Biology subjects

Popa, T.

Publications and source records attributed to Popa, T..

10 recordsLinked to original sources

bioRxiv2026

Holotomography reveals biophysical remodeling of mouse oocytes during post-ovulatory aging

Routine assessment of oocyte state in reproductive biology and clinical embryology still relies largely on two-dimensional transmitted-light morphology, leaving the underlying three-dimensional intracellular organization largely unmeasured. Here, we use holotomography to reconstruct volumetric refractive index (RI) distributions in unlabeled live mouse oocytes and combine this imaging with sparse-annotation, AI-assisted compartment segmentation and multidimensional feature extraction across geometry, RI statistics, dry-mass density, and intracellular texture. Applied to an in vitro model of post-ovulatory aging, holotomography-derived biophysical profiles separated fresh and aged oocytes more strongly than two-dimensional brightfield-derived features, and feature-family ablation indicated that non-morphological descriptors contributed substantially to this separation. At the population level, aged oocytes showed coordinated ooplasmic remodeling, including reduced volume, increased RI heterogeneity, and increased dry-mass density while total dry mass was broadly conserved. These findings demonstrate a label-free quantitative framework for detecting post-ovulatory aging-associated biophysical remodeling in intact mammalian oocytes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/733271v1_ufig1.gif" ALT="Figure 1"> View larger version (89K): org.highwire.dtl.DTLVardef@c7257aorg.highwire.dtl.DTLVardef@6d92f0org.highwire.dtl.DTLVardef@1c9f7eborg.highwire.dtl.DTLVardef@b36637_HPS_FORMAT_FIGEXP M_FIG C_FIG

Developmental Biology↗

bioRxiv2026

Functional cerebellar connectomes interfacing motor adaptation and reinforcement feedback

Motor adaptation is driven by sensory prediction errors, yet reinforcement feedback can alter the speed and retention of adaptive behaviors. The cerebellum is central in motor adaptation, but posterior lobules, especially Lobule VI (CB6) and Crus I (CBcrus1), also participate in reinforcement-related signaling. Serotoninergic and dopaminergic systems, key modulators of motivational processes, directly influence cerebellar activity. However, how these neuromodulatory systems contribute to cerebellar network organization and to reinforcement-based adaptation in humans remains unclear. We employed a multimodal framework (Receptor-Enriched Analysis of functional Connectivity by Targets; REACT) using PET-derived Serotonin/Dopamine Transporter (SERT/DAT) templates to enrich resting-state functional Magnetic Resonance Imaging (rs-fMRI). We estimated SERT- and DAT-enriched functional connectivity from CB6 and CBcrus1 within motor-adaptation and reinforcement-learning networks, and tested their correlations with performance in a visuomotor adaptation task completed under reward and punishment. Our findings show lobule-specific neuromodulatory organization within the cerebellum. CB6 exhibited predominantly DAT- and SERT-enriched connectivity with motor adaptation networks, while CBcrus1 showed stronger SERT-enriched communication extending to both motor and reinforcement networks. Crucially, distinct cerebello-cortical neuromodulatory networks predicted individual differences in adaptation rate. DAT-enriched CBcrus1 connectivity was linked to punishment-driven adaptation, whereas SERT-enriched cerebello-orbitofrontal connectivity predicted faster adaptation across both reward and punishment contingencies. Furthermore, we observed overlaps between SERT- and DAT-enriched networks in the medial orbitofrontal area for Crus I, which predicted retention following punishment, underscoring the role of convergent neuromodulation in stabilizing adapted movements. We conclude that partially segregated yet convergent cerebello-cortical networks support interactions between motor and motivational behaviors, with combined and opposing effects of serotonergic and dopaminergic neuromodulation accounting for the speed and retention of adaptive behaviors.

neuroscience↗

bioRxiv2025

Novel Predictive Spatial Biomarker in Non-Small Cell Lung Carcinoma: The Diversity of Niches Unlocking Treatment Sensitivity (DONUTS)

Probabilistic spatial modelling techniques developed on large-scale tumor-immune Atlases ([~]35M individually mapped cells; 50,000 high power fields) were used to characterize predictive features of treatment-responsive lung cancer. We identified CD8+FoxP3+ cell density as a robust pre-treatment biomarker for outcomes across disease stages and therapy types. In parallel, single-cell RNAseq studies of CD8+FoxP3+ T-cells revealed an activated, early effector phenotype, substantiating an anti-tumor role, and contrasting with CD4+FoxP3+ T-regulatory cells. A spatial biomarker was developed using an empirical probabilistic model to define the immediate cell neighbors or niche surrounding CD8+FoxP3+ cells and proximity to the tumor-stromal boundary. The resultant Diversity of Niches Unlocking Treatment Sensitivity (DONUTS) are more prevalent than the CD8+FoxP3+ cells themselves, mitigating sampling error in small biopsies. Further, the DONUTS only require four markers, are additive to PD-L1, and associate with tertiary lymphoid structure counts. Taken together, the DONUTS represent a next-generation predictive biomarker poised for clinical implementation. HIGHLIGHTSO_LILarge-scale tumor-immune Atlases drive robust computational biomarker development C_LIO_LICD8+FoxP3+ cells are anti-tumor T-cells and predict response to therapy C_LIO_LIThe niches or spatial donuts around CD8+FoxP3+ cells boost biomarker performance C_LIO_LICD8+FoxP3+ donuts are hallmarks of a larger immune organization that includes TLS C_LI

pathology↗

bioRxiv2024

Emergence of Pre-movement Beta Activity with Stable Sensorimotor Predictions to Facilitate Motor Adjustments

Adaptive behavior enables flexible responses to environmental changes. This process is particularly crucial when transitioning between environments with different features, relying on the progressive formation of expectations based on prior experience. In humans, beta oscillations are central to adaptive behavior. Yet, the brain mechanisms underlying the detection of environmental changes, and the iterative update needed to progressively improve behavioral performance remain elusive. Here, we reveal that beta activity emerges in a cerebello-cortical network two seconds before action initiation, as the features of a new environment become known and behavioral outcomes become more predictable. Within this period, the cerebellum and parietal cortex drive prefrontal activity to form expectations. Using a single-trial approach, we establish that beta bursts before action initiation predict performance in the upcoming trial based on previous outcomes. These findings uncover a novel anticipatory mechanism that reflects predictive processes critical for stabilizing performance and adapting to environmental changes.

neuroscience↗

bioRxiv2023

Effects of hippocampal noninvasive theta-burst stimulation on consolidation of associative memory in healthy older adults

Stimulation of deep brain areas can offer benefits against cognitive impairments associated with aging. So far, this was only possible via invasive methods accompanied by risks. Grossman et al. proposed a new noninvasive stimulation technique, transcranial temporal interference electric stimulation (tTIS), which can be steered to target and modulate activity of deep brain structures. Memory capacity depends on subcortical structures such as the hippocampus, hence, modulation of hippocampal activity could benefit declining cognitive functions. The current study investigates whether theta-burst patterned tTIS targeting the hippocampus influences performance of associative memory in older adults. We found that theta-burst patterned tTIS, but not the control stimulation, improved recollection time in a follow-up 24h after the stimulation, suggesting that theta-burst patterned tTIS can influence the efficiency of longer-term encoding. This outcome indicates that tTIS may provide a new noninvasive deep brain stimulation method to modulate senescent memory processes.

neuroscience↗

bioRxiv2023

Not only a matter of age: Machine learning-based characterization of the differential effect of brain stimulation on skill acquisition

Brain stimulation shows potential at enhancing cognitive and motor functions in humans. However, multiple studies assessing its effects on behavior show heterogeneous results, especially in healthy older subjects. We propose a new method to predict an individuals likelihood and the magnitude of the benefit from stimulation, based on the baseline performance of a sequential motor task, framed in the context of their age. Our results show a differential effect of stimulation, in which individuals with less efficient learning mechanisms benefit from stimulation, while those possessing optimal learning strategies resent a detrimental effect. Importantly, this differential effect was determined by ones ability to integrate task-relevant information at the early stages of training, and not the age. This study paves the way towards the personalized application of stimulation to maximize its effects, and constitutes the first steps to implement an individualized translational clinical intervention, based on the state of the neural system. TeaserAge notwithstanding, brain stimulation is most effective in deficient neural systems, while being detrimental to optimal systems Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/544579v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@bcfab0org.highwire.dtl.DTLVardef@ee55e9org.highwire.dtl.DTLVardef@14a7519org.highwire.dtl.DTLVardef@14de600_HPS_FORMAT_FIGEXP M_FIG C_FIG Main findingAnodal transcranial direct current stimulation (atDCS), applied over the hand representation of the motor cortex concomitant to the training of a sequential motor sequence, has differential effects as a function of the recipients ability to integrate task-relevant information at the early stages of training. Stimulation benefits individuals with seemingly less efficient learning mechanisms, enabling the rapid storage of the spatial coordinates of the motor sequence and an accelerated optimization of the accuracy of execution. In contrast, individuals possessing optimal learning mechanisms experience detrimental effects of stimulation, leading to drops in the accuracy of execution.

neuroscience↗

bioRxiv2022

Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills

Reinforcement feedback can improve motor learning, but the underlying brain mechanisms remain underexplored. Especially, the causal contribution of specific patterns of oscillatory activity within the human striatum is unknown. To address this question, we exploited an innovative, non-invasive deep brain stimulation technique called transcranial Temporal Interference Stimulation (tTIS) during reinforcement motor learning with concurrent neuroimaging, in a randomised, sham-controlled, double-blind study. Striatal tTIS applied at 80Hz, but not at 20Hz, abolished the benefits of reinforcement on motor learning. This effect was related to a selective modulation of neural activity within the striatum. Moreover, 80Hz, but not 20Hz tTIS increased the neuromodulatory influence of the striatum on frontal areas involved in reinforcement motor learning. These results show for the first time that tTIS can non-invasively and selectively modulate a striatal mechanism involved in reinforcement learning, opening new horizons for the study of causal relationships between deep brain structures and human behaviour.

neuroscience↗

bioRxiv2022

LTP-like noninvasive striatal brain stimulation enhances striatal activity and motor skill learning in humans

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here, we show for the first time successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, fMRI studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional roles. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.

neuroscience↗

bioRxiv2021

Black-box testing in motor sequence learning

During learning of novel motor sequences, practice leads to the consolidation of hierarchical structures, namely motor chunks, facilitating the accurate execution of sequences at increasing speeds. Recent studies show that such hierarchical structures are largely represented upstream of the primary motor cortex in the motor network, suggesting their function to be more related to the encoding, storage, and retrieval of sequences rather than their sole execution. We isolated different components of motor skill acquisition related to the consolidation of spatiotemporal features and followed their evolution over training. We found that optimal motor skill acquisition relies on the storage of the spatial features of the sequence in memory, followed by the optimization of its execution and increased execution speeds (i.e., a shift in the speed-accuracy trade-off) early in training, supporting the model proposed by Hikosaka in 1999. Contrasting the dynamics of these components during ageing, we identified less-than-optimal mechanisms in older adults explaining the observed differences in performance. We applied noninvasive brain stimulation in an attempt to support the aging brain to compensate for these deficits. The present study found that anodal direct current stimulation applied over the motor cortex restored the mechanisms involved in the consolidation of spatial features, without directly affecting the speed of execution of the sequence. This led older adults to sharply improve their accuracy, resulting in an earlier yet gradual emergence of motor chunks. The results suggest the early storage of the sequence in memory, largely independent of motor practice, is crucial for an optimal motor acquisition and retrieval of this motor behavior. Nevertheless, the consolidation of optimal temporal patterns, detected as motor chunks at a behavioral level, is not a direct consequence of storing the sequence elements, but rather of motor practice.

neuroscience↗

bioRxiv2018

Modulation of Resting Connectivity Between the Mesial Frontal Cortex and Basal Ganglia

The mesial prefrontal cortex, cingulate cortex and the ventral striatum are key nodes of the human mesial fronto-striatal circuit involved in decision-making and executive function and pathological disorders. Here we ask whether deep wide-field repetitive transcranial magnetic stimulation (rTMS) targeting the mesial prefrontal cortex (MPFC) influences resting state functional connectivity. In Study 1, we examined functional connectivity using resting state multi-echo and independent components analysis in 154 healthy subjects to characterize default connectivity in the MPFC and mid-cingulate cortex (MCC). In Study 2, we used inhibitory, 1 Hz deep rTMS with the H7-coil targeting MPFC and dorsal anterior cingulate (dACC) in a separate group of 20 healthy volunteers and examined pre-and post-TMS functional connectivity using seed-based and independent components analysis. In Study 1, we show that MPFC and MCC have distinct patterns of functional connectivity with MPFC-ventral striatum showing negative, whereas MCC-ventral striatum showing positive functional connectivity. Low-frequency rTMS decreased functional connectivity of MPFC and dACC with the ventral striatum. We further showed enhanced connectivity between MCC and ventral striatum. These findings emphasize how deep inhibitory rTMS using the H7-coil can influence underlying network functional connectivity by decreasing connectivity of the targeted MPFC regions, thus potentially enhancing response inhibition and decreasing drug cue reactivity processes relevant to addictions. The unexpected finding of enhanced default connectivity between MCC and ventral striatum may be related to the decreased influence and connectivity between the MPFC and MCC. These findings are highly relevant to the treatment of disorders relying on the mesioprefrontal-cingulo-striatal circuit.

neuroscience↗