bioRxiv Subject Collection: Neuroscience's Journal

Curriculum learning inspired by behavioral shaping trains neural networks to adopt animal-like decision making strategies
Recurrent neural networks (RNN) are ubiquitously used in neuroscience to capture both neural dynamics and behaviors of living systems. However, when it comes to complex cognitive tasks, traditional methods for training RNNs can fall short in capturing crucial aspects of animal behavior. To address this challenge, we leverage a commonly used (though rarely appreciated) approach from the experimental neuroscientist's toolkit: behavioral shaping. Taking as target a temporal wagering task previously studied in rats, we designed a pretraining curriculum of simpler cognitive tasks that are prerequisites for performing it well. These pretraining tasks are not simplified versions of the temporal wagering task, but rather reflect relevant sub-computations. We show that this approach is required for RNNs to adopt similar strategies as rats, including long-timescale inference of latent states, which conventional pretraining approaches fail to capture. Mechanistically, our pretraining supports the development of key dynamical systems features needed for implementing both inference and value-based decision making. Overall, our approach addresses a gap in neural network model training by incorporating inductive biases of animals, which is important when modeling complex behaviors that rely on computational abilities acquired from past experiences.

The multiverse of data preprocessing and analysis in graph-based fMRI: A systematic literature review of analytical choices fed into a decision support tool for informed analysis
The large number of different analytical choices researchers use may be partly responsible for the replication challenge in neuroimaging studies. For robustness analysis, knowledge of the full space of options is essential. We conducted a systematic literature review to identify the analytical decisions in functional neuroimaging data preprocessing and analysis in the emerging field of cognitive network neuroscience. We found 61 different steps, with 17 of them having debatable options. Scrubbing, global signal regression, and spatial smoothing are among the controversial steps. There is no standardized order in which different steps are applied, and the options within several steps vary widely across studies. By aggregating the pipelines across studies, we propose three taxonomic levels to categorize analytical choices: 1) inclusion or exclusion of specific steps, 2) distinct sequencing of steps, and 3) parameter tuning within steps. To facilitate access to the data, we developed a decision support app with high educational value called METEOR, which allows researchers to explore the space of choices as reference for well-informed robustness (multiverse) analysis.

Kalium channelrhodopsins effectively inhibit neurons in the small model animals
The analysis of neural circuits has been revolutionized by optogenetic methods. Light-gated chloride-conducting anion channelrhodopsins (ACRs)--recently emerged as powerful neuron inhibitors. For cells or sub-neuronal compartments with high intracellular chloride concentrations, however, a chloride conductance can have instead an activating effect. The recently discovered light-gated, potassium-conducting, kalium channelrhodopsins (KCRs) might serve as an alternative in these situations, with potentially broad application. As yet, KCRs have not been shown to confer potent inhibitory effects in the small genetically tractable animals. Here, we evaluated the utility of KCRs to suppress behavior and inhibit neural activity in Drosophila, C. elegans, and zebrafish. In direct comparisons with ACR1, a KCR1 variant with enhanced plasma-membrane trafficking displayed comparable potency, but with improved properties that include reduced toxicity and superior efficacy in putative high-chloride cells. This comparative analysis of behavioral inhibition between chloride- and potassium-selective silencing tools establishes KCRs as next-generation optogenetic inhibitors for in vivo circuit analysis in behaving animals.

Value construction through sequential sampling explains serial dependencies in decision making
Many decisions are expressed as a preference for one item over another. When these items are familiar, it is often assumed that the decision maker assigns a value to each of the items and chooses the item with the highest value. These values may be imperfectly recalled, but are assumed to be stable over the course of an interview or psychological experiment. Choices that are inconsistent with a stated valuation are thought to occur because of unspecified noise that corrupts the neural representation of value. Assuming that the noise is uncorrelated over time, the pattern of choices and response times in value-based decisions are modeled within the framework of Bounded Evidence Accumulation (BEA), similar to that used in perceptual decision-making. In BEA, noisy evidence samples accumulate over time until the accumulated evidence for one of the options reaches a threshold. Here, we argue that the assumption of temporally uncorrelated noise, while reasonable for perceptual decisions, is not reasonable for value-based decisions. Subjective values depend on the internal state of the decision maker, including their desires, needs, priorities, attentional state, and goals, which may change over time. These internal states may change over time, or undergo revaluation, as will the subjective values. We reasoned that these hypothetical value changes should be detectable in the pattern of choices made over a sequence of decisions. We reanalyzed data from a well-studied task in which participants were presented with pairs of snacks and asked to choose the one they preferred. Using a novel algorithm (Reval), we show that the subjective value of the items changes significantly during a short experimental session (about 1 hour). Values derived with Reval explain choice and response time better than explicitly stated values. They also better explain the BOLD signal in the ventromedial prefrontal cortex, known to represent the value of decision alternatives. Revaluation is also observed in a BEA model in which successive evidence samples are not assumed to be independent. We argue that revaluation is a consequence of the process by which values are constructed during deliberation to resolve preference choices.

Non-Degenerate Two-Photon Imaging of Deep Rodent Cortex using Indocyanine Green in the water absorption window
We present a novel approach for deep vascular imaging in rodent cortex at excitation wavelengths susceptible to water absorption using two-photon microscopy with photons of dissimilar wavelengths. We demonstrate that non-degenerate two-photon excitation (ND-2PE) enables imaging in the water absorption window from 1400-1550 nm using two synchronized excitation sources at 1300 nm and 1600 nm that straddle the absorption window. We explore the brightness spectra of indocyanine green (ICG) and assess its suitability for imaging in the water absorption window. Further, we demonstrate in vivo imaging of the rodent cortex vascular structure up to 1.2 mm using ND-2PE. Lastly, a comparative analysis of ND-2PE at 1435 nm and single-wavelength, two-photon imaging at 1300 nm and 1435 nm is presented. Our work extends the excitation range for fluorescent dyes to include water absorption regimes and underscores the feasibility of deep two-photon imaging at these wavelengths.

"Bayesian anchoring" and the fourfold pattern of risk attitudes
Experiments on decision making under uncertainty are known to display a classical pattern of risk aversion and risk seeking referred to as "fourfold pattern" (or "reflection effect") , but recent experiments varying the speed and order of mental processing have brought to light a more nuanced phenomenology. We model experiments though a Bayesian formalization of the anchor-and-adjust heuristic observed in empirical studies on cognitive bias. Using only elementary assumptions on constrained information processing, we are able to infer three separate effects found in recent observations: (1) the reported enhancement of the fourfold pattern for quicker decision processes; (2) the observed decrease of fluctuations for slower decision-making trials; (3) the reported dependence of the outcome on the order in which options are processed. The application of Bayesian modeling offers a solution to recent empirical riddles by bridging two heretofore separate domains of experimental inquiry on bounded rationality.

Age-Related Decline in BBB Function is More Pronounced in Males than Females
The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a novel non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our novel DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietotemporal and hippocampal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders.

Pupil size and eye movements differently index effort in both younger and older adults
The assessment of mental effort is increasingly relevant in neuro-cognitive and lifespan domains. Pupillometry - the measure of the pupil size - is often used to assess effort but has disadvantages. Analysis of eye movements may provide an alternative, but research has been limited to easy and difficult task demands in younger adults. An effort measure must be sensitive to the whole effort profile, including 'giving-up' effort investment, and capture effort in different age groups. The current study comprised three experiments in which younger and older adults (both sexes) listened to speech masked by background babble at different signal-to-noise ratios associated with easy, difficult, and impossible speech comprehension. We expected individuals to invest little effort for easy and impossible speech ('giving up') but to exert effort for difficult speech. Indeed, pupil size was largest for difficult, but lower for the easy and impossible speech conditions. In contrast, gaze dispersion decreased with increasing speech masking in both age groups. Critically, gaze dispersion during difficult speech returned to levels similar to easy speech after sentence offset, where acoustic stimulation was similar across conditions, whereas gaze dispersion during impossible speech continued to be reduced. These findings show that a reduction in eye movements is not a byproduct of acoustic factors, but instead suggest that neuro-cognitive processes, different from arousal-related systems regulating the pupil size, drive reduced eye movements during high task demands. The current data thus show that effort in one sensory domain (audition) differentially impacts distinct functional properties in another sensory domain (vision).

Vaping and smoking cue reactivity in young adult electronic cigarette users who have never smoked combustible cigarettes: a functional neuroimaging study
Introduction: The rapid growth in the use of electronic cigarettes (e-cigarettes) among young adults who have never smoked combustible cigarettes is concerning, as it raises the potential for chronic vaping and nicotine addiction. A key characteristic of drug addiction is the elevated neural response to conditioned drug-related cues (i.e., cue reactivity). Generalized reactivity to both vaping and smoking cues may signify an increased risk for smoking initiation in non- smoking vapers. In this study, we used functional magnetic resonance imaging (fMRI) to evaluate brain responses to vaping and smoking cues in young adult never-smoking vapers. Methods: Sixty-six young adult never-smoking vapers underwent functional MRI while viewing visual cues pertaining to vaping, smoking, and nicotine-unrelated unconditioned reward (i.e., food). A priori region-of-interest analysis combined with exploratory whole-brain analysis was performed to characterize neural reactivity to vaping and smoking cues in comparison to food cues. Results: The medial prefrontal cortex and the posterior cingulate cortex, regions that play a key role in drug cue reactivity, showed significantly increased neural response to vaping cues compared to food cues. The posterior cingulate cortex additionally showed increased neural responses to smoking cues compared to food cues. Conclusions: Despite never having smoked combustible cigarettes, young adult vapers exhibited heightened neural susceptibility to both vaping and smoking cues within brain systems associated with cue reactivity. The findings shed light on the mechanisms underlying nicotine addiction and smoking initiation risk in this critical population and may contribute to the development of science-based interventions and regulatory measures in the future.

Generation and benchmarking of a collection of hiPSC lines from Schizophrenia Patients with Diverse Clinical Profiles
Limited therapeutic advancements in Schizophrenia (SCZ) depend on the heterogeneous nature of the disorder, impacting drug development and clinical trials that assume uniform therapy response, neglecting individual genetic and epigenomic variability. Disease modeling using human induced pluripotent stem cells (hiPSCs) is ideally suited for precision medicine, enabling individualized treatment approaches. Here, we describe the generation of patient-specific lines from somatic cells of SCZ individuals with well-defined diverse clinical trajectories using a Sendai virus-based reprogramming system. Karyotypically and CGH-array validated, the generated hiPSCs expressed diagnostic markers and demonstrated functional pluripotency. Converting these hiPSCs into neural progenitor cells enables the identification of aberrant cellular phenotypes associated with specific pathologically relevant neural phenotypes. This collection of hiPSC lines serves as a platform for developing therapeutic compounds targeting neural populations, potentially addressing early-stage disease alterations.

Intricate response dynamics enhances stimulus discrimination in the resource-limited C. elegans chemosensory system
Sensory systems evolved intricate designs to accurately encode perplexing environments. However, this encoding task may become particularly challenging for animals harboring a small number of sensory neurons. Here, we studied how the compact resource-limited chemosensory system of C. elegans uniquely encodes a range of chemical stimuli. We find that each stimulus is encoded using a small and unique subset of neurons, where only a portion of the encoding neurons sense the stimulus directly, and the rest are recruited via inter-neuronal communication. Furthermore, while most neurons show stereotypical response dynamics, some neurons exhibit versatile dynamics that are either stimulus specific or network-activity dependent. Notably, it is the collective dynamics of all responding neurons which provides valuable information that ultimately enhances stimulus identification, particularly when required to discriminate between closely-related stimuli. Together, these findings demonstrate how a compact and resource-limited chemosensory system can efficiently encode and discriminate a diverse range of chemical stimuli.

ARViS: A bleed-free multi-site automated injection robot for accurate, fast, and dense delivery of virus to mouse and marmoset brains
Genetically encoded fluorescent sensors continue to be developed and improved. If they could be expressed across multiple cortical areas in non-human primates, it would be possible to measure a variety of spatiotemporal dynamics of primate-specific cortical activity. Here, we develop an Automated Robotic Virus injection System (ARViS) for broad expression of a biosensor. ARViS consists of two technologies: image recognition of vasculature structures on the cortical surface to determine multiple injection sites without hitting them, and robotic control of micropipette insertion perpendicular to the cortical surface with 50-m precision. In mouse cortex, ARViS sequentially injected virus solution into 100 sites over a duration of 100-minutes with a bleeding probability of only 0.1% per site. Furthermore, ARViS successfully achieved 266-site injections over the frontoparietal cortex of a common marmoset. We demonstrate one-photon and two-photon calcium imaging in the marmoset frontoparietal cortex, illustrating the effective expression of biosensors delivered by ARViS.

Individual Differences in Belief Updating and Phasic Arousal Are Related to Psychosis Proneness
Many decisions entail the updating of beliefs about the state of the environment, a process that may go awry in psychosis. When environments are subject to hidden changes in their state, optimal belief updating requires non-linear modulation of sensory evidence, which may be subserved by pupil-linked, phasic arousal. Here, we analyzed behavior and pupil responses during evidence accumulation in a changing environment in a community sample of human participants and assessed their subclinical psychotic experiences (psychosis proneness). Subjects most prone to psychosis showed overall less flexible belief updating profiles, with diminished weighting of late evidence. These same subjects also exhibited overall smaller pupil responses and less reliable pupil encoding of computational variables governing the adaptive belief updating. The observed changes in belief updating and arousal dynamics may account for the emergence of cognitive biases in psychotic psychopathology. Our results open a new window on the pathophysiology of mental disorders.

Emotion-related impulsivity is related to orbitofrontal cortical sulcation
Background: Emotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the neuroanatomy of the orbitofrontal cortex (OFC). Informed by a growing body of research indicating that the morphology of cortical folds (sulci) can produce insights into behavioral outcomes, the present study modeled the association between ERI and the sulcal morphology of OFC at a finer scale than previously conducted. Methods: Analyses were conducted in a transdiagnostic sample of 118 individuals with a broad range of psychiatric syndromes. We first manually defined over 2000 sulci across the 118 participants. We then implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI and test whether effects were specific to ERI as compared to non-emotion-related impulsivity. Results: The LASSO regression revealed bilateral associations of ERI with the depth of eight OFC sulci. These effects were specific to ERI and were not observed in non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker. Conclusions: The results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology.

Altering subjective time perception leads to correlated changes in neural activity and delay discounting impulsivity
Several accounts of delay discounting suggest subjective time perception as a contributing factor to individually varying discount rates. That is, one may seem impatient if their subjective perception of delay is longer than others' perception of it. Here we build upon the behavioral and neural research on time perception, and we investigate the effects of manipulating an individual's subjective time perception on their discount rates and neural activity. Using a novel time-counting task, we found that participants' discount rates are affected by our manipulations of time perception and that neural activity also correlates with our manipulations in brain regions, such as the anterior insula and the superior temporal gyri, which have been implicated in time perception. We link these behavioral and neural findings together by showing that the degree of neural activity change in response to our manipulation is predictive of the degree of change in the participants' discount rates.

Neonatal sensitivity to vocal emotions: A milestone at 37 weeks of gestational age
Emotional responsiveness in neonates, particularly their ability to discern vocal emotions, plays an evolutionarily adaptive role in human communication and adaptive behaviors. The developmental trajectory of emotional sensitivity in neonates is a crucial area of inquiry for understanding the foundations of early social-emotional functioning. However, the precise onset of this sensitivity in neonates and its relationship with gestational age (GA) remain subjects of investigation. In a study involving 120 healthy neonates categorized into six groups based on their GA (ranging from 35 and 40 weeks), we delved into their emotional responses to vocal stimuli. These stimuli encompassed disyllables with happy and neutral prosodies, alongside acoustically matched nonvocal control sounds. The assessments occurred during natural sleep states in neonates, utilizing the odd-ball paradigm and event-related potentials. The results unveil a distinct developmental milestone at 37 weeks GA, marking the point at which neonates exhibit heightened perceptual acuity for emotional vocal expressions. This newfound ability is substantiated by the presence of the mismatch response, akin to an initial form of adult mismatch negativity, elicited in response to positive emotional vocal prosody. Notably, this perceptual shift's specificity becomes evident when no such discrimination is observed in acoustically matched control sounds. Neonates born before 37 weeks GA do not display this level of discrimination ability. This critical developmental milestone carries significant implications for our understanding of early social-emotional development, shedding light on the role of gestational age in shaping early perceptual abilities. Moreover, it introduces the potential for a valuable screening tool in the context of autism, which is characterized by atypical social-emotional functions. This study makes a substantial contribution to the broader field of developmental neuroscience and holds promise for early intervention in neurodevelopmental disorders.

GABAB- GluK1 kainate receptor interplay modulates amygdala excitability and behavioral response to chronic stress
Amygdala hyperexcitability is a hallmark for stress-induced anxiety disorders. Stress-associated changes in both principal neurons and interneurons contribute to the increased excitability, but how exactly these mechanisms perturb function of behaviorally relevant circuits in the amygdala remains unclear. Here, we show that GluK1 subunit-containing kainate receptors in parvalbumin (PV) interneurons maintain high GABA release and control excitability of lateral amygdala (LA) principal neurons via tonic GABAB-receptor-mediated inhibition. Downregulation of GluK1 expression in PV interneurons after chronic restraint stress (CRS) releases the tonic inhibition and increases excitability of LA principal neurons. Stress-induced LA hyperexcitability facilitates glutamatergic transmission selectively to central amygdala PKC{delta}-expressing neurons, implicated in fear generalization. Consistent with significance in anxiogenesis, absence of GluK1-GABAB regulation confers resilience against CRS-induced LA hyperexcitability and anxiety-like behavior. Our data reveal a unique novel mechanism involving crosstalk between glutamatergic and GABAergic systems in the regulation of amygdala excitability in response to chronic stress.

Gaze and Arrows: does the Gaze Following Patch in the posterior temporal cortex differentiate social and symbolic spatial cues?
The Gaze Following Patch (GFP) is located in the posterior temporal cortex and has been described as a cortical module dedicated to processing other people's gaze direction in a domain-specific manner. Thus, it appears to be the neural correlate of Baron-Cohen's Eye-Direction Detector (EDD) which is one of the core modules in his Mindreading System - a neurocognitive model for the Theory of Mind concept. Inspired by Jerry Fodor's ideas on the modularity of the mind, Baron-Cohen proposed that, among other things, the individual modules are domain-specific. In the case of the EDD this means that it exclusively processes eye-like stimuli to extract gaze direction and that other stimuli, that may carry directional information as well, are processed elsewhere. If the GFP is indeed EDD's neural correlate it must meet this expectation. To test this, we compared the GFP's BOLD activity during gaze-direction following with the activity during arrow-direction following. Contrary to the expectation based on the assumption of domain specificity we did not find a differentiation between gaze and arrow-direction following. In fact, we were not able to reproduce the GFP as presented in previous studies. A possible explanation is that in the present study - unlike previous work -, the gaze stimuli did not contain an obvious change of direction that represented a visual motion. Hence, the critical stimulus component responsible for the identification of the GFP in previous experiments might have been visual motion.

Projection-Targeted Photopharmacology Reveals Distinct Anxiolytic Roles for Presynaptic mGluR2 in Prefrontal- and Insula-Amygdala Synapses
Dissecting how membrane receptors regulate neural circuit function is critical for deciphering basic principles of neuromodulation and mechanisms of therapeutic drug action. Classical pharmacological and genetic approaches are not well-equipped to untangle the roles of specific receptor populations, especially in long-range projections which coordinate communication between brain regions. Here we use viral tracing, electrophysiological, optogenetic, and photopharmacological approaches to determine how presynaptic metabotropic glutamate receptor 2 (mGluR2) activation in the basolateral amygdala (BLA) alters anxiety-related behavior. We find that mGluR2-expressing neurons from the ventromedial prefrontal cortex (vmPFC) and posterior insular cortex (pIC) preferentially target distinct cell types and subregions of the BLA to regulate different forms of avoidant behavior. Using projection-specific photopharmacological activation, we find that mGluR2-mediated presynaptic inhibition of vmPFC-BLA, but not pIC-BLA, connections can produce long-lasting decreases in spatial avoidance. In contrast, presynaptic inhibition of pIC-BLA connections decreased social avoidance, novelty-induced hypophagia, and increased exploratory behavior without impairing working memory, establishing this projection as a novel target for the treatment of anxiety disorders. Overall, this work reveals new aspects of BLA neuromodulation with therapeutic implications while establishing a powerful approach for optical mapping of drug action via photopharmacology.

Simultaneous, cortex-wide and cellular-resolution neuronal population dynamics reveal an unbounded scaling of dimensionality with neuron number
The brain's remarkable properties arise from collective activity of millions of neurons. Widespread application of dimensionality reduction to multi-neuron recordings implies that neural dynamics can be approximated by low-dimensional "latent" signals reflecting neural computations. However, what would be the biological utility of such a redundant and metabolically costly encoding scheme and what is the appropriate resolution and scale of neural recording to understand brain function? Imaging the activity of one million neurons at cellular resolution and near-simultaneously across mouse cortex, we demonstrate an unbounded scaling of dimensionality with neuron number. While half of the neural variance lies within sixteen behavior-related dimensions, we find this unbounded scaling of dimensionality to correspond to an ever-increasing number of internal variables without immediate behavioral correlates. The activity patterns underlying these higher dimensions are fine-grained and cortex-wide, highlighting that large-scale recording is required to uncover the full neural substrates of internal and potentially cognitive processes.

Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinsons disease
Activating LRRK2 mutations cause Parkinsons disease. Previously, we showed that cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2 mutant mice. Single nucleus RNA sequencing shows that cilia loss in cholinergic interneurons correlates with higher LRRK2 expression and decreased glial derived neurotrophic factor transcription. Nevertheless, much higher LRRK2 expression is seen in medium spiny neurons that have normal cilia in mice and humans. In parallel with decreased striatal dopaminergic neurite density, LRRK2 G2019S neurons show increased autism-linked CNTN5 adhesion protein expression; glial cells show significant loss of ferritin heavy chain. Human striatal tissue from LRRK2 pathway mutation carriers and idiopathic Parkinsons disease show similar cilia loss in cholinergic interneurons and astrocytes and overall loss of such neurons. These data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinsons disease.

Exploration of the EEG response to periodic thermal and vibrotactile stimuli
Under certain conditions, a stimulus applied at a given frequency will lead to a periodic variation of neural activity at the same frequency. Taking advantage of this periodicity, it is possible to tag this response in the EEG frequency spectrum. Frequency tagging of sustained periodic noxious heat stimuli led to the recording of phase-locked and non-phase-locked responses whose functional significance remains unclear. This study aimed at assessing whether such responses can also be recorded during the repetitive presentation of brief innocuous cold, noxious heat and vibrotactile stimuli. Comparison between the responses obtained with different stimulation modalities should inform us on the nature of the neural processes underlying these responses (modality aspecific, somatosensory, thermosensory, nociceptive). Comparison between upper and lower limb stimulation should inform us on the somatotopic organization of these responses and, therefore, on their potential sources. Based on our results, on one hand, trains of brief innocuous cold, noxious heat and vibrations can elicit phase-locked and non-phase-locked responses which appear highly similar to those evoked by sustained periodic noxious heat stimuli when frequency tagged. On the other hand, when analysed in the time domain or using time-frequency decomposition, these responses appeared highly similar to those that can be recorded following isolated brief noxious heat or tactile stimuli. These responses consisted in phase-locked activity corresponding to the vertex potential, thought to reflect modality non-specific attentional processes, and in an alpha-to-beta ERD originating in the S1/M1 area contralateral to the stimulated hand, probably reflecting non-specific somatosensory activity.

Personal Mastery Attenuates the Association between Greater Perceived Discrimination and Lower Amygdala and Anterior Hippocampal Volume in a Diverse Sample of Older Adults
There is limited research investigating whether perceived discrimination influences brain structures that subserve episodic memory, namely the hippocampus and amygdala. Our rationale for examining these regions build on their known sensitivity to stress and functional differences along the long-axis of the hippocampus, with the anterior hippocampus and amygdala implicated in emotional and stress regulation. We defined perceived discrimination as the unfair treatment of one group by a dominant social group without the agency to respond to the event. A potential moderator of perceived discrimination is personal mastery, which we operationally defined as personal agency. Our primary goals were to determine whether perceived discrimination correlated with amygdala and anterior hippocampal volume, and if personal mastery moderated these relationships. Using FreeSurfer 7.1.0, we processed T1-weighted images to extract bilateral amygdala and hippocampal volumes. Discrimination and personal mastery were assessed via self-report (using the Experiences of Discrimination and Sense of Control questionnaires, respectively). Using multiple regression, greater perceived discrimination correlated with lower bilateral amygdala and anterior hippocampal volume, controlling for current stress, sex, education, age, and intracranial volume. Exploratory subfield analyses showed these associations were localized to the anterior hippocampal CA1 and subiculum. As predicted, using a moderation analysis, personal mastery attenuated the relationship between perceived discrimination and amygdala and anterior hippocampal volume. Here, we extend our knowledge on perceived discrimination as a salient psychosocial stressor with a neurobiological impact on brain systems implicated in stress, memory, and emotional regulation, and provide evidence for personal mastery as a moderating factor of these relationships.

Translational validation of shotgun proteomics findings in cerebrospinal fluid of sporadic cerebral amyloid angiopathy patients
Background: Prior research conducted in model rats of CAA Type 1 (rTg-DI) identified a range of cerebrospinal fluid biomarker candidates associated with sCAA pathology. This list of potential biomarkers includes the lysosomal proteases cathepsins B and S (CTSB/CTSS) and hexosaminidase B (HEXB). It is yet unknown if these findings obtained in rTg-DI rats translate to differential protein levels and/or enzyme activities in cerebrospinal fluid (CSF) of sCAA patients. In this study, we attempted to validate CTSB, CTSS and HEXB in CSF as potential biomarkers for sCAA in a human population. Materials and methods: We have included sCAA patients (n = 34) and control participants (n = 27) from our BIONIC/CAFE cohort. We analysed the CSF of these participants with ELISA for protein levels of CTSB and CTSS. Additionally, we used in-house enzyme assays to determine activity levels of total hexosaminidase and hexosaminidase A (HEXA) in CSF. The proportion of HEXA activity to total HEX activity was used as a proxy for HEXB activity. Results: CSF CTSB and CTSS protein levels were not significantly different between sCAA and controls (p = 0.21 and p = 0.34). Total HEX activity was unaltered as well (p = 0.11), whereas a significant decrease was observed in HEXA activity levels (p = 0.05). HEXA / total HEX activity levels (as a proxy for HEXB activity) were unaltered between sCAA patients and controls (p = 0.19). Additionally, CTSB and CTSS protein levels positively associated with total HEX activity (rsp = 0.37, p = 0.005; rsp = 0.40, p = 0.003). Conclusion: The contrasting results between biomarker discovery in rats and validation in human participants highlight the challenges and complexities of biomarker research. These findings offer valuable insights into the nuances of disease and the difficulties in translating laboratory findings using animal models to clinical practice. Understanding these discrepancies is essential for improving the precision of biomarker translation, ensuring clinical relevance, and developing comprehensive biomarker panels for CAA and related conditions.

Understanding functional brain reorganisation for naturalistic piano playing in novice pianists
Learning to play the piano is a unique complex task, integrating multiple sensory modalities and higher-order cognitive functions. Longitudinal neuroimaging studies on adult novice musicians show training-related functional changes in music perception tasks. The reorganisation of brain activity while actually playing an instrument was studied only on a very short time-frame of a single fMRI session, and longer interventions have not yet been performed. Thus, our aim was to investigate the dynamic complexity of functional brain reorganisation while playing the piano within the first half year of musical training. We scanned twenty-four novice keyboard learners (female, 18-23yo) using fMRI while they played increasingly complex musical pieces after 1, 6, 13 and 26 weeks of training. Playing music evoked responses bilaterally in the auditory, inferior frontal and supplementary motor areas, and the left sensorimotor cortex. The effect of training over time, however, invoked widespread changes encompassing the right sensorimotor cortex, cerebellum, superior parietal cortex, anterior insula and hippocampus, among others. As the training progressed, the activation of these regions decreased while playing music. Post-hoc analysis revealed region-specific time-courses for independent auditory and motor regions of interest. These results suggest that while the primary sensory, motor and frontal regions are associated with playing music, the training decreases the involvement of higher-order cognitive control and integrative regions, and basal ganglia. Moreover, training might affect distinct brain regions in different ways, providing evidence in favour of the dynamic nature of brain plasticity.

Long-horizon associative learning explains human sensitivity to statistical and network structures in auditory sequences
Networks are a useful mathematical tool for capturing the complexity of the world. In a previous behavioral study, we showed that human adults were sensitive to the high-level network structure underlying auditory sequences, even when presented with incomplete information. Their performance was best explained by a mathematical model compatible with associative learning principles, based on the integration of the transition probabilities between adjacent and non-adjacent elements with a memory decay. In the present study, we explored the neural correlates of this hypothesis via magnetoencephalography (MEG). Participants passively listened to sequences of tones organized in a sparse community network structure comprising two communities. An early difference (~150 ms) was observed in the brain responses to tone transitions with similar transition probability but occurring either within or between communities. This result implies a rapid and automatic encoding of the sequence structure. Using time-resolved decoding, we estimated the duration and overlap of the representation of each tone. The decoding performance exhibited exponential decay, resulting in a significant overlap between the representations of successive tones. Based on this extended decay profile, we estimated a long-horizon associative learning novelty index for each transition and found a correlation of this measure with the MEG signal. Overall, our study sheds light on the neural mechanisms underlying human sensitivity to network structures and highlights the potential role of Hebbian-like mechanisms in supporting learning at various temporal scales.

Invariant Neural Representation of Parts of Speech in the Human Brain
Elucidating the internal representation of language in the brain has major implications for cognitive science, brain disorders, and artificial intelligence. A pillar of linguistic studies is the notion that words have defined functions, often referred to as parts of speech. Here we recorded invasive neurophysiological responses from 1,801 electrodes in 20 patients with epilepsy while they were presented with two-word phrases consisting of an adjective and a noun. We observed neural signals that distinguished between these two parts of speech. The selective signals were circumscribed within a small region in the left lateral orbitofrontal cortex. The representation of parts of speech showed invariance across visual and auditory presentation modalities, robustness to word properties like length, order, frequency, and semantics, and even generalized across different languages. This selective, invariant, and localized representation of parts of speech for nouns versus adjectives provides key elements for the compositional processing of language.

Transcriptome Analysis Identifies An ASD-Like Phenotype In Oligodendrocytes And Microglia From C58/J Amygdala That Is Dependent On Sex and Sociability
Background: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. Methods: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. Results: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. Limitations: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its potential as an ASD therapeutic. Conclusions: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.

Bidirectional fear modulation by discrete anterior insular circuits in mice
The brain's ability to appraise threats and execute appropriate defensive responses is essential for survival in a dynamic environment. Humans studies have implicated the anterior insular cortex (aIC) in subjective fear regulation and its abnormal activity in fear/anxiety disorders. However, the complex aIC connectivity patterns involved in regulating fear remain under investigated. To address this, we recorded single units in the aIC of freely moving mice that had previously undergone auditory fear conditioning, assessed the effect of optogenetically activating specific aIC output structures in fear, and examined the organization of aIC neurons projecting to the specific structures with retrograde tracing. Single-unit recordings revealed that a balanced number of aIC pyramidal neurons' activity either positively or negatively correlated with a conditioned tone-induced freezing (fear) response. Optogenetic manipulations of aIC pyramidal neuronal activity during conditioned tone presentation altered the expression of conditioned freezing. Neural tracing showed that non-overlapping populations of aIC neurons project to the amygdala or the medial thalamus, and the pathway bidirectionally modulated conditioned fear. Specifically, optogenetic stimulation of the aIC-amygdala pathway increased conditioned freezing, while optogenetic stimulation of the aIC-medial thalamus pathway decreased it. Our findings suggest that the balance of positive and negative neuronal activity in the aIC and the distinct efferent circuits interact collectively to modulate fear behavior.

Structural and sequential regularities modulate phrase-rate neural tracking
Electrophysiological brain activity has been shown to synchronize with the quasi-regular repetition of grammatical phrases in connected speech (so-called phrase-rate neural tracking). Current debate centers around whether this phenomenon is best explained in terms of the syntactic properties of phrases or in terms of syntax-external information, such as the sequential repetition of parts of speech. As these two factors were confounded in previous studies, much of the literature is compatible with both accounts. Here, we used electroencephalography (EEG) to determine if and when the brain is sensitive to both types of information. Twenty native speakers of Mandarin Chinese listened to isochronously presented streams of monosyllabic words, which contained either grammatical two-word phrases (e.g., catch fish, sell house) or non-grammatical word combinations (e.g., full lend, bread far). Within the grammatical conditions, we varied two structural factors: the position of the head of each phrase and the type of attachment. Within the non-grammatical conditions, we varied the consistency with which parts of speech were repeated. Tracking was quantified through evoked power and inter-trial phase coherence, both derived from the frequency-domain representation of EEG responses. As expected, neural tracking at the phrase rate was stronger in grammatical sequences than in non-grammatical sequences without syntactic structure. Moreover, it was modulated by both attachment type and head position, revealing the structure-sensitivity of phrase-rate tracking. We additionally found that the brain tracks the repetition of parts of speech in non-grammatical sequences. These data provide an integrative perspective on the current debate about neural tracking effects, revealing that the brain utilizes regularities computed over multiple levels of linguistic representation in guiding rhythmic computation.

NRV: An open framework for in silico evaluation of peripheral nerve electrical stimulation strategies
Electrical stimulation of peripheral nerves has been used in various pathological contexts for rehabilitation purposes or to alleviate the symptoms of neuropathologies, thus improving the overall quality of life of patients. However, the development of novel therapeutic strategies is still a challenging issue requiring extensive in vivo experimental campaigns and technical development. To facilitate the design of new stimulation strategies, we provide a fully open source and self-contained software framework for the in silico evaluation of peripheral nerve electrical stimulation. Our modeling approach, developed in the popular and well-established Python language, uses an object-oriented paradigm to map the physiological and electrical context. The framework is designed to facilitate multi-scale analysis, from single fiber stimulation to whole multifascicular nerves. It also allows the simulation of complex strategies such as multiple electrode combinations and waveforms ranging from conventional biphasic pulses to more complex modulated kHz stimuli. In addition, we provide automated support for stimulation strategy optimization and handle the computational backend transparently to the user. Our framework has been extensively tested and validated with several existing results in the literature.