Biology subjects

Dimitriou, M.

Publications and source records attributed to Dimitriou, M..

14 recordsLinked to original sources

bioRxiv2026

Independent Online Visuomotor Control to Cursor and Target Motion

Skilled control of visually-guided reaching is fundamental for many daily activities. Visual information about hand and target position are used for movement planning and online corrections through rapid visuomotor feedback responses. Such feedback control is generally believed to implicate a single error signal, representing a difference vector between hand and target position. Here, we directly assess whether shared or independent systems serve visually-guided feedback control. We tested whether feedback gains can be independently modulated by hand/cursor and target motion through manipulating the task-relevance of each signal during goal-directed reaching. Our results demonstrate that the gains of visuomotor feedback responses to perturbed hand and target motion can be set independently of one another, at the same time, as a function of task-relevance. By dissociating feedback control of cursor and target signals, our findings support the existence of two independent visuomotor feedback pathways, revealing a more flexible neural architecture for goal-directed action.

neuroscience↗

bioRxiv2026

Rapid experience-dependent tuning of spinal and transcortical stretch reflexes supports goal-directed movement

The short-latency stretch reflex (SLR) is the fastest sensorimotor response in human limbs. The spinal SLR is traditionally viewed as automatic and resistant to rapid plasticity, while adaptive feedback is often attributed to transcortical mechanisms underlying the long-latency reflex. Using high-density surface electromyography (64-channel arrays) from the pectoralis major and posterior deltoid during an instructed-delay reaching task, we probed reflex gains with brief perturbations delivered during action preparation. Pre-perturbation muscle activity showed no systematic goal-directed change. After task familiarization and with sufficient preparation time, SLR gains decreased progressively (logarithmically) with experience when the planned movement was expected to stretch the homonymous muscle. This tuning occurred both with and without agonist muscle pre-loading and predicted the observed improvements in reaching performance. Early transcortical responses showed comparable tuning across load conditions. Our study shows that spinal feedback circuits can progressively adapt within a single session to support the performance of goal-directed movements. HighlightsO_LIThe short-latency stretch reflex adapts rapidly with experience in planned reaching C_LIO_LISpinal reflex tuning occurs with and without agonist muscle pre-loading C_LIO_LIReflex tuning evolves logarithmically and predicts reaching performance C_LIO_LIEarly transcortical reflex gains show comparable experience-dependent tuning C_LI

neuroscience↗

bioRxiv2025

Preparation duration shapes the goal-directed tuning of stretch reflex responses

Stretch reflex responses are important for counteracting perturbations, and the modulation of stretch reflex gains can assist the voluntary movement quality and performance. Recent findings suggest that movement preparation includes goal-directed tuning of muscle spindles, facilitating a concurring modulation of reflex gains. In the context of delayed-reach, goal-directed modulation of stretch reflex gains is present when the homonymous muscle is unloaded (i.e., antagonist load) and the preparatory delay is sufficiently long (>250 ms and <750 ms). This study examined how multiple preparatory delays impact the goal-directed modulation of short- and long-latency stretch reflex (SLR and LLR) gains of the pectoralis, anterior and posterior deltoid muscles in a delayed-reach task. We used electromyographic signals to quantify stretch reflex responses of healthy subjects that experienced haptic perturbations induced by a robotic manipulandum in a delayed-reach task. We found that a preparatory delay of 300 ms is sufficient for goal-directed tuning of SLR responses in the pectoralis and posterior deltoid muscles, and 400 ms allows for even stronger goal-directed tuning of stretch reflex responses. In contrast, there was no goal-directed modulation in the SLR of the anterior deltoid. Tuning of LLR gains was robustly goal-dependent throughout, with negligible modulation across preparatory delays. Our results clarify the minimum preparatory time required for goal-directed tuning of stretch reflex gains and characterise the relationship between reflex gains and preparation duration. This relationship is not strictly linear, likely reflecting the interplay of multiple feedback mechanisms functioning at different time frames.

neuroscience↗

bioRxiv2024

Temporal shift in task factor influence across the stretch reflex

Mechanical perturbations applied to the arm can elicit reflexive actions. These rapid corrective responses include the stretch reflex, which consists of different components: the short-latency reflex (SLR) as well as the early and late long-latency reflex (LLR). In this study, we explore how different task factors dynamically influence these reflex components in the context of a specific delayed-reach paradigm. Using multiple linear regression (MLR), we analysed reflex responses from seven muscles actuating the right arm to examine the effects of mechanical load, preparatory delay, perturbation and target direction, as well as their two-factor interactions. The MLR analysis shows that our delayed-reach tasks engaged shoulder girdle muscles, whereas the biceps and triceps primarily acted as stabilizing muscles, with rapid responses triggered regardless of perturbation direction. Specifically, our analyses show that the earliest corrective response, the SLR, exhibited some task/target-dependent modulation particularly in muscles of the shoulder girdle, although background (pre-)loading decreased this modulation. The SLR was primarily influenced by the main factors Load and Perturbation, along with the interaction Load x Perturbation. Perturbations aligned with the load direction were associated with increased electromyographic (EMG) activity across all examined muscles. While there was a small but significant effect of load during the early LLR, this effect diminished by the late LLR epoch. Task-dependent modulation was most pronounced at the late LLR epoch, suggesting greater top-down modulation of this reflex component. In particular, the late LLR was shaped by the factors Perturbation and Target, as well as the interaction Perturbation x Target. Targets and perturbations in opposing directions resulted in heightened EMG activity, and shoulder muscles exhibited stronger LLR responses for targets located farther along the muscle shortening direction. Across all reflex epochs, a longer preparatory delay (750 ms) was associated with higher EMG activity.

neuroscience↗

bioRxiv2024

Modeling Sensorimotor Processing with Physics-Informed Neural Networks

Proprioception is essential for planning and executing precise movements. Muscle spindles, the key mechanoreceptors for proprioception, are the principle sensory neurons enabling this process. Emerging evidence suggests spindles act as adaptable processors, modulated by gamma motor neurons to meet task demands. Yet, the specifics of this modulation remain unknown. Here, we present a novel, physics-informed neural network model that integrates biomechanics and neural dynamics to capture spindle function with high fidelity and efficiency, while maintaining computational tractability. Through validation across multiple experimental datasets and species, our model not only outperforms existing approaches but also reveals key drivers of variability in spindle responses, offering new insights into proprioceptive mechanisms.

neuroscience↗

bioRxiv2024

Local muscle pressure stimulates the principal receptors for proprioception

Proprioception plays a crucial role in motor coordination and self-perception. Muscle spindles are the principal receptors for proprioception. They are believed to encode muscle stretch and signal limb position and velocity. Here, we applied percutaneous pressure to a small area of extensor muscles at the forearm while recording spindle afferent responses, skeletal muscle activity and hand kinematics. Three levels of sustained pressure were applied on the spindle-bearing muscle when the hand was relaxed and immobile ( isometric condition) and when the participants hand moved rhythmically at the wrist. As hypothesized to occur due to compression of the spindle capsule, we show that muscle pressure is an adequate stimulus for human spindles in isometric conditions, and that pressure enhances spindle responses during stretch. Interestingly, release of sustained pressure in isometric conditions lowered spindle firing below baseline rates. Our findings urge a re-evaluation of muscle proprioception in sensorimotor function and various neuromuscular pathologies. HIGHLIGHTSO_LILocal muscle pressure is an adequate stimulus for spindles in isometric conditions C_LIO_LIRelease of pressure in isometric conditions lowers spindle firing below baseline rates C_LIO_LILocal muscle pressure enhances spindle afferent responses during muscle stretch C_LI

neuroscience↗

bioRxiv2023

Erythroid differentiation intensifies RNA mis-splicing in SF3B1-mutant myelodysplastic syndromes with ring sideroblasts

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly originate from mutations in the splicing factor SF3B1 (SF3B1mt). SF3B1mt cause RNA mis-splicing, mechanistically established as the major driver of RS development. However, little is known about RS fate and biology after their initial formation in the human bone marrow. We here achieve isolation of viable RS from patient samples, enabling the first complete investigation of SF3B1mt development from stem cell to RS. We show that RS skew MACS-isolated CD34+ data towards erythroid features not recapitulated in single-cell RNAseq. We demonstrate that RS divide, differentiate, enucleate and actively respond to mis-splicing/oxidative stress, decreasing wildtype stem cell fitness via GDF15 overproduction. We identify circulating RS as a uniform clinical feature associated with disease burden. Finally, we establish that SF3B1mt mis-splicing intensifies during erythroid differentiation and demonstrate through combined transcriptomics/proteomics an uncoupling of RNA/protein biology in RS encompassing severe and dysfunctional mis-splicing of proapoptotic genes. Statement of significanceWe here combine a novel method for RS isolation with state-of-the-art multiomics to perform the first complete investigation of SF3B1mt MDS-RS hematopoiesis from stem cell to RS. We identify the survival mechanisms underlying SF3B1mt erythropoiesis and establish an active role for erythroid differentiation and RS themselves in SF3B1mt MDS-RS pathogenesis.

cancer biology↗

bioRxiv2023

Congruent visual cues speed dynamic motor adaptation

Motor adaptation to novel dynamics occurs rapidly using sensed errors to update the current motor memory. This adaption is strongly driven by proprioceptive and visual signals, that indicate errors in the motor memory. Here we extend this previous work by investigating whether the presence of additional visual cues could increase the rate of motor adaptation, specifically when the visual motion cue is congruent with the dynamics. Six groups of participants performed reaching movements while grasping the handle of a robotic manipulandum while an additional cue (red object) was connected to the cursor. After a baseline, either a unidirectional (3 groups) or bidirectional (3 groups) velocity dependent force field was applied during the reach. For each group, the movement of the red object relative to the cursor was either congruent with the force field dynamics, incongruent with the force field dynamics or constant (fixed distance). Participants adapted more to the unidirectional force fields than to the bidirectional force field groups. However, across both force fields, groups in which the visual cues matched the type of force field (congruent visual cue) exhibited higher final adaptation level at the end of learning compared to either the control or incongruent conditions. In all groups, we observed an additional congruent cue assisted the formation of the motor memory of the external dynamics. We then demonstrate that a state estimation based model that integrates proprioceptive and visual information can successfully replicate the experimental data. New & NoteworthyWe demonstrate that adaptation to novel dynamics is stronger when additional online visual cues that are congruent with the dynamics are presented during adaptation, compared to either a constant or incongruent visual cue. This effect was found regardless of whether a bidirectional or unidirectional velocity dependent force field was presented to the participants. We propose that this effect might arise through the inclusion of this additional visual cue information within the state estimation process.

neuroscience↗

bioRxiv2022

Goal-directed modulation of stretch reflex gains is reduced in the non-dominant upper limb

Most individuals experience their dominant arm as being more dexterous than the non-dominant arm, but the neural mechanisms underlying this asymmetry in motor behaviour are unclear. Using a delayed reach task, we have recently demonstrated strong goal-directed tuning of stretch reflex gains in the dominant upper limb of human participants. Here, we used an equivalent experimental paradigm to address the neural mechanisms that underlie the preparation for reaching movements with the non-dominant upper limb. We found only minor goal-directed differences in the short latency stretch reflex of the non-dominant limb. There were consistent effects of load, preparatory delay duration and target direction on the long latency stretch reflex. However, by comparing stretch reflex responses in the non-dominant arm with those previously documented in the dominant arm, we demonstrate that goal-directed tuning of short and long latency stretch reflexes is markedly weaker in the non-dominant limb. The results indicate that the motor performance asymmetries across the two upper limbs is partly due to the more sophisticated control of reflexive stiffness in the dominant limb, likely facilitated by the superior goal-directed control of muscle spindle receptors. Our findings therefore suggest that independent fusimotor control plays a role in determining performance of complex motor behaviours and support existing proposals that the dominant arm is better supplied for executing more complex tasks, such as trajectory control. Key pointsO_LIMost of us routinely rely on the dominant arm to perform more complex and demanding motor tasks, but the mechanisms enabling the superior motor performance of the dominant limb are unclear. C_LIO_LIA better understanding of the motor asymmetry across the two arms might provide key insight into core sensorimotor principles. C_LIO_LIThis study shows that goal-directed tuning of short and long latency stretch reflexes in the non-dominant arm is markedly weaker than in the dominant arm. C_LIO_LIOur results suggest that the more sophisticated control of reflexive stiffness in the dominant limb, likely facilitated by superior fusimotor control, partly underpins the laterality of motor performance. C_LI

neuroscience↗

bioRxiv2022

Assistive loading promotes goal-directed tuning of stretch reflex gains

Voluntary movements are prepared before they are executed. Preparatory activity has been observed across the CNS and recently documented in first order neurons of the human PNS i.e., in muscle spindles. The changes seen in these sensory organs suggest that the independent modulation of stretch reflex gains may represent an important component of movement preparation. The aim of the current study was to further investigate the preparatory modulation of short- and long-latency stretch reflex responses ( SLR and LLR) of the dominant upper limb. Specifically, we investigated how different target parameters (target distance and direction) affect the preparatory tuning of stretch reflex gains in the context of goal-directed reaching, and whether any such tuning depends on preparation duration and the direction of background loads. We found that target distance produced only small variations in reflex gains. In contrast, both SLR and LLR gains were strongly modulated as a function of target direction, in a manner that facilitated the upcoming voluntary movement. This goal-directed tuning of SLR and LLR gains was present or enhanced when the preparatory delay was sufficiently long (>250 ms) and the homonymous muscle was unloaded i.e., when a background load was first applied in the direction of homonymous muscle action (assistive loading). The results extend further support for a relatively slow-evolving process in reach preparation that functions to modulate reflexive muscle stiffness, likely via the independent control of fusimotor neurons. Such control can augment voluntary goal-directed movement and is triggered or enhanced when the homonymous muscle is unloaded. Significance StatementIt is well-known that movement preparation improves motor performance. That is, briefly delaying the onset of a goal-directed movement can significantly benefit the overall quality of movement. However, the mechanisms underlying movement preparation remain unclear. In this study we examined the preparatory modulation of short- and long-latency stretch reflex responses in the dominant upper limb. We found that goal-directed tuning of stretch reflex gains is consistently triggered or enhanced in cases where preparation is sufficiently long (>250 ms) and a background - assistive- load is first applied in the direction of homonymous muscle action. A better understanding of movement preparation will likely also benefit the development of rehabilitation regimes and movement augmentation devices.

neuroscience↗

bioRxiv2022

Identification of GTF2IRD1 as a novel transcription factor essential for acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood malignancy characterized by clonal accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Transcription factors are the most frequently mutated and dysregulated genes in AML, and they have critical roles in AML pathogenesis and progression. In this study, we performed large-scale RNA interference screens in MLL-AF9-transformed AML cells and identified GTF2IRD1 as a novel transcription factor essential for the survival of various types of myeloid leukemic cells in vitro and in vivo, but not for primary normal hematopoietic cells. Inhibition of GTF2IRD1 reduced the frequency of primary childhood and adult AML cells, including cell populations enriched for leukemia-initiating cells. In animal models for AML, inhibition of GTF2IRD1 significantly delayed the disease progression. Loss of GTF2IRD1 promoted accumulation of AML cells in the G0 phase of the cell cycle but caused minor effects in apoptosis induction. In line with this, RNA sequencing analysis revealed a significant downregulation of E2F targets as a consequence of genetic inhibition of GTF2IRD1. Taken together, we identified GTF2IRD1 as a transcription factor with a selective importance in AML, and our findings may contribute to the development of improved therapeutic inventions for the disease.

cancer biology↗

bioRxiv2020

Goal-dependent tuning of muscle spindle receptors during movement preparation

Voluntary movements are believed to be advantageously prepared before they are executed, but the neural mechanisms at work have been unclear. For example, there are no overt changes in skeletal muscle activity during movement preparation. Here, using a delayed-reach manual task, we demonstrate a decrease in the firing rate of human muscle afferents (primary spindles) when preparing stretch rather than shortening of the spindle-bearing muscle. This goal-dependent modulation of proprioceptors begun early after target onset but was markedly stronger at the latter parts of the preparatory period. In two additional experiments, whole-arm perturbations during reach preparation revealed a congruent modulation of stretch reflex gains of shoulder and upper arm muscles. Our study shows that movement preparation can involve sensory elements of the peripheral nervous system. We suggest that central preparatory activity can also reflect sensory control, and preparatory tuning of muscle spindle mechanoreceptors is a component of planned reaching movements.

neuroscience↗

bioRxiv2019

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active replication comprises only cells with intact provirus that can be reactivated. We confirmed that latently infected cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of viral latency during proviral chromatin maturation in cultures of primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.

microbiology↗

bioRxiv2017

Task-dependent modulation of spinal and transcortical stretch reflexes linked to motor learning rate

It is generally believed that task-dependent control of body configuration ( posture) is achieved by adjusting voluntary motor activity and transcortical long-latency reflexes. Spinal monosynaptic circuits are thought not to be engaged in such task-level control. Similarly, being in a state of motor learning has been strongly associated only with an upregulation of feedback responses at transcortical latencies and beyond. In two separate experiments, the current study examined the task-dependent modulation of stretch reflexes by perturbing the hand of human subjects while they were waiting for a Go signal to move at the different stages of a classic kinematic learning task (visuomotor rotation). Although the subjects had to resist all haptic perturbations equally, the study leveraged that task-dependent feedback controllers may already be loaded at the movement anticipation stage. In addition to an upregulation of short- and long-latency reflex gains during early exposure to the visual distortion, I found a relative inhibition of reflex responses in the washout stage (sensory realignment state). For more distal muscles (brachioradialis), this inhibition also extended to the monosynaptic reflex response ( R1). These R1 gains reflected individual motor learning performance in the visuomotor task. The results demonstrate that the systems control policy in visuomotor adaptation can also include inhibition of proprioceptive reflexes, and that aspects of this policy can affect monosynaptic spinal circuits. The latter finding suggests a novel form of state-related control, probably realized by independent control of fusimotor neurons, through which segmental circuits can tune to higher-level features of a sensorimotor task.\n\nAdditional InformationO_ST_ABSConflict of interestC_ST_ABSThe author declares no conflict of interest.\n\nAuthor contributionsM.D. devised, designed and implemented the project, analyzed the data and wrote the manuscript. The author approves the final version of the manuscript and is fully accountable for all aspects of the work. The experiments were performed at the Department of Integrative Medical Biology, Ume[a] University, Sweden.\n\nFundingThis work was financially supported through grants awarded to M.D. by the Kempe Foundation, the local Foundation for Medical Research (\"Insamlingsstiftelsen\") and the Swedish Research Council (project 2016-02237).

neuroscience↗