBS) method at the level of individual subjects, and investigated generalization across subjects. RESULTS: We show that our algorithm can generate larger average power reduction of the BCG at critical frequencies, while simultaneously improving task relevant EEG based classification. CONCLUSION: The presented deep learning architecture can be used to reduce BCG related artifacts in EEG-fMRI recordings. SIGNIFICANCE: We present a deep learning approach that can be used to suppress the BCG artifact in EEG-fMRI without the use of additional hardware. This method may have scope to be combined with current hardware methods, operate in real-time and be used for direct modeling of the BCG.

Decomposing Simon task BOLD activation using a drift-diffusion model framework.

The Simon effect is observed in spatial conflict tasks where the response time of subjects is increased if stimuli are presented in a lateralized manner so that they are incongruous with the response information that they represent symbolically. Previous studies have used fMRI to investigate this phenomenon, and while some have been driven by considerations of an underlying model, none have attempted to directly tie model and BOLD response together. It is likely that this is due to Simon models having been predominantly descriptive of the phenomenon rather than capturing the full spectrum of behavior at the level of individual subjects. Sequential sampling models (SSM) which capture full response distributions for correct and incorrect responses have recently been extended to capture conflict tasks. In this study we use our freely available framework for fitting and comparing non-standard SSMs to fit the Simon effect SSM (SE-SSM) to behavioral data. This model extension includes specific estimates of automatic response bias and a conflict counteraction parameter to individual subject behavioral data. We apply this approach in order to investigate whether our task specific model parameters have a correlate in BOLD response. Under the assumption that the SE-SSM reflects aspects of neural processing in this task, we go on to examine the BOLD correlates with the within trial expected decision-variable. We find that the SE-SSM captures the behavioral data and that our two conflict specific model parameters have clear across subject BOLD correlates, while other model parameters, as well as more standard behavioral measures do not. We also find that examining BOLD in terms of the expected decision-variable leads to a specific pattern of activation that would not be otherwise possible to extract.

Modifying response times in the Simon task with transcranial random noise stimulation.

Perceptual decisions pervade our every-day lives, and can align or conflict with inbuilt biases. We investigated these conflicting biases by applying transcranial random noise stimulation (tRNS) while subjects took part in a visual Simon task - a paradigm where irrelevant spatial cues influence the response times of subjects to relevant colour cues. We found that tRNS reduces the response time of subjects independent of the congruence between spatial and colour cues, but dependent on the baseline response time, both between subjects and across conditions within subjects. We consider the reduction in response time to be non-specific to the Simon task, and cast our interpretations in terms of drift-diffusion models, which have been previously used as mechanistic explanations for decision-making processes. However, there have been few extensions of the drift-diffusion model to the Simon effect, and so we first elaborate on this interpretation, and further extend it by incorporating the potential action of tRNS.

Evaluating psychological distress data.

Kessler k6 psychological distress scores are analyzed using a count model and item response theory (IRT) models are applied to the items which produce the k6 score and generate an alternative distress score, θ* . Other ways of utilizing the constituent items are also examined. The data used in the analysis comes from the 2014 National Survey of Drug Use and Health. Three important results emerge. First, θ* and k6 are not highly correlated and their distributions are quite different. The k6 score gives a much more favourable picture of mental health than θ* . Second, k6 does a much better job in explaining participation in treatment programs than θ* suggesting a very limited role for IRT methods in the analysis of psychological distress data. As a diagnostic tool k6 is an effective and simple way of summarizing the item data. Third, for researchers interested in which individual characteristics determine psychological distress better results are obtained by analyzing the six constituent items which are used to generate the k6 score using ordered probability models rather than k6 itself.

Synthesis, self-assembly, and immunological activity of α-galactose-functionalized dendron-lipid amphiphiles.

Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendron-lipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendron-lipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in water through a solvent exchange process resulted in vesicles for the 0 through 2nd generation systems and micelles for the 3rd and 4th generation systems. The critical aggregation concentrations decreased with increasing dendron generation, suggesting that the effects of increasing molar mass dominated over the effects of increasing the hydrophilic weight fraction. The binding of the assemblies to Griffonia simplicifolia Lectin I (GSL 1), a protein with specificity for α-Gal was studied by quantifying the binding of fluorescently labeled assemblies to GSL 1-coated beads. It was found that binding was enhanced for amphiphiles containing higher generation dendrons. Despite their substantial structural differences with the natural ligands for the CD1d receptor, the glycodendron-lipid hybrids were capable of stimulating invariant natural killer T (iNKT) cells, a class of innate-like T cells that recognize lipid and glycolipid antigens presented by CD1d and that are implicated in a wide range of diseases and conditions including but not limited to infectious diseases, diabetes and cancer.

Current prevalence rate of latex allergy: Why it remains a problem?

OBJECTIVES: This article aims to review the current prevalence rate of latex allergy among healthcare workers, susceptible patients, and the general public, and to investigate why latex is still a ubiquitous occupational health hazard. METHODS: Scientific publications on PubMed, particularly those published within the last five years, and current regulations from agencies such as Food and Drug Administration (FDA) were reviewed. Consumer and commercial products that may contain latex were also surveyed. RESULTS: Approximately 12 million tons of natural rubber latex is produced annually and is widely used to manufacture millions of consumer and commercial products. Only limited number of latex-derived products have been approved and regulated by government agencies, such as FDA, whereas the majority of finished products do not label whether they contain latex. Owing to millions of unidentifiable products containing latex and many routes for exposure to latex, preventing contact with latex allergens and reducing the prevalence of latex allergy are more difficult than expected. Reported data suggest that the average prevalence of latex allergy worldwide remains 9.7%, 7.2%, and 4.3% among healthcare workers, susceptible patients, and general population, respectively. CONCLUSIONS: Latex-derived products are ubiquitous, and latex allergy remains a highly prevalent health risk in many occupations and to the general population. Developing alternative materials and increasing the ability to identify and label latex-derived products will be practicable approaches to effectively control the health risks associated with latex.

Comparison of Slip Training in VR Environment And on Moveable Platform.

Slip training is gaining popularity as an innovative fall intervention approach. The objective of this study was to compare the efficacy of two different slip training modality (moveable platform and virtual reality) in reducing fall frequency and improving reactive recovery in older adults. Thirty-six healthy older adults were involved in a laboratory study, and were equally and randomly divided into the control group, the moveable platform training (MPT) group, and the virtual reality training (VRT) group. The MPT was achieved by inducing slips using a custom built sliding device consisting of a low friction, motorized moveable platform. The VRT was conducted by inducing visual perturbation in a head mounted display while subjects walked on a treadmill. All groups performed slip trials (kinematics, kinetics and EMG data were collected) on an actual slippery floor surface before and after a training session. The results indicated a significant reduction in fall frequency in both training groups. Between MPT and VRT groups, significant differences were also found in forward trunk rotations, peak knee angular velocity, ankle coactivity, and muscular activity in tibialis anterior. It was concluded that slip training in VR environment could produce comparable results in fall intervention.

Laparoscopic orchiopexy for intra-abdominal testes-a single institution review.

OBJECTIVE: To report success, complication, and atrophy rates, as well as cost analysis and surgeon preference, for standard laparoscopic versus laparoscopic Fowler-Stephens (FS) approaches to intra-abdominal testes. PATIENTS AND METHODS: The records of children who underwent laparoscopic orchiopexy for impalpable testes at our institution were reviewed. Two groups were assessed: Group 1, who underwent a standard laparoscopic orchiopexy; and Group 2, who underwent either a single-stage or two-stage FS orchiopexy. Success was defined as an intrascrotal testis without atrophy. Cost analysis was performed by obtaining operating room charges for the procedures. Surgeon preference was evaluated by calculating the number of each type of orchiopexy performed. RESULTS: From 1998 to 2005, 61 laparoscopic orchiopexies were performed on 46 patients. In Group 1, 31 orchiopexies were performed on 22 patients. In Group 2, 30 orchiopexies were performed in 26 patients. Eight orchiopexies were performed on 7 patients in a single stage, whereas 22 orchiopexies in 19 patients were performed in two stages. Two patients underwent both unilateral FS and laparoscopic orchiopexy. Success rates for Groups 1 and 2 were 96.7% and 83.3%, respectively. There were three complications in Group 1 (9.7%) and nine complications in Group 2 (30%). Atrophy rates for the two groups were 6.5% (2/31) and 16.7% (4/24), respectively. The average operating room cost for a standard laparoscopic approach was $3686, $3604 for the first stage and $3909 for the second stage of a two-stage FS approach, and $3785 for a single-stage FS approach. CONCLUSIONS: Data from this series suggest that completing a laparoscopic orchiopexy in a single operation without ligating the testicular vessels has comparable, if not better, success rates to those of FS procedures, while reducing cost and potentially reducing complications. Outcomes between single- and two-stage FS approaches are similar, but the former can be accomplished at half the cost.

Does graded return-to-work improve sick-listed workers' chance of returning to regular working hours?

Using Danish register and survey data, we examine the effect of a national graded return-to-work program on the probability of sick-listed workers returning to regular working hours. During program participation, the sick-listed worker works fewer hours and receives the normal hourly wage for the hours worked and sickness benefit for the hours off work. When the worker's health improves, working hours are increased until the sick-listed worker is able to work regular hours. Taking account of unobserved differences between program participants and non-participants, we find that participation in the program significantly increases the probability of returning to regular working hours.

Drug driving and the management of risk: the perspectives and practices of a sample of problem drug users.

This paper reports on a qualitative study of the attitudes and risk management strategies of a sample of problem drug users in relation to driving while under the influence of drugs. Interviews were conducted with 26 individuals (21 men and 5 women) all of whom had been addicted to heroin and had admitted to driving while under the influence of illegal drugs. The drug users reported four main strategies for managing the risks associated with drug driving: attempting to limit their drug intake to their tolerance level; delaying driving after taking a drug until they felt safe; stopping driving if they felt unsafe while behind the wheel; and avoiding driving altogether under the influence of certain drugs. However, the interviewees' accounts of their drug driving behaviour suggest that these strategies are not only far from reliable, they may also act to encourage drug driving by creating a false sense of security. The reassurance they provide may also undermine any educational messages targeting drug driving. There was little in the problem users' accounts to suggest that media campaigns or a more effective method of detection would have much influence upon their behaviour. The paper concludes that the most realistic approach to the problem may be to incorporate drug driving interventions within drug treatment programmes.

How much does obesity matter? Results from the 2001 Canadian Community Health Survey.

A five category self-reported health indicator together with the self-reported prevalence of diabetes and heart disease for older Canadians, are examined using data from five cohorts of men and women from the 2001 Canadian Community Health Survey. Consistent with other studies we find that smoking and dietary behaviors are highly correlated with general self-reported health, diabetes, and heart disease. Individual standardized weight, the body mass index, was negatively associated with health outcomes for all age groups, but became less important with age as socioeconomic variables became more important. Socioeconomic variables explained more of the variation in health outcomes than the combined effects of tobacco use and excessive weight problems. In addition, there is compelling evidence that obesity could overtake smoking as the leading cause of health problems in Canada.

Intercity differences in drug use by pre-teenage school children.

BACKGROUND: Regional variations in rates of drug use have been described previously in relation to adolescents. However, reasons for these differences are not clear. Previous publications pointed to higher rates of drug use by Glasgow children compared to children living in Newcastle upon Tyne. This paper explores the hypothesis that a higher rate of drug use in Glasgow is due to higher availability there. METHOD: School surveys were conducted in Glasgow and Newcastle upon Tyne on a total of 2,318 children aged 10-12. These concerned aspects of behaviour, lifestyle, family life and drug use. FINDINGS: The data indicate that the higher rate of drug use by Glasgow children was attributable to greater opportunities for children to gather at leisure centres and other venues and activities facilitating exposure to more drug-experienced young people.