bioRxiv Subject Collection: Neuroscience's Journal

Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, with TDP-43 pathology present in over 90% of cases. While neuroinflammation is a recognized hallmark, the role of microglia in ALS pathogenesis remains incompletely understood. Here, we demonstrate that TDP-43 regulates microglial function via triglyceride metabolism. Using shRNA-mediated TARDBP knockdown in human monocyte-derived microglia-like cells (MDMi), we observed suppressed cholesterol biosynthesis, upregulation of fatty acid metabolism genes, lipid droplet accumulation, enhanced phagocytic activity, and increased IL-1{beta} production. Inhibiting diacylglycerol acyltransferase (DGAT) enzymes reduced lipid droplet formation, phagocytosis, and IL-1{beta}, directly linking the triglyceride pathway to microglial activation. Patient-derived MDMi from both sporadic and TARDBP-mutant ALS cases showed overlapping as well as distinct alterations, some of which were reversed by DGAT inhibition. Our findings identify dysregulated triglyceride metabolism as a novel pathway through which TDP-43 mediates microglial dysfunction, highlighting a potential therapeutic target for ALS.

Proteomic and Kinetic Characterization of Prion Seeding in Distinct Human CJD Strains Unveils Early Diagnostic Biomarkers
To enhance understanding of early diagnosis, disease progression, and molecular signatures of human prion strains, we analyzed prion seeding activity in Creutzfeldt Jakob disease (CJD) infected mice using the real-time quaking-induced conversion (RT-QuIC) assay. Infectious prion strains derived from CJD-MM1 and VV2 human brain tissues were inoculated into tg340, tg361 (expressing ~4x human PrP-M129 or PrP-V129), and tg650 (expressing ~6x human PrP-M129) mice. We examined 188 brain samples from confirmed CJD-infected and control mice at pre-clinical and clinical stages. Region- and strain-specific differences in seeding activity emerged at pre-clinical stages. Lag phases ranged from 7.5 - 24.5 h across regions and stages: MM1-infected tg340 cortex displayed prolonged lag (~24.5 h), while VV2-infected tg341 cortex showed minimal seeding. In contrast, VV2 cerebellum exhibited shorter lag phases at clinical stage but significantly reduced fluorescence signals at pre-clinical stage. Proteomic profiling (SWATH-MS) revealed 500 and 682 differentially expressed proteins in MM1 and VV2 models, respectively. Early pre-clinical alterations included Gnl1, Stxbp1, Pllp, Nefh, Ahsa1, Rala, and Atp2b2 in MM1, and Tnc, Calb2, Dnaja1, Hpcal1, Prkca, and Syn2 in VV2, correlating with detectable prion replication. Functional analyses suggested distinct compensatory responses: MM1 involved metabolic reprogramming and vesicle clearance, while VV2 showed early calcium signaling disturbances and structural impairment. These findings demonstrate that RT-QuIC combined with proteomics enables sensitive detection of strain-specific pre-clinical changes, providing mechanistic insights into prion pathogenesis and identifying potential biomarkers for early diagnosis. Key words: Prion diseases, Creutzfeldt-Jakob disease (CJD), RT-QuIC, molecular profiling, prion seeding activity, biomarkers, SWATH-MS, disease progression.

REM sleep prefrontal ripple chains mediate distinct cortical-hippocampal reactivation patterns compared to NREM ripples
REM (rapid eye movement) and non-REM (NREM) sleep stages are both critical for systems memory consolidation in hippocampal-cortical circuits. However, the physiological mechanisms underlying REM memory processes remain relatively unclear compared to NREM memory reactivation. Here we report, in rodents, the existence of prefrontal cortical (PFC) high-frequency ripple chains in REM sleep during consolidation of recently acquired spatial memory. High-density tetrode recordings in hippocampal area CA1 and PFC reveal that, in contrast to NREM cortical ripples, REM cortical ripples occur in characteristic chains that are phase modulated by theta oscillations in phasic REM sleep, corresponding to increased CA1-PFC theta coherence and delineating periods of enhanced hippocampal-cortical communication. REM ripple chains sequentially organize sparse PFC ensemble reactivation of behavioral activity during periods of local suppression, distinct from widespread reactivation bursts during NREM ripples. REM ripple chains also selectively engage CA1 neuronal populations that shift preferred theta-phase from behavior to REM sleep. Co-reactivation of PFC and CA1 neurons during REM ripple chains was linked to CA1 activity suppression during NREM PFC ripples, and to differential changes in CA1 neuronal firing rates in sleep, suggesting REM-driven regulation of hippocampal excitability. A cortical network model incorporating the effects of acetylcholine can reproduce the distinct REM and NREM activity patterns, providing a mechanistic basis for widespread coactivity during NREM cortical ripples, compared to sparse, temporally extended reactivation on a background of local suppression during REM ripple chains. Overall, these findings establish a role for PFC ripples in regulating distinct dual sleep stage cortical-hippocampal reactivation patterns.

Social observation influences the trajectory of performance monitoring across trials: evidence from single-trial estimates of the ERN and CRN
The error-related negativity (ERN) and correct-related negativity (CRN) are event-related potentials (ERPs) that reflect performance monitoring following error and correct responses, respectively. Prior work demonstrates the ERN is sensitive to the motivational significance of errors, which increases under social observation. However, most studies testing how social observation impacts performance monitoring rely on trial-averaged ERPs, potentially obscuring meaningful fluctuations in ERN/CRN over time. Here, we had participants complete a Flanker task twice (social observation vs. alone) and employed mixed-effects modeling of single-trial ERPs to test if social observation impacts ERN/CRN trajectories over short (within blocks) or long (between blocks) timescales. We found that social observation selectively influenced ERN/CRN trajectories over short timescales: for blocks performed under social observation (but not alone), ERN magnitudes increased across trials and CRN magnitudes decreased. At longer timescales, ERN/CRN significantly decreased across all blocks, regardless of social observation and consistent with a vigilance decrement. To our knowledge, this is the first demonstration that social observation influences performance monitoring trajectories over short timescales. Results highlight the importance of analyzing ERN/CRN trajectories over relatively short timescales to fully characterize the impact of social observation on performance monitoring dynamics. These findings lay the groundwork for future investigation into whether social observation interacts with individual differences in motivation/affect to differentially impact performance monitoring dynamics.

Virtual Reality and Tablet Cognitive Training Improve Attention and Academic Skills Without Dose Effects
We evaluated the cognitive and academic effects of a closed-loop video game delivered in virtual reality (VR) and tablet formats, at two different dosages, in a school-based setting. A total of 158 children aged 8-9 with a range of attention abilities completed 30 training sessions over 10 weeks. Compared to an expectancy-matched control group, both VR and tablet training led to significant improvements in teacher-rated inattention, performance-based attention tasks, and eye-tracking measures. While both VR and tablet versions of the intervention showed benefits on specific attention-related and academic outcomes, the VR version showed select advantages in both regards. Notably, intervention dose did not significantly moderate outcomes, suggesting that efficacy may depend more on reaching a threshold of engagement than on total duration. These findings demonstrate the utility and benefits of using each type of technology to enhance measures of cognitive and academic abilities as part of a regular school curriculum.

Patch-Clamp Single-Cell Proteomics in Acute Brain Slices: A Framework for Recording, Retrieval, and Interpretation
Single-cell proteomics (SCP) is a powerful method for interrogating the molecular composition of neurons, yet its application to acute brain slices has remained limited. Patch-clamp electrophysiology provides direct information on neuronal excitability, synaptic inputs, and ion channel function, making it a natural partner for SCP. However, combining these techniques introduces unique challenges: neurons must be both physiologically characterized and physically collected, and variability during retrieval from the brain slice can affect how faithfully proteomic measurements reflect in situ physiology. Here, we introduce a framework for interpreting patch-SCP outcomes that considers retrieval quality in terms of both the amount of material collected and the synaptic contents being recovered. Using a shotgun strategy in which all patched neurons were collected regardless of electrophysiological outcome, we systematically benchmarked the retrieval of pyramidal neurons in the rat medial prefrontal cortex. Capacitance measured during gigaseal-preserved retrieval correlated with protein identifications, providing a proxy for linking soma size to proteome yield. Preservation of neuronal spiking during relocation was associated with broader synaptic enrichment and recovery of transmembrane proteins. By comparison, torn or aspirated neurons produced small proteomes with poor synaptic representation and neurons with lost gigaseals or no recordings displayed variable outcomes that could still yield substantial molecular information. Together, these results establish shotgun patch-SCP as both proof-of-concept and a practical framework for linking neuronal physiology with proteomics in semi-intact circuits.

Effects of TMS on the decoding, electrophysiology, and representational geometry of priority in working memory
The flexible control of working memory (WM) requires prioritizing immediately task-relevant information while maintaining information with potential future relevance in a deprioritized state. Using double-serial retrocuing (DSR) with simultaneous EEG recording, we investigated how single pulses of transcranial magnetic stimulation (spTMS) to right intraparietal sulcus impacts neural representations of unprioritized memory items (UMI), relative to irrelevant memory items (IMI) that are no longer needed for the trial. Twelve human participants (8 female) performed DSR plus a single-retrocue task, while spTMS was delivered during delay periods. Multivariate pattern analysis revealed that spTMS restored decodability of the UMI concurrent with stimulation, and that of the IMI several timesteps later, after the evoked effects of spTMS were no longer present in the EEG signal. This effect was carried by the alpha and low-beta frequency bands. Analyses of the EEG showed two effects selective to the UMI: both the retrocue designating the UMI and spTMS produced phase shifts in the low-beta band. These results were mirrored by representational geometry analyses, which revealed larger cue-related and spTMS-related rotations of the UMI-representing subspace, compared to the prioritized subspace spTMS. These findings demonstrate that deprioritization involves active neural mechanisms distinct from the processing of the IMI, and that these are supported by low-beta oscillatory dynamics in parietal cortex. We hypothesize that the mechanism underlying spTMS-triggered involuntary retrieval of the UMI is the disruption of the encoding of priority status, which may depend on oscillatory dynamics in the low-beta band.

Fusogen-induced recovery of spinal cord function andmorphology after complete transection
Background: Spinal cord injury is a critical issue in neurosurgery, lacking established clinical methods for functional restoration. This study reports the effects of a fusogen sealant, composed of polyethylene glycol and chitosan, in an experimental model of complete spinal cord transection in pigs. Objective: To evaluate the functional and morphological recovery of the spinal cord in an animal model of complete transection following treatment with a polyethylene glycol-chitosan conjugate.Materials and methods: Hungarian Mangalica pigs (m = 20.0 {+/-} 2.0 kg, N = 5) underwent complete transection of the thoracic spinal cord, followed by an extended laminectomy and transpedicular fixation. In the experimental group (N = 3), a synthesized gel based on a polyethylene glycol-chitosan conjugate was applied to the spinal gap; the other group (N = 2) served as a control. The postoperative period lasted 60 days and included multi-component rehabilitation. Clinical-functional status was assessed using established neurological scales. In vivo retrograde tracing of the spinal cord was performed using hydroxystilbamidine (FluoroGold). Following the experiment, immunofluorescent histology was conducted using primary antibodies to neurofilament (NF-200), a fluorochrome-conjugated secondary antibody, and the nuclear dye 4',6-diamidino-2-phenylindole (DAPI). The resulting morphology was examined via fluorescence and light microscopy. Results: Control animals maintained lower paraplegia, anesthesia, and pelvic dysfunction throughout the experiment. In contrast, the experimental group showed positive changes, including the return of sensation from day two. By the end of the study, all animals in this group could assume an upright posture and ambulate on all limbs. These outcomes were statistically significant. Microscopy revealed axons traversing the injury site in the experimental group, whereas control samples showed degenerative post-traumatic changes. Conclusions: This study demonstrates that a fusogen sealant based on a polyethylene glycol-chitosan conjugate promotes significant morphofunctional recovery after complete spinal cord transection, supporting its therapeutic potential. Keywords: spinal cord injury, polyethylene glycol, PEG, chitosan, PEG-chitosan, Neuro-PEG, fusogens, fusogen sealants.

Distinct perceptual and conceptual representations of natural actions along the lateral and dorsal visual streams: an EEG-fMRI fusion study
Actions are the building blocks of our dynamic visual world, yet the neural computations supporting action perception are not well understood. How does perceptual and conceptual information unfold in the brain when we observe what others are doing? We collected EEG and fMRI data while participants viewed short videos and sentences depicting naturalistic actions. Using representational similarity analysis, we found a posterior-to-anterior gradient along the lateral pathway, from perceptual features to conceptual, modality-invariant representations. Among conceptual features, the target of actions (i.e. whether the action was directed at an object, a person, or the self) explained the most unique variance in EEG responses. In fMRI, we found distinct conceptual representations along the ventral, dorsal, and lateral pathways, with the target of actions specifically encoded in lateral occipitotemporal cortex (LOTC) and posterior superior temporal sulcus (pSTS). Finally, EEG-fMRI fusion revealed rapid processing along the lateral and dorsal pathways. Together, our results disentangle the perceptual and conceptual components of action understanding and characterize the underlying spatiotemporal dynamics in the human brain.

Comparative distribution of the hypothalamic neurons activated during Wakefulness and Paradoxical (REM) sleep using TRAP2-red mice: contribution of Orexin, MCH, Lhx6 and a new marker Meis2
Study objectives: Paradoxical sleep (PS) is a state involving numerous hypothalamic neuronal subpopulations, many remaining neurochemically uncharacterized. Our goal was to compare hypothalamic neurons active during Wakefulness or PS rebound (PSR) and explore their potential overlap, with a focus on melanin-concentrating-hormone (MCH), Orexin (Orx), Lhx6 and a new contingent of Meis2-expressing neurons. Method: In the same TRAP2-red mouse, neurons activated during Wakefulness (4h) and PSR (2h) express TdTomato and c-Fos, respectively. Double-labelling and triple immunofluorescence with neurochemical markers were performed to characterize and quantify cell populations in hypothalamic structures. Results: Twelve hypothalamic structures showed distinct activation patterns. The anterior hypothalamic area (AHA), zona incerta (ZI) and tuberal nucleus contained more activated neurons during PSR than Wakefulness, whereas the paraventricular hypothalamic (PVN) and supraoptic (SO) nuclei were predominantly activated during Wakefulness. MCH and Lhx6 neurons were mainly recruited during PSR, whereas Orx neurons were activated during both. A ventral subpopulation of MCH neurons showed higher activation during PSR than the dorsal subpopulation. Additionally, ~30% of the c-Fos+ neurons in ZI and AHA express Meis2. A similar proportion of TdTomato+ neurons positive for Meis2 were encountered in PVN and SO. Overall, ~20% of all hypothalamic neurons activated during PSR are now neurochemically identified. Conclusion: Our study identifies new neuronal populations activated during PSR in AHA and tuberal nucleus. We further get evidence that Meis2 delineates novel neuronal populations activated during PSR. In summary, our results using TRAP2-red mice characterize new cell populations activated during Wakefulness or PSR, opening experimental paths for determining their function regarding vigilance states.

OfUSA: OpenfUS Analyzer, a versatile open-source framework for the analysis and visualization of functional ultrasound imaging data across animal models
Functional ultrasound (fUS) imaging is rapidly gaining interest for its unprecedented ability to study large-scale brain dynamics, yet its adoption and broader dissemination have been hindered by the lack of standardized tools and methodologies to analyze and interpret its rich datasets. We present OpenfUS Analyzer (OfUSA), a companion software suite designed to help researchers quickly engage with fUS data and perform the full range of analyses needed to generate publication-ready results and figures without relying on additional software. OfUSA offers a versatile and modular architecture including preprocessing, recording quality assessment, signal dynamics exploration, statistical analysis and visualization. These functions are separated yet easily combined into analytic pipelines through a programming-free graphical interface. The framework can be applied across species and experimental contexts, either by registering data to anatomical atlases, as shown here for the mouse brain, or by analyzing data without atlas constraints, as illustrated in a primate dataset. This flexibility, together with its comprehensive functionality, makes OfUSA a practical solution for standardized and reproducible analysis of fUS data in both preclinical and translational research. Using OfUSA, we demonstrate the capacity to detect stimulus-evoked responses with high sensitivity, identify their spatial localization within brain networks, and quantify both their extent and temporal dynamics. These results highlight the software's ability to capture robust activation patterns and provide detailed insights into brain function, thereby accelerating the use of fUS as a powerful tool for systems neuroscience.

Trait-Relevant Tasks Improve Personality Prediction from Structural-Functional Brain Network Coupling
Personality traits capture stable patterns of behavior and thought, and neurobiological correlates were identified in structural and functional brain networks. Here, we investigate whether the coupling between structural and functional brain networks (SC-FC coupling), during resting state and seven tasks of varying trait-relevance, is associated with individual differences in the Big Five personality traits. We used diffusion-weighted and functional magnetic resonance imaging from 764 participants of the Human Connectome Project and modelled individual differences in SC-FC coupling with similarity and communication measures. These measures approximate functional interactions unfolding on top of the structural connectome and were set in relation to individual variations in personality traits. Significant associations were only observed during trait-relevant tasks: for agreeableness during social cognition, and conscientiousness could be predicted from task-general coupling patterns. We conclude that optimizing trait-relevance of tasks during neuroscientific measurements presents a promising means to increase effect sizes in studies on brain-behavior associations.

PEDOT:PSS conducting eutectogel for enhanced electrical recording and stimulation in implantable neural interfaces
Conductive polymers such as PEDOT:PSS are widely used in bioelectronic interfaces due to their mixed ionic-electronic conductivity and biocompatibility. However, their mechanical fragility and limited processability constrain their performance in implantable devices. Deep eutectic solvents (DES), when combined with PEDOT:PSS, form eutectogels that enable thick, soft coatings. Here, we present a PEDOT:PSS-based eutectogel incorporating choline chloride: lactic acid and GOPS, integrated into flexible thin-film electrode arrays for sciatic nerve interfacing. These implants feature an array of electrodes and a pre-formed spiral geometry to conformally wrap small-diameter nerves. Devices were fabricated using standard photolithography and reactive ion etching techniques, allowing side-by-side comparison of PEDOT:PSS/DES with conventional PEDOT:PSS electrodes. PEDOT:PSS/DES enabled single-layer films up to 800 nm thick, significantly greater than PEDOT:PSS, and yielding over two-fold improvements in impedance and charge injection capacity in vitro. Acute in vivo electrophysiology in rats confirmed enhanced neural recording and stimulation capabilities, with lower impedance, higher capacitance, and reduced motor activation thresholds. While PEDOT:PSS/DES more reliably elicited motor responses at lower stimulation currents, electromyogram signal amplitudes from the tibialis anterioris at matched stimulation levels were comparable between materials. These results suggest that while superior electrochemical properties improve neural interface performance, local electrode-tissue interactions remain critical. Overall, this work establishes DES-modified PEDOT:PSS as a promising electrode material for soft neural interfaces and highlights its potential for advancing implantable bioelectronics.

Early micro and nanoscopic responses of microglia to blood-brain barrier modulation by transcranial-focused ultrasound
Modulation of the blood-brain barrier (BBB) using transcranial-focused ultrasound (FUS) has rapidly progressed to clinical trials. In combination with phospholipid microspheres, also known as microbubbles, administered in the bloodstream, ultrasound energy is guided by magnetic resonance imaging (MRI) to target specific brain regions with millimetric precision. At the targeted area, the interaction between FUS and microbubbles increases local BBB permeability for 4 to 6 hours, with an ensuing inflammation that resolves within days to weeks. Microglia, as the resident immune cells of the brain, are triggered by FUS-BBB modulation, although the time course of this response is unclear. Thus, the goal of this study was to characterize the early cellular (i.e., density, distribution, and morphology) and subcellular (i.e., ultrastructure) changes in microglial activities following FUS-BBB modulation. Methods: We targeted the hippocampi of adult mice with FUS, in the presence of intravenous microbubbles and guided by MRI, and performed analyses 1 hour and 24 hours after FUS-BBB modulation. Microglia were investigated at the population, cellular and subcellular levels, where hippocampal BBB permeability was identified by the entry of endogenous immunoglobulin (Ig)G in the parenchyma. Respective outcome measures included i) the density and distribution of ionized calcium binding adaptor molecule-positive (Iba)1-positive (+) cells; ii) the morphology of the soma and processes of Iba1+ cells; and iii) the quantification of microglial organelles (e.g., phagosomes) and contacts with blood vessels and synapses using chip mapping scanning electron microscopy. Results: No significant changes in baseline density and distribution of microglia were found in IgG-positive hippocampal areas at 1 hour and 24 hours after FUS-BBB modulation. By contrast, FUS-BBB modulation was associated with more elongated microglial cell bodies at both time points. The relative distribution of morphologies at 1 hour shifted toward compact shapes with stubby processes, whereas at 24 hours, shapes were bigger, with fewer processes. At the nanoscale, microglia maintained their interactions with blood vessel elements, except vessels most affected by swollen endfeet, which occurred regardless of treatment. In the parenchyma, 24 hours after FUS-BBB modulation, microglia reduced the frequency of contacts with pre-synaptic elements and extracellular space pockets, while showing features of increased metabolic demand and reduced lysosomal activity. Conclusion: At 1 hour and 24 hours after FUS-BBB modulation, traits of microglial surveillance activity were largely maintained, with shifts in the shape of a subset of cells, which adopted a morphology associated with injury shielding. FUS-BBB modulation also appears to temporarily modify the digestive, but not the phagocytic activity, of microglia and to reduce pre-synaptic remodeling early after treatment.

Psilocybin ameliorates neuropathic pain-like behaviour in mice and facilitates gabapentin-mediated analgesia
Chronic pain states are challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin can produce a sustained anti-nociceptive effect in a model of chronic neuropathic pain in male and female mice. Psilocybin anti-nociceptive effects were mediated by 5-HT2A receptors, although additional mechanisms might also be involved. Furthermore, a single dose of psilocybin caused a significant increase in the anti-nociceptive potential of gabapentin, a widely used treatment for neuropathic pain consistent with the establishment of longer lasting changes in network processing. Overall, these findings present the first preclinical evidence that psilocybin could be a valuable approach for treating chronic pain from nerve injury and serve as a new therapeutic addition for pain management.

Task-Parametrized Dynamics: Representation of Time and Decisions in Recurrent Neural Networks
How do recurrent neural networks (RNNs) internally represent elapsed time to initiate responses after learned delays? To address this question, we trained RNNs on delayed decision-making tasks of increasing complexity: binary decisions, context-dependent decisions, and perceptual integration. We analyzed RNN dynamics after training using eigenvalue spectra, connectivity structure, and population trajectories, and found that 1) distinct dynamical regimes emerge across networks trained on the same task whereby oscillatory dynamics support precise timing, and integration supports evidence accumulation, 2) a population-wide representation of time and decision variables emerges rather than dedicated sub-populations to tracking time and other task-specific variables; and 3) the neural trajectories align only with the output weights near decision points, as shown by trajectory readout correlations, revealing task-driven coordination of precisely timed task representation and readout. These results show that RNNs can use either integration or oscillations to represent time, and highlight how structured connectivity enables diverse solutions to temporal computation problems, consistent with biological principles of degeneracy and functional redundancy.

Distribution of big tau isoforms in the human central and peripheral nervous system
Objective: To characterize the distribution of big tau, a longer tau isoform expressed in the peripheral nervous system (PNS) and select central nervous system (CNS) regions, and to examine its relationship with aging and neurodegeneration. Methods: We performed mass spectrometric sequencing of big tau sequence and mapped its distribution across the human nervous system. Postmortem samples included brains from Alzheimer disease (AD), disease controls, and amyotrophic lateral sclerosis (ALS); spinal cord from young controls, disease controls and ALS; and peripheral nerves. Big and small tau levels were also quantified in the cerebrospinal fluid (CSF) from young normal controls, amyloid positive and amyloid negative participants. Results: Human big tau results from the insertion of 355 amino acids in the tau protein, encoded by the exon 4a-long and not exon 4a-short. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms, expanding the known human tau repertoire. Total tau concentration is ~ 1000-fold higher in the brain than in PNS, where big tau rises sharply along a central-to-peripheral gradient, comprising ~ 50 % of total tau in peripheral nerves compared to only ~ 1 % in brain. CSF big tau levels remain unaltered with CSF A{beta} abnormalities in AD, unlike the small tau isoform, which increases significantly with concomitant A{beta} and cognitive abnormalities. Interpretation: Big tau exhibits a distinct distribution in the human nervous system, decoupled from the changes associated with brain-derived small tau in AD. These findings open opportunities for developing specific blood-based biomarkers to differentiate CNS versus PNS disorders.

Cortical Origins of the Flash-Lag Effect distortions: The Influence of Retinotopic Map Architecture
The flash-lag effect (FLE) is an illusion whereby the position of a moving object is perceived as being offset in the direction of movement when compared to a flashed static stimulus. This perceptual misalignment has been posited as a key phenomenon in explaining our ability to accurately predict the future position of moving objects, despite the delays in neuronal processing. Our working hypothesis is that the FLE is resulting from the anticipation generated by propagation of neural activity within visual cortical retinotopical maps. According to this hypothesis, the FLE should be affected by discontinuities and anisotropies of the retinotopic map architecture. Using psychophysics we show that the FLE is strongly affected by crossing and the direction of motion in respect to retinotopic features, such as vertical and horizontal meridians and the fovea. The specificity of how early visual cortical retinotopic maps are splitted and magnified around these features led us to suggest that the FLE distortions emerge from propagation in retinotopically organized networks, particularly V1. This work bridges the gap between human psychophysics and the known constraints of retinotopic maps layout, offering a testable framework for future studies of motion position encoding in the visual hierarchy.

Decoding human lifespan from neural noise and explaining age-related changes in fractal dimension and gamma oscillations using fractional harmonic oscillator
Predicting human lifespan is a longstanding objective of biomedical research. Traditional statistical models estimate mortality risk or biological age but not lifespan. We propose a two-parameter model based on stochastic fractional harmonic oscillator for neural signals. The model computes maximum human lifespan using 1/f slope, the measure of neural power decay with frequency, which is indicative of neural noise. Using slope rate from electroencephalographic and electrocorticographic datasets, we estimate the mean lifetimes of healthy adults and epileptic patients as 76.9 and 69.7 years, resulting in 89.4% and 96.9% accuracy respectively. Additionally, the present model resolves the inconsistency in age-related changes of fractal dimension (FD) and captures naturally the non-monotonic variation of stimulus-induced gamma power. Thus, the present model provides a simple way to estimate lifespan while explaining age-related changes in slope, FD and power simultaneously, thereby, paving the way for individualized lifetime measurements and unveiling fundamental principles governing life.

Neural correlates of perceptual biases in duration perception
How we perceive a current event depends not only on its immediate context, but also on how our internal expectations are shaped by prior experience. In time perception, these expectations manifest as systematic biases, namely sequential dependence, where the current percept is influenced by the previous stimulus, and central tendency, the overestimation of short durations and underestimation of long ones. Both perceptual biases, corresponding to individual beliefs about stimulus generation, can vary substantially between participants. However, the neural correlates of these individual beliefs and their effects are unknown. Here, we investigate how these biases and their individual variations are reflected in neural responses in a duration reproduction task. Our EEG results show that in the frontocentral region, the Contingent Negative Variation (CNV) while experiencing the current stimulus depends on the previous stimulus regardless of whether sequential dependence is high or low. In contrast, in the right parietal region, CNV significantly correlated with the amount of sequential dependence. Central tendency was associated with frontocentral CNV amplitude and post-stimulus P2 components. A Bayesian model of time perception reproduced the observed neural dynamics, suggesting that internal estimates and expectations of stimulus offset are reflected in EEG responses. Our results demonstrate that both forms of perceptual bias, sequential dependence and central tendency, are reflected in neural activity while experiencing the ongoing stimulus, suggesting that both biases directly affect the measurement of time.

Long non-coding RNA Cerox1 targets components of the mitochondrial electron transport chain to regulate the memory impairment caused by sleep deprivation
Sleep deprivation (SD) impairs long-term memory, but the molecular mechanisms underlying the impact of sleep loss on memory are poorly understood. Molecular changes driven by SD have thus far focused on transcription and translation. Long non-coding RNAs (lncRNAs), a class of regulatory RNAs, have recently been recognized as an important player in memory research. However, it remains unclear how sleep deprivation modulates the expression of lncRNAs or their targets to lead to memory impairment. In this study, we explored the role of lncRNAs in the disruption of spatial memory caused by SD. We examined a set of synapse-associated lncRNAs that were identified through a transcriptome analysis after SD. Among them, we discovered that the lncRNA Cerox1 is downregulated in dorsal hippocampus following SD, and its levels recover after 2.5 hours of rebound sleep. Sleep is critical for the regulation of metabolism and sleep loss impairs mitochondrial function. Both sleep deprivation and Cerox1 knockdown were found to reduce complex I activity of the mitochondrial electron transport chain. This reduction of complex I activity is linked to the decrease in expression of a subset of complex I subunits including Ndufs1, Ndufs3, Ndufa3 and Ndufs6. Overexpression of Cerox1 has the opposite effect, leading to increased complex I activity. Sleep deprivation reduced ATP levels in the dorsal hippocampus, while Cerox1 overexpression restored it. SD disrupted memory consolidation, and this impairment was rescued when Cerox1 was overexpressed. Cerox1 transcript contains multiple miRNA binding sites that regulate the activity of the lncRNA. Notably, overexpression of Cerox1 transcript lacking miRNA binding sites did not rescue the memory deficit caused by SD. Our findings demonstrated that the impairment of memory consolidation after SD is linked to lncRNA-mediated control of mitochondrial electron transport chain activity essential for sustaining energy requirements.

Excitatory cholecystokinin neurons in CA3 area regulate the navigation learning and neuroplasticity
Hippocampus, a key hub of neural circuits for spatial learning and memory, has attracted tremendous studies. Neuronal information processing in the hippocampus can be regulated by many types of neuropeptides. Cholecystokinin (CCK), the most abundant neuropeptide in the central nervous system which is involved in modulating neuronal functions, such as cognition, memory and neuroplasticity, is widely expressed in the hippocampus. However, whether local excitatory CCK neurons modulates hippocampal function is still unclear. In this study, we showed that CA1 pyramidal neurons receive projections from excitatory CCK neurons in area CA3 (CA3CCK neurons). Subsequently, activation of the CA1-projecting CA3CCK neurons triggers the release of CCK. Then, we found that activity of CA3CCK-CA1 neurons supports the hippocampal-dependent tasks. Furthermore, inhibition of CA3CCK-CA1 projections or knockdown of CA3CCK gene expression markedly impaired the behavioral tasks and neuroplasticity. Taken together, these results may add to a better understanding of how neuromodulators regulate the neural functions in central nervous system.

Altered network function in hippocampus after sub-chronic activation of Cannabis receptors in peri-adolescence
The Cannabinoid 1-receptor (CB1R) is found in particularly high levels in the hippocampus (HPC), increased CB1R density and binding observed in patients with schizophrenia, and epidemiological studies suggest that regular cannabis use during adolescence is a risk factor for the disease. Historically, concerns around adolescent marijuana use focused on the development of psychosis later in life, however recent findings indicate that cognitive domains may also be at risk. CB1R was shown to interfere with neuronal network oscillations and to impair sensory gating and memory function. Neuronal oscillations are essential in multiple cognitive functions and their impairment was documented in neurological and psychiatric diseases. The aim of this study was to investigate how adolescent pre-treatment with the CB1R selective agonist CP-55940 may lead to abnormalities in theta synchronization in adulthood. Rats were pre-treated with CP-55940 (n=11, 6 males, 5 females) or vehicle (n=8, 4 males, 4 females) during adolescence (daily i/p injections between PND 32-36 or PND 42-46, n=10 and 9, respectively). They were then tested in adulthood (PND 70-88, n=17 or PND 111-115, n=2) under urethane anesthesia. Hippocampal theta rhythm was elicited by brainstem stimulation at 5 intensity levels one hour before and up to 5 hours after injection. We found a lasting significant decrease in theta power after CP-55940 in adult rats which was aggravated further in rats pre-treated in adolescence with the CB1R agonist. The effect was significantly larger (p=0.0462) in rats pre-treated during early adolescence (PND 32-36) compared to the group pre-treated during late adolescence (PND 42-46). We conclude that 1. Exposure to cannabis during adolescence leads to increased sensitivity to CB1R agonist in adulthood; 2. Early adolescence, a critical period for development of HPC networks generating theta rhythm, is particularly prone to this sensitivity.

Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease
BACKGROUND: Alzheimer disease (AD) is associated with amyloid plaques and can be caused by autosomal dominant mutations in APP or PSEN1/2, which form an enzyme substrate complex. Decreases in catalysis of AD mutant APP and PSEN1 supports the hypothesis that membrane delimitation of KAT5 could contribute to AD. METHODS: We compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human WT and AD neurons. RESULTS: The Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons. DISCUSSION: This analysis supports the hypothesis that KAT5 nuclear signaling down stream of APP cleavage plays a pivotal role in neuronal homeostasis and immune regulation.

Loss of PIKfyve in Rod Photoreceptors and RPE Cells Leads to Endolysosomal Dysfunction and Retinal Degeneration
Photoreceptor outer segment (OS) degradation is primarily mediated by retinal pigment epithelial (RPE) cells through daily phagocytosis of shed distal OS tips. In contrast, much less is understood about the cell-autonomous mechanisms photoreceptors use to clear mislocalized molecules caused by protein misfolding or trafficking defects. Mislocalized or excess rhodopsin that fails to reach the OS is retained in the inner segment or cell body, where it is presumably degraded via the endolysosomal system. We identify PIKfyve, a phosphoinositide kinase that generates PI(3,5)P2, as a key regulator of this pathway. Using Translating Ribosome Affinity Purification (TRAP), we find that PIKfyve is highly expressed in rod photoreceptors. Rod-specific PIKfyve deletion causes progressive retinal degeneration, marked by inner segment vacuolation, elevated LAMP1/2, thinning of the outer nuclear layer, and eventual loss of rod and cone function. Loss of one copy of PIKfyve in rod photoreceptors accelerates degeneration in P23H rhodopsin mutant mice. In RPE cells, PIKfyve loss disrupts phagocytosis and autophagy, leading to accumulation of rhodopsin, LAMP1, LC3A/B, and lipid droplets, along with metabolic disturbances. These findings demonstrate that PIKfyve is essential for photoreceptor and RPE health by regulating lysosomal function, phagocytosis, autophagy, and metabolism, and suggest that enhancing PIKfyve activity could be a therapeutic strategy for retinal degenerative diseases.

Pharmacological Modulation of MC4R in the Periaqueductal Gray Does Not Alter Social Behavior
Competing motivational drives are integral to survival and encompass a spectrum of internal physiological needs such as hunger to external goals like social connection. Elucidating how these motivational states interact at the neural level is critical to our understanding of adaptive behavior. Hunger-driven behaviors are primarily initiated by agouti-related peptide (AgRP), an inverse agonist of the melanocortin 4 receptor (MC4R), which acts to promote feeding by suppressing MC4R signaling. MC4R is present in the periaqueductal gray (PAG), a midbrain region involved in pain, appetite, and social behavior. A pilot study found a dense concentration of AgRP fibers in the PAG of male rats, suggesting a potential link between hunger-related signaling and social behavior in this region. To investigate the role of AgRP and MC4R in the PAG on social interaction, we conducted a within-subject dose-response experiment using male rats. Subjects received bilateral microinjections (0.5 L/side) of either vehicle, an MC4R agonist (THIQ), or an antagonist (HS014) into the PAG prior to a five-minute social exploration (SE) test with a novel juvenile conspecific. Contrary to our hypothesis, pharmacological manipulation of MC4R activity in the PAG did not produce significant changes in social interaction time, suggesting that MC4R in the PAG may not directly play a major role in modulating social behavior in rodents. These results highlight the complexity of the neural circuitry involved in social motivation, hunger, and other competing motivational states.

Lateral septal inhibition of nucleus basalis through direct and indirect pathways in focal limbic seizures
Temporal lobe epilepsy (TLE) is the most common form of epilepsy and is characterized by focal seizures originating from limbic structures, including the hippocampus. Patients with TLE often experience impaired consciousness. A recent awake mouse model study demonstrated decreased cortical cholinergic innervation during focal seizures with impaired consciousness, based on cortical slow wave activity and decreased behavioral responsiveness. But the underlying mechanisms for reduced cortical cholinergic activity are not fully understood. This study employs the same awake mouse model combined with electrophysiology recordings in key network nodes, cell-specific calcium imaging in the lateral septum, and neurotransmitter sensing in one of the major subcortical cholinergic systems, the nucleus basalis of Meynert (NBM). We demonstrate that decreased cortical cholinergic innervation during focal seizures comes from both direct inhibition and indirect de-excitation of the NBM, showing a parallel pathway NBM suppression mechanism from the LS directly and through the paratenial thalamic nucleus indirectly. This work contributes to a deeper understanding of the neural processes involved in impaired consciousness during focal seizures and may open the way to new treatments for this disorder.

Beyond Circadian: A Yearlong Electroencephalography Study Reveals Hidden Ultralong-term Sleep Cycles
Sleep is essential for brain function and overall health. While circadian rhythms and sleep stages across the night have been well-characterized, long-term variations in sleep remain poorly understood. We used a novel technology, subcutaneous electroencephalography, to collect yearlong sleep recordings from 20 healthy individuals. We investigated intrinsic and extrinsic drivers of sleep variability and identified recurring multi-day cycles of 8-60 days in sleep duration, latency, architecture, and stability. Additionally, sleep was modulated by external factors including season, weather, weekends and holidays. This reveals that while sleep processes are governed by internal dynamics, they remain sensitive to environmental influences. These results uncover a previously unrecognized temporal variation in human sleep and suggest new directions for understanding sleep patterns and their relevance to health and disease.

Cannflavin B ameliorates social and anxiety deficits and neuronal systems dysfunction in adolescent rats exposed to prenatal valproic acid
There has been growing interest in natural products as potential therapeutics for the core and comorbid symptoms of autism spectrum disorders. Almost all the studies on autism have focused on the therapeutic benefits of cannabis and its associated cannabinoids. In this study the potential therapeutic efficacy of cannflavin B, a related, yet non-psychoactive component of the Cannabis sativa plant, was evaluated. Using prenatal valproic acid (VPA) exposure in rats, a model that has been widely used to study aspects of autism, we showed that cannflavin B was anxiolytic in the female VPA rats, and normalized sociality in VPA animals of both sexes. When neuronal oscillatory activity was examined, in female VPA rats cannflavin B normalized alterations in low frequency power within the cingulate cortex (Cg), and theta-gamma cross frequency coupling between the dorsal hippocampus (dHIP) and the prefrontal cortex (PFC). In male VPA animals, cannflavin B induced frequency-specific alterations in power within the PFC, Cg, and dHIP and ameliorated the VPA-induced suppression of oscillatory coherence between all three regions. In each brain region, cannflavin B also attenuated the sex-specific VPA-induced elevations in microglia. In vitro, cannflavin B normalized VPA-induced elevations in cortical and HIP neuronal activity and promoted more organized cortical firing. These findings demonstrate cannflavin B normalizes behavioural and neuronal systems function alterations induced by prenatal VPA in rats. The present study highlights the importance of alternative cannabis compounds in autism and other disorders.

Movie-trained transformer reveals novel response properties to dynamic stimuli in mouse visual cortex
Understanding how the brain encodes complex, dynamic visual stimuli remains a fundamental challenge in neuroscience. Here, we introduce ViV1T, a transformer-based model trained on natural movies to predict neuronal responses in mouse primary visual cortex (V1). ViV1T outperformed state-of-the-art models in predicting responses to both natural and artificial dynamic stimuli, while requiring fewer parameters and reducing runtime. Despite being trained exclusively on natural movies, ViV1T accurately captured core V1 properties, including orientation and direction selectivity as well as contextual modulation, despite lacking explicit feedback mechanisms. ViV1T also revealed novel functional features. The model predicted a wider range of contextual responses when using natural and model-generated surround stimuli compared to traditional gratings, with novel model-generated dynamic stimuli eliciting maximal V1 responses. ViV1T also predicted that dynamic surrounds elicited stronger contextual modulation than static surrounds. Finally, the model identified a subpopulation of neurons that exhibit contrast-dependent surround modulation, switching their response to surround stimuli from inhibition to excitation when contrast decreases. These predictions were validated through semi-closed-loop in vivo recordings. Overall, ViV1T establishes a powerful, data-driven framework for understanding how brain sensory areas process dynamic visual information across space and time. Code available at https://github.com/bryanlimy/ViV1T-closed-loop

Multi-Source Neural Activity Indices and Spatial Filters for EEG/MEG Inverse Problem: An Extension to MNE-Python
Accurate EEG/MEG source localization is essential for understanding brain function, yet remains challenging because the inverse problem is inherently ill-posed. In spatial filtering (beamforming) approaches, single-source LCMV spatial filters, though widely used, suffer from source cancellation when sources are correlated - a common experimental scenario. Multi-source frameworks, such as the multi-source minimum-variance pseudo-unbiased reduced-rank (MV-PURE) method, offer improved reconstruction and robust neural activity indices, yet their adoption has been limited by incomplete theory and lack of accessible implementations. In this paper, we present a rigorous derivation of multi-source neural activity indices and spatial filters, establishing a complete analytical framework with automated parameter selection. The resulting compact algebraic forms enable straightforward implementation. To facilitate adoption, we provide a full implementation extending MNE-Python, along with an accompanying tutorial, and demonstrate its utility on EEG experimental data, highlighting the practical advantages of multi-source spatial filtering for source localization and reconstruction.

Dual AAV gene therapy using laminin-linking proteins ameliorates muscle and nerve defects in LAMA2-related muscular dystrophy
Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to AAV's limited packaging capacity and potential immune responses to transgene products, especially in patients lacking endogenous protein. LAMA2-related muscular dystrophy (LAMA2 MD), a severe congenital disorder caused by loss of laminin-2, presents both hurdles: the LAMA2 gene exceeds AAV capacity, and severely affected patients do not produce the native protein. Here, we developed an AAV-based therapy using two engineered linker proteins derived from endogenously expressed components. These linker proteins restore laminin receptor binding and polymerization, enabling reassembly of a functional basement membrane. Dual AAV delivery of the linkers in a severe LAMA2 MD mouse model resulted in robust expression and significant improvements in muscle histology and function. Employing myotropic capsids enabled therapeutic efficacy at lower vector doses. However, muscle-specific targeting unmasked a LAMA2-related peripheral neuropathy. To address this, we expressed one linker under a muscle-specific promoter and the other under a ubiquitous promoter, delivered via AAV9 or AAV8. This approach achieved near-complete phenotypic restoration when administered neonatally and provided significant benefit when given at progressed disease stages. Our strategy offers a mutation-independent, size-compatible, and potentially immune-tolerable treatment for LAMA2 MD with broad clinical potential.

Coincidence detection supported by electrical synapses is shaped by the D-type K+ current
Electrical synapses mediated by gap junctions are widespread in the mammalian brain, playing essential roles in neural circuit function. Beyond their role synchronizing neuronal activity, they also support complex computations such as coincidence detection, a circuit mechanism in which differences in input timing are encoded by the firing rates of coupled neurons, enabling preferential responses to synchronous over temporally dispersed inputs. Electrical coupling allows each neuron to act as a current sink for its partner during independent depolarizations, thereby reducing excitability. In contrast, synchronous inputs across the network minimize voltage differences through gap junctions, reducing current shunting and increasing spiking probability. However, the contribution of intrinsic neuronal properties to coincidence detection remains poorly understood. Here, we investigated this issue in the Mesencephalic Trigeminal (MesV) Nucleus of mice, a structure composed of somatically-coupled neurons. Using whole-cell recordings and pharmacological tools, we examined the role of the D-type K+ current (ID), finding that it critically shapes both the intrinsic electrophysiological properties of MesV neurons and the dynamics of electrical synaptic transmission. Its fast activation kinetics and subthreshold voltage range of activation make ID a key determinant of transmission strength and timing. Furthermore, the ID, likely mediated by Kv1 subunits, is expressed at the soma and the axon initial segment. Finally, we characterized two key parameters of coincidence detection, precision (time window for effective input summation) and gain (differential response to coincident versus dispersed inputs), finding that ID enhances precision by accelerating membrane repolarization and reduces the gain by limiting neuronal excitability.

Novel monoclonal antibodies against the C-terminal HEAT domain of Huntingtin
BACKGROUND: Reliable detection of huntingtin (HTT) is essential for understanding Huntington's disease (HD) biology and evaluating therapeutic strategies. However, high-quality monoclonal antibodies (mAbs) against the HTT C-terminal domain remain limited. OBJECTIVE: We sought to generate and validate novel monoclonal antibodies targeting the HTT C-terminal HEAT containing domain to better detect HTT independently of potential effects of polyglutamine length that can impact some N-terminally targeted antibodies. METHODS: We immunized mice with a highly purified, well characterized recombinant protein corresponding to the HTT C-terminal domain. We generated monoclonal antibody producing hybridoma cell lines and characterized the antibodies using parental and HTT-knockout cell lines in common immuno-applications. RESULTS: Three novel, independent hybridoma lines producing anti-HTT monoclonal antibodies were derived. Using CRISPR-edited HTT knockout cell lines we identified one clone, anti-HTT [2F8], that was specific and effective across Western blot, immunofluorescence, and ELISA assays. All antibodies bound full-length HTT irrespective of HAP40 interaction or polyQ length and showed no cross-reactivity to the N-terminal HEAT domain. CONCLUSIONS: These C-terminal HTT mAbs are thus valuable additional tools for studying endogenous HTT function in both normal and disease contexts.

Aging diminishes interlaminar functional connectivity in the mouse cortical V1 and CA1 hippocampal regions
Aging disrupts brain network integration and is a significant risk factor for cognitive decline and neurological diseases, yet the circuit-level mechanisms underlying these changes remain unclear. Most previous studies have utilized cross-sectional or acute approaches, limiting insights into the longitudinal dynamics of the neural network. In this study, we chronically recorded laminar electrophysiological activity in both the primary visual cortex (V1) and hippocampal CA1 region of young (2-month-old) and aged (13-month-old) mice over 16 weeks. This approach allowed us to directly assess how aging modulates functional connectivity within hierarchically connected cortical and hippocampal circuits. We found that single-unit spiking activity and the signal-to-noise ratio were largely preserved in aged versus young mice, suggesting intact neuronal firing properties. However, aged mice showed global reductions in local field potential (LFP) power and a selective decrease in coherence across delta, alpha-beta, and gamma frequency bands within and between cortical layers and V1-CA1 pathways, while phase amplitude coupling remained unaffected. Interestingly, population level excitatory activity in CA1 was increased in aged animals. These findings indicate that aging selectively impairs network-level synchrony and temporal coordination in specific frequency bands and regions, with minimal loss of single-neuron function. Our results highlight the necessity of longitudinal, multi-region measurements to uncover the multi-scale vulnerabilities of the aging brain. Understanding the depth- and region-dependent circuit changes will guide strategies to preserve cortical-hippocampal communication and cognitive function in aging, as well as enhance neural interface technologies for older populations.

The ventral visual stream for reading converges on the transmodal language network
Reading bridges sensation and cognition. To derive meaning from written words, visual input is first processed in unimodal (i.e., sensory-specific) visual streams and then engages a distributed language network (LANG) that includes classic perisylvian language areas and supports transmodal (i.e., sensory-nonspecific) functions. A reading-relevant region in the inferotemporal cortex (ITC), sometimes called the visual word form area (VWFA), has been the subject of controversy because it displays properties of both systems: it responds to meaningless written pseudowords, implying a unimodal visual function, but also responds to meaningful speech, implying a transmodal function. We investigated whether precision functional mapping could help clarify this region's role in reading. We characterized a stream of visual regions along the ITC that responded preferentially to visual orthographic forms (i.e., written pseudowords, consonant strings, and real words). Network mapping revealed that only the most anterior region of this "orthographic stream" was connected to the LANG network and accordingly showed responses to meaningful speech. Furthermore, this anterior region was more selective, responding preferentially to text-based stimuli, whereas the more posterior regions of the stream were additionally activated by perceptually similar images (i.e., number strings, foreign script). Our results support that connections to the LANG network may drive specialization along the orthographic stream for writing. This basal language network region may represent an interface between visual and transmodal language systems, thus serving as a critical nexus for reading.

Hemispheric laterality of the putamen predicts pseudoneglect
Healthy individuals tend to exhibit a subtle leftward attentional bias, a phenomenon termed pseudoneglect. While this bias is thought to reflect a right-hemisphere dominance when allocating spatial attention, the contribution of subcortical structures remains poorly understood. Although lesion and neuroimaging studies in clinical populations have implicated asymmetries in the basal ganglia and thalamus to dysfunction in spatial attention, it remains unclear whether naturally occurring subcortical asymmetries in healthy individuals predict behavioural biases in spatial attention. In this study, we investigated whether volumetric asymmetries in subcortical structures are associated with biases in spatial attention in a non-clinical population. This was achieved by using the landmark task to assess spatial biases, alongside acquiring T1-weighted MRI data from 44 healthy participants. The subcortical regions were segmented using the FIRST algorithm to estimate the volumetric asymmetry of specific regions. We found that variability in pseudoneglect was predicted by the degree of leftward lateralisation of putamen volume, indicating that the putamen contributes to the magnitude of spatial attention biases. This also suggests that the left putamen may support right-hemisphere neocortical dominance through the indirect pathway. These findings bridge anatomical and behavioural measures, highlighting the functional relevance of subcortical asymmetry in shaping attentional processes in the healthy brain. Our findings pave the way for early diagnosis of neurological disorders associated with subcortical atrophies including Parkinson's Disease and dementia.

How do visual and conceptual factors predict the composition of typical scene drawings?
Imagine you are asked to draw a typical bedroom, what would you put on paper? Your choice of objects is likely to depend on visual occurrence statistics (i.e., the objects present in previously encountered bedrooms) and semantic relations between objects and scenes (i.e., the semantic relationship between the bedroom and its constituent objects). To investigate how these two factors contribute to the composition of typical scene drawings, we analyzed 1,192 drawings of six indoor scene categories, obtained from 303 participants. For each object featured in the drawings, we estimated its visual occurrence frequency from the ADE20K dataset of annotated scene images, and its semantic relatedness to the scene concept from a word2vec language processing model. Across all scenes of a given category, generalized linear models revealed that visual and conceptual factors both predicted the likelihood of an object featuring in the scene drawings, with a combined model outperforming both single-factor models. We further computed the visual and semantic specificity of objects for a given scene, that is, how diagnostic an object is for the scene. Object specificity offered only weak predictive power when predicting the selection of objects, yet even infrequently drawn objects remained diagnostic of their scenes. Taken together, we show that visual and conceptual factors jointly shape the composition of typical scene drawings. By releasing a large dataset of typical scene drawings alongside this work, we further provide a starting point for future studies exploring other critical properties of human drawings.