Biology subjects

Sulzer, J.

Publications and source records attributed to Sulzer, J..

9 recordsLinked to original sources

bioRxiv2024

Neural correlates of kinematic features of passive finger movement revealed by univariate and multivariate fMRI analyses

Finger movements are associated with a relatively large neural representation. Passive finger movement - which involves refraining from actively performing or resisting movement - is a robust approach to investigate the neural representation of kinesthesia and proprioception in the brain. While some studies have characterized the neural correlates of passive finger movement, they have relied solely on mass univariate analysis, potentially affecting result sensitivity. Additionally, limited consideration has been given to stimulus duration, a factor closely tied to some kinematic features (amplitude and velocity), which recently proposed modeling approaches now take into account. Here, we reanalyzed previously published data using univariate and multivariate analysis to understand how kinesthesia is neurally encoded in neurotypical subjects in two separate experiments. Systematic passive stimulation of the fingers was provided using an MR-compatible robot while functional magnetic resonance imaging data was recorded. Our analyses consisted of univariate and multivariate approaches, conducted separately for each kinematic feature and adjusted for stimulus duration, regardless of whether brain activation scales with it. We provide a detailed mapping of brain areas related to amplitude, velocity, and direction of passive finger movement, including sensorimotor, subcortical, and cerebellar areas. In general, multivariate pattern analysis was more sensitive than the univariate approach in identifying brain regions associated with passive finger movement. Our univariate analysis demonstrated that activity in sensorimotor and subcortical areas was higher for larger amplitudes and slower velocities, which opposes to the original studys results, likely due to our treatment of stimulus duration as a confounder specified as a parametric modulator. A novel result, we also demonstrated that brain activity in sensorimotor areas was higher for extension compared to flexion of passive finger movement. In terms of kinematic features, a larger neural representation was found for amplitude and direction compared to velocity of passive finger movement. This indicates that kinesthesia and proprioception may be more reliant on displacement than kinematic aspects of passive finger movement. While univariate analyses are limited in addressing spatial heterogeneity and subject-level variability, our multivariate analyses showed increased sensitivity in identifying brain regions encoding passive movement. Our findings may extend the knowledge of how the brain encodes physical movements and may help design neurorehabilitation strategies.

neuroscience↗

bioRxiv2024

Proton-pump inhibitors increase C. difficile infection risk by altering pH rather than by affecting the gut microbiome based on a bioreactor model

Clostridioides difficile infections often occur after antibiotic use, but they have also been linked to proton-pump inhibitor (PPI) therapy. The underlying mechanism--whether infection risk is due to a direct effect of PPIs on the gut microbiome or changes in gastrointestinal pH--has remained unclear. To disentangle both possibilities, we studied the impact of the proton-pump inhibitor omeprazole and pH changes on key members of the human gut microbiome and stool-derived microbial communities from different donors in vitro. We then developed a custom multiple-bioreactor system to grow a model human microbiome community in chemostat mode and tested the effects of omeprazole exposure, pH changes, and their combination on C. difficile growth within this community. Our findings show that changes in pH significantly affect the gut microbial communitys biomass and the abundances of different strains, leading to increased C. difficile growth within the community. However, omeprazole treatment alone did not result in such effects. These findings imply that the higher risk of C. difficile infection following proton-pump inhibitor therapy is probably because of alterations in gastrointestinal pH rather than a direct interaction between the drug and the microbiome. This understanding paves the way for reducing infection risks in proton-pump inhibitor therapy.

microbiology↗

bioRxiv2023

OPERANT REFLEX CONDITIONING SIMULATION ENVIRONMENT REVEALS EFFECTS OF FEEDBACK PARAMETERS

Operant conditioning of neural activation has been researched for decades in humans and animals. Many theories suggest two parallel learning processes, implicit and explicit. The degree to which feedback affects these processes individually remains to be fully understood and may contribute to a large percentage of non-learners. Our goal is to determine the explicit decision-making processes in response to feedback representing an operant conditioning environment. We developed a simulated operant conditioning environment based on a feedback model of spinal reflex excitability, one of the simplest forms of neural operant conditioning. We isolated the perception of the feedback signal from self-regulation of an explicit unskilled visuomotor task, enabling us to quantitatively examine feedback strategy. Our hypothesis was that feedback type, signal quality and success threshold affect operant conditioning performance and operant strategy. Healthy individuals (N = 41) were instructed to play a web application game using keyboard inputs to rotate a virtual knob representative of an operant strategy. The goal was to align the knob with a hidden target. Participants were asked to "down-condition" the amplitude of the virtual feedback signal, which was achieved by placing the knob as close as possible to the hidden target. We varied feedback type (knowledge of performance, knowledge of results), success threshold (easy, moderate, difficult), and biological variability (low, high) in a factorial design. Parameters were extracted from real operant conditioning data. Our main outcomes were the feedback signal amplitude (performance) and the mean change in dial position (operant strategy). We observed that performance was modulated by variability, while operant strategy was modulated by feedback type. These results show complex relations between fundamental feedback parameters and provide the principles for optimizing neural operant conditioning for non-responders.

neuroscience↗

bioRxiv2022

A network of small RNAs regulates sporulation initiation in C. difficile

The obligate anaerobic, enteric pathogen Clostridioides difficile persists in the intestinal tract by forming antibiotic resistant endospores that contribute to relapsing and recurrent infections. Despite the importance of sporulation for C. difficile pathogenesis, environmental cues, and molecular mechanisms regulating sporulation initiation remain ill defined. Here, using RIL-seq to capture the Hfq-dependent RNA-RNA interactome, we discovered a network of small RNAs that bind to mRNAs encoding sporulation-related genes. We show that two of these small RNAs, SpoX and SpoY, regulate translation of the master regulator of sporulation, Spo0A, in an opposing manner, which ultimately leads to altered sporulation rates. Infection of antibiotic-treated mice with SpoX and SpoY deletion mutants revealed a global effect on gut colonization and intestinal sporulation. Our work uncovers an elaborate RNA-RNA interactome controlling the physiology and virulence of C. difficile and identifies a complex post-transcriptional layer in the regulation of spore formation in this important human pathogen.

molecular biology↗

bioRxiv2019

Individual differences in the mechanistic control of the dopaminergic midbrain

The dopaminergic midbrain is associated with brain functions, such as reinforcement learning, motivation and decision-making that are often disturbed in neuropsychiatric disease. Previous research has shown that activity in the dopaminergic midbrain can be endogenously modulated via neurofeedback, suggesting potential for non-pharmacological interventions. However, the robustness of endogenous modulation, a requirement for clinical translation, is unclear. Here, we examined how self-modulation capability relates to regulation transfer. Moreover, to elucidate potential mechanisms underlying successful self-regulation, we studied individual prediction error coding, and, during an independent monetary incentive delay (MID) task, individual reward sensitivity. Fifty-nine participants underwent neurofeedback training either in a veridical or inverted feedback group. Successful self-regulation was associated with post-training activity within the cognitive control network and accompanied by decreasing prefrontal prediction error signals and increased prefrontal reward sensitivity in the MID task. The correlative link of dopaminergic self-regulation with individual differences in prefrontal prediction error and reward sensitivity suggests that reinforcement learning contributes to successful self-regulation. Our findings therefore provide new insights in the control of dopaminergic midbrain activity and pave the way to improve neurofeedback training in neuropsychiatric patients.

neuroscience↗

bioRxiv2019

Rectus femoris hyperreflexia predicts knee flexion angle in post-stroke Stiff-Knee gait

Stiff-knee gait (SKG) after stroke is often accompanied by decreased knee flexion angle during the swing phase. The decreased knee flexion has been hypothesized to originate from excessive quadriceps activation. However, it is unclear whether this activation is due to poor timing or hyperreflexia, both common post-stroke impairments. The goal of this study was to investigate the relation between quadriceps hyperreflexia in post-stroke SKG with knee flexion angle during walking. The rectus femoris (RF) H-reflex was recorded in eleven participants with post-stroke SKG and ten healthy controls during standing and walking during toe-off. In order to separate the effects of poorly timed quadriceps muscle activation from hyperreflexia, healthy individuals voluntarily increased quadriceps activity using RF electromyographic (EMG) biofeedback during standing and pre-swing upon H-reflex stimulation. We observed a negative correlation (R = -0.92, p=0.001) between knee flexion angle and RF H-reflexes in post-stroke SKG. In contrast, H-reflex amplitude in healthy individuals in presence (R = 0.47, p = 0.23) or absence (R = -0.17, p = 0.46) of increased RF activity had no correlation with knee flexion angle. The RF H-reflex amplitude differed between standing and walking in healthy individuals, including when RF activity was increased voluntarily (d = 2.86, p = 0.007), but was not observed post-stroke (d =0.73, p = 0.296). Thus, RF reflex modulation is impaired in post-stroke SKG. Further, RF hyperreflexia, as opposed to overactivity, may play a role in knee flexion kinematics in post-stroke SKG. Interventions targeting self-regulated quadriceps hyperreflexia may be effective in promoting better neural control of the knee joint and thus better quality of walking post-stroke.

bioengineering↗

bioRxiv2019

Hip circumduction is not a compensation for reduced knee flexion angle during gait

It has long been held that hip abduction compensates for reduced swing-phase knee flexion angle, especially in those after stroke. However, there are other compensatory motions such as pelvic obliquity (hip hiking) that could also be used to facilitate foot clearance with greater energy efficiency. Our previous work suggested that hip abduction may not be a compensation for reduced knee flexion after stroke. Previous study applied robotic knee flexion assistance in people with post-stroke Stiff-Knee Gait (SKG) during pre-swing, finding increased abduction despite improved knee flexion and toe clearance. Thus, our hypothesis was that hip abduction is not a compensation for reduced knee flexion. We simulated the kinematics of post-stroke SKG on unimpaired individuals with three factors: a knee orthosis to reduce knee flexion, an ankle-foot orthosis commonly worn by those post-stroke, and matching gait speeds. We compared spatiotemporal measures and kinematics between experimental factors within healthy controls and with a previously recorded cohort of people with post-stroke SKG. We focused on frontal plane motions of hip and pelvis as possible compensatory mechanisms. We observed that regardless of gait speed, knee flexion restriction significantly increased pelvic obliquity (2.79{degrees}, p<0.01) compared to unrestricted walking (1.5{degrees}, p<0.01), but similar to post-stroke SKG (3.4{degrees}). However, those with post-stroke SKG had significantly greater hip abduction (8.2{degrees}) compared to unimpaired individuals with restricted knee flexion (4.2{degrees}, p<0.05). These results show that pelvic obliquity, not hip abduction, compensates for reduced knee flexion angle. Thus, other factors, possibly neural, facilitate exaggerated hip abduction observed in post-stroke SKG.

bioengineering↗

bioRxiv2018

Neuromusculoskeletal simulation reveals abnormal rectus femoris-gluteus medius reflex coupling in post-stroke gait

Post-stroke gait is often accompanied by muscle impairments that result in adaptations such as hip circumduction to compensate for lack of knee flexion. Our previous work robotically enhanced knee flexion in individuals post-stroke with Stiff-Knee Gait (SKG), however, this resulted in greater circumduction, suggesting the existence of abnormal coordination in SKG. The purpose of this work is to investigate two possible mechanisms of the abnormal coordination: 1) an involuntary coupling between stretched quadriceps and abductors, and 2) a coupling between volitionally activated knee flexors and abductors. We used previously collected kinematic, kinetic and EMG measures from nine participants with chronic stroke and five healthy controls during walking with and without the applied knee flexion torque perturbations in the pre-swing phase of gait in the neuromusculoskeletal simulation. The measured muscle activity was supplemented by simulated muscle activations to estimate the muscle states of the quadriceps, hamstrings and hip abductors. We used linear mixed models to investigate two hypotheses: H1) association between quadriceps and abductor activation during an involuntary period (reflex latency) following the perturbation and H2) association between hamstrings and abductor activation after the perturbation was removed. We observed significantly higher rectus femoris (RF) activation in stroke participants compared to healthy controls within the reflex latency period following the perturbation based on both measured (H1, p < 0.001) and simulated (H1, p = 0.022) activity. Simulated RF and gluteus medius (GMed) activations were correlated only in those with SKG, which was significantly higher compared to healthy controls (H1, p = 0.030). There was no evidence of voluntary synergistic coupling between any combination of hamstrings and hip abductors (H2, p > 0.05) when the perturbation was removed. The RF-GMed coupling suggests an underlying abnormal reflex coordination pattern in post-stroke SKG. These results challenge earlier assumptions that hip circumduction in stroke is simply a kinematic adaptation due to reduced toe clearance. Instead, abnormal coordination may underlie circumduction, illustrating the deleterious role of abnormal coordination in post-stroke gait.

bioengineering↗

bioRxiv2018

Self-regulation of the Dopaminergic Reward Circuit in Cocaine Users with Mental Imagery and Neurofeedback

Background: Enhanced drug-related reward sensitivity accompanied by impaired sensitivity to non-drug related rewards in the mesolimbic dopamine system are thought to underlie the broad motivational deficits and dysfunctional decision-making frequently observed in cocaine use disorder (CUD). Effective approaches to modify this imbalance and reinstate non-drug reward responsiveness are urgently needed. Here we examine whether cocaine users (CU) can use mental imagery of non-drug rewards to self-regulate the ventral tegmental area and substantia nigra (VTA/SN). We expected that compulsive and obsessive thoughts about cocaine consumption would hamper the ability to self-regulate the VTA/SN. Finally, we tested if self-regulation of the VTA/SN can be improved with real-time fMRI (rtfMRI) neurofeedback (NFB).\n\nMethods: Twenty-two CU and 28 healthy controls (HC) were asked to voluntarily up-regulate VTA/SN activity with rewarding non-drug imagery alone, or combined with rtfMRI NFB of VTA/SN activity. Obsessive-compulsive drug use was measured with the Obsessive Compulsive Cocaine Use Scale (OCCUS).\n\nResults: CU were able to induce activity in the dopaminergic midbrain and other reward regions with reward imagery. The ability to self-regulate the VTA/SN was reduced in those with more severe obsessive-compulsive drug use. NFB enhanced the effect of non-drug imagery.\n\nConclusion: CU can voluntary activate their reward system through non-drug related imagery and improve this ability with rtfMRI NFB. Combining reward imagery and rtFMRI NFB has great potential for modifying the maladapted reward sensitivity and reinstating non-drug reward responsiveness. This motivates further work to examine the therapeutic potential of cognitive neurostimulation in CUD.

neuroscience↗