Flexible multi-step hypothesis testing of human ECoG data using cluster-based permutation tests with GLMEs.

BACKGROUND: Time series analysis is critical for understanding brain signals and their relationship to behavior and cognition. Cluster-based permutation tests (CBPT) are commonly used to analyze a variety of electrophysiological signals including EEG, MEG, ECoG, and sEEG data without a priori assumptions about specific temporal effects. However, two major limitations of CBPT include the inability to directly analyze experiments with multiple fixed effects and the inability to account for random effects (e.g. variability across subjects). Here, we propose a flexible multi-step hypothesis testing strategy using CBPT with Linear Mixed Effects Models (LMEs) and Generalized Linear Mixed Effects Models (GLMEs) that can be applied to a wide range of experimental designs and data types. METHODS: We first evaluate the statistical robustness of LMEs and GLMEs using simulated data distributions. Second, we apply a multi-step hypothesis testing strategy to analyze ERPs and broadband power signals extracted from human ECoG recordings collected during a simple image viewing experiment with image category and novelty as fixed effects. Third, we assess the statistical power differences between analyzing signals with CBPT using LMEs compared to CBPT using separate t-tests run on each fixed effect through simulations that emulate broadband power signals. Finally, we apply CBPT using GLMEs to high-gamma burst data to demonstrate the extension of the proposed method to the analysis of nonlinear data. RESULTS: First, we found that LMEs and GLMEs are robust statistical models. In simple simulations LMEs produced highly congruent results with other appropriately applied linear statistical models, but LMEs outperformed many linear statistical models in the analysis of "suboptimal" data and maintained power better than analyzing individual fixed effects with separate t-tests. GLMEs also performed similarly to other nonlinear statistical models. Second, in real world human ECoG data, LMEs performed at least as well as separate t-tests when applied to predefined time windows or when used in conjunction with CBPT. Additionally, fixed effects time courses extracted with CBPT using LMEs from group-level models of pseudo-populations replicated latency effects found in individual category-selective channels. Third, analysis of simulated broadband power signals demonstrated that CBPT using LMEs was superior to CBPT using separate t-tests in identifying time windows with significant fixed effects especially for small effect sizes. Lastly, the analysis of high-gamma burst data using CBPT with GLMEs produced results consistent with CBPT using LMEs applied to broadband power data. CONCLUSIONS: We propose a general approach for statistical analysis of electrophysiological data using CBPT in conjunction with LMEs and GLMEs. We demonstrate that this method is robust for experiments with multiple fixed effects and applicable to the analysis of linear and nonlinear data. Our methodology maximizes the statistical power available in a dataset across multiple experimental variables while accounting for hierarchical random effects and controlling FWER across fixed effects. This approach substantially improves power leading to better reproducibility. Additionally, CBPT using LMEs and GLMEs can be used to analyze individual channels or pseudo-population data for the comparison of functional or anatomical groups of data.

Reliability of visual review of intracranial electroencephalogram in identifying the seizure onset zone: A systematic review and implications for the accuracy of automated methods.

Visual review of intracranial electroencephalography (iEEG) is often an essential component for defining the zone of resection for epilepsy surgery. Unsupervised approaches using machine and deep learning are being employed to identify seizure onset zones (SOZs). This prompts a more comprehensive understanding of the reliability of visual review as a reference standard. We sought to summarize existing evidence on the reliability of visual review of iEEG in defining the SOZ for patients undergoing surgical workup and understand its implications for algorithm accuracy for SOZ prediction. We performed a systematic literature review on the reliability of determining the SOZ by visual inspection of iEEG in accordance with best practices. Searches included MEDLINE, Embase, Cochrane Library, and Web of Science on May 8, 2022. We included studies with a quantitative reliability assessment within or between observers. Risk of bias assessment was performed with QUADAS-2. A model was developed to estimate the effect of Cohen kappa on the maximum possible accuracy for any algorithm detecting the SOZ. Two thousand three hundred thirty-eight articles were identified and evaluated, of which one met inclusion criteria. This study assessed reliability between two reviewers for 10 patients with temporal lobe epilepsy and found a kappa of .80. These limited data were used to model the maximum accuracy of automated methods. For a hypothetical algorithm that is 100% accurate to the ground truth, the maximum accuracy modeled with a Cohen kappa of .8 ranged from .60 to .85 (F-2). The reliability of reviewing iEEG to localize the SOZ has been evaluated only in a small sample of patients with methodologic limitations. The ability of any algorithm to estimate the SOZ is notably limited by the reliability of iEEG interpretation. We acknowledge practical limitations of rigorous reliability analysis, and we propose design characteristics and study questions to further investigate reliability.

Selecting the Reaction Path in On-Surface Synthesis through the Electron Chemical Potential in Graphene.

The organometallic on-surface synthesis of the eight-membered sp2 carbon-based ring cyclooctatetraene (C8H8, Cot) with the neighboring rare-earth elements ytterbium and thulium yields fundamentally different products for the two lanthanides, when conducted on graphene (Gr) close to the charge neutrality point. Sandwich-molecular YbCot wires of more than 500 Å length being composed of an alternating sequence of Yb atoms and upright-standing Cot molecules result from the on-surface synthesis with Yb. In contrast, repulsively interacting TmCot dots consisting of a single Cot molecule and a single Tm atom result from the on-surface synthesis with Tm. While the YbCot wires are bound through van der Waals interactions to the substrate, the dots are chemisorbed to Gr via the Tm atoms being more electropositive compared to Yb atoms. When the electron chemical potential in Gr is substantially raised (n-doping) through backside doping from an intercalation layer, the reaction product in the synthesis with Tm can be tuned to TmCot sandwich-molecular wires rather than TmCot dots. By use of density functional theory, it is found that the reduced electronegativity of Gr upon n-doping weakens the binding as well as the charge transfer between the reaction intermediate TmCot dot and Gr. Thus, the assembly of the TmCot dots to long TmCot sandwich-molecular wires becomes energetically favorable. It is thereby demonstrated that the electron chemical potential in Gr can be used as a control parameter in an organometallic on-surface synthesis to tune the outcome of a reaction.

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling.

RATIONALE: We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. OBJECTIVE: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. METHODS AND RESULTS: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. CONCLUSIONS: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article.

A cholinergic basal forebrain feeding circuit modulates appetite suppression.

Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.

Assessing dosing errors in legacy and low dose tip ENFit® syringes.

WHAT IS KNOWN AND OBJECTIVE: To avoid misconnections between different medical devices, a unique standardized design of connectors (ENFit® ) for enteral medical devices has been developed. It was expected that the syringes with these connectors will replace the pre-existing syringes, henceforth referred to as legacy syringes. However, the changes in the connector's design led to concerns regarding dosing errors for low volume syringes (≤2 ml). Therefore, novel low dose tip (LDT) syringes were designed to address these concerns. These LDT syringes can connect with the standardized ENFit® male connectors. Only a few studies have investigated dosing errors, and findings have largely been mixed. The objective of this report was to calculate the contributions of unavoidable dosing errors for LDT syringes, compare with legacy syringes and to suggest strategies to optimize dose accuracy for enteral applications. METHODS: Studies performed with a limited number of syringes to date may not reflect the actual diversity of dosing error that can occur across syringe orientations, batches, manufacturers, medications, etc. A computer-aided design software SolidWorks® was used to calculate the dosing errors in 0.5 and 1.0 ml legacy syringe connectors and were compared with dosing errors in LDT syringe connectors with the same nominal volume. Influence of orientation during delivery, spillage and flushing on dosing error was also investigated. RESULTS AND DISCUSSION: For 0.5 and 1.0 ml LDT syringes, in absence of medication in the moat area, the maximum dosing error will be ±5% when delivering 100% of nominal volume, which is also equal to the dosing error in 0.5 and 1.0 ml slip tip legacy syringes. However, with medication present in moat area, and with syringe reused during flushing, the LDT dosing error can range from 1% to 18% and 28% to 35% for 1.0 and 0.5 ml syringes, respectively. The corresponding dosing error for legacy syringes would be when the same syringe is used for flushing or when syringe disengages pointing vertically up. The corresponding dosing errors for legacy syringes could range from -7 to 12% and -9% to 19% for 1.0 and 0.5 ml syringes, respectively. Dosing errors for legacy and LDT syringes increase as the nominal capacity of syringe reduces, or when the dose delivered is lower than the nominal capacity of the syringe. WHAT IS NEW AND CONCLUSION: For LDT syringes, dosing errors can be reduced by clearing the moat area of the syringe and by using a new syringe for flushing post-delivery of medication. For legacy syringes, dosing errors can be minimized by ensuring the female connector points up during disengagement from the syringe post-medication administration, and by using a new syringe for flushing.

Spin Crossover in a Cobalt Complex on Ag(111).

The Co-based complex [Co(H2 B(pz)(pypz))2 ] (py=pyridine, pz=pyrazole) deposited on Ag(111) was investigated with scanning tunneling microscopy at ≈5 K. Due to a bis(tridentate) coordination sphere the molecules aggregate mainly into tetramers. Individual complexes in these tetramers undergo reversible transitions between two states with characteristic image contrasts when current is passed through them or one of their neighbors. Two molecules exhibit this bistability while the other two molecules are stable. The transition rates vary linearly with the tunneling current and exhibit an intriguing dependence on the bias voltage and its polarity. We interpret the states as being due to S=1 /2 and 3 /2 spin states of the Co2+ complex. The image contrast and the orders-of-magnitude variations of the switching yields can be tentatively understood from the calculated orbital structures of the two spin states, thus providing first insights into the mechanism of electron-induced excited spin-state trapping (ELIESST).

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

A Radiolucent Electromagnetic Tracking System for Use with Intraoperative X-ray Imaging.

In recent times, the use of electromagnetic tracking for navigation in surgery has quickly become a vital tool in minimally invasive surgery. In many procedures, electromagnetic tracking is used in tandem with X-ray technology to track a variety of tools and instruments. Most commercially available EM tracking systems can cause X-ray artifacts and attenuation due to their construction and the metals that form them. In this work, we provide a novel solution to this problem by creating a new radiolucent electromagnetic navigation system that has minimal impact on -ray imaging systems. This is a continuation of our previous work where we showed the development of the Anser open-source electromagnetic tracking system. Typical electromagnetic tracking systems operate by generating low frequency magnetic fields from coils that are located near the patient. These coils are typically made from copper, steel, and other dense radiopaque materials. In this work, we explore the use of low density aluminum to create these coils and we demonstrate that the effect on X-ray images is significantly reduced as a result of these novel changes in the materials used. The resulting field generator is shown to give at least a 60% reduction in the X-ray attenuation in comparison to our earlier designs. We verify that the system accuracy of approximately 1.5 mm RMS error is maintained with this change in design.

Planar Body-Mounted Sensors for Electromagnetic Tracking.

Electromagnetic tracking is a safe, reliable, and cost-effective method to track medical instruments in image-guided surgical navigation. However, patient motion and magnetic field distortions heavily impact the accuracy of tracked position and orientation. The use of redundant magnetic sensors can help to map and mitigate for patient movements and magnetic field distortions within the tracking region. We propose a planar inductive sensor design, printed on PCB and embedded into medical patches. The main advantage is the high repeatability and the cost benefit of using mass PCB manufacturing processes. The article presents new operative formulas for electromagnetic tracking of planar coils on the centimetre scale. The full magnetic analytical model is based on the mutual inductance between coils which can be approximated as being composed by straight conductive filaments. The full model is used to perform accurate system simulations and to assess the accuracy of faster simplified magnetic models, which are necessary to achieve real-time tracking in medical applications.

Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network.

The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGF-mediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis.

Development of barium-based low viscosity contrast agents for micro CT vascular casting: Application to 3D visualization of the adult mouse cerebrovasculature.

Recent advances in three-dimensional (3D) fluorescence microscopy offer the ability to image the entire vascular network in entire organs, or even whole animals. However, these imaging modalities rely on either endogenous fluorescent reporters or involved immunohistochemistry protocols, as well as optical clearing of the tissue and refractive index matching. Conversely, X-ray-based 3D imaging modalities, such as micro CT, can image non-transparent samples, at high resolution, without requiring complicated or expensive immunolabeling and clearing protocols, or fluorescent reporters. Here, we compared two "homemade" barium-based contrast agents to the field standard, lead-containing Microfil, for micro-computed tomography (micro CT) imaging of the adult mouse cerebrovasculature. The perfusion pressure required for uniform vessel filling was significantly lower with the barium-based contrast agents compared to the polymer-based Microfil. Accordingly, the barium agents showed no evidence of vascular distension or rupture, common problems associated with Microfil. Compellingly, perfusion of an aqueous BaCl2 /gelatin mixture yielded equal or superior visualization of the cerebrovasculature by micro CT compared to Microfil. However, phosphate-containing buffers and fixatives were incompatible with BaCl2 due to the formation of unwanted precipitates. X-ray attenuation of the vessels also decreased overtime, as the BaCl2 appeared to gradually diffuse into surrounding tissues. A second, unique formulation composed of BaSO4 microparticles, generated in-house by mixing BaCl2 and MgSO4 , suffered none of these drawbacks. These microparticles, however, were unable to pass small diameter capillary vessels, conveniently labeling only the arterial cerebrovasculature. In summary, we present an affordable, robust, low pressure, non-toxic, and straightforward methodology for 3D visualization of the cerebrovasculature.

In Vitro Leakage Testing of Tissue Containment Bags When Subjected to Power Morcellation Forces.

STUDY OBJECTIVE: To determine the ability of tissue containment systems to prevent leakage of cancer cell surrogates when subjected to forces encountered during power morcellation procedures. DESIGN: In vitro study. SETTING: Medical device research laboratory. INTERVENTIONS: Samples from 7 different legally marketed tissue containment bags (1 of which is indicated for power morcellation) were subjected to dye and bacteriophage penetration tests at pressures ranging from 0.5 to 50 times the insufflation pressure. The minimum pressure required to cause bag leakage was measured. Subsequently, the morcellation leakage safety factor for each bag was determined as the ratio of the minimum leakage pressure of the bag to the total pressure contributed from insufflation pressure and mechanical forces acting during the power morcellation procedure. MEASUREMENT AND MAIN RESULTS: The leakage performance of the bags varied markedly from brand to brand. No correlation was found between leakage pressure and the bag material or the total bag thickness. The leakage pressures ranged from 26 mmHg to >1293 mmHg for the 7 bags, and safety factors ranged from 1 to 50 when only the insufflation pressure was considered. However, if the morcellation forces were included in the calculation, the safety factor dropped by 6-fold for all brands and dropped below 1, indicating likelihood of leakage, for 2 of the 7 brands. CONCLUSION: This study provides a mechanism for more realistically simulating the conditions experienced by containment bags during morcellation and quantifying the level of safety provided by the bags.

Suppression of wrinkle formation in graphene on Ir(111) by high-temperature, low-energy ion irradiation.

Graphene on Ir(111) is irradiated with small fluences of 500 eV He ions at temperatures close to its chemical vapor deposition growth temperature. The ion irradiation experiments explore whether it is possible to suppress the formation of wrinkles in Gr during growth. It is found that the release of thermal mismatch strain by wrinkle formation can be entirely suppressed for an irradiation temperature of 880 °C. A model for the ion beam induced suppression of wrinkle formation in supported Gr is presented, and underpinned by experiments varying the irradiation temperature or involving intercalation subsequent to irradiation.

Taking an engineer's view: Implications of network analysis for computational psychiatry.

An engineer's viewpoint on psychiatry asks: What are the failure modes that underlie psychiatric dysfunction? And: How can we modify the system? Psychiatry has made great strides in understanding and treating disorders using biology; however, failure modes and modification access points can also exist extrinsically in environmental interactions. The network analysis suggested by Borsboom et al. in the target article provides a new viewpoint that should be incorporated into current theoretical constructs, not placed in opposition to them.

Peripheral tumour targeting using open-source virtual bronchoscopy with electromagnetic tracking: a multi-user pre-clinical study.

Objectives: The goal was to demonstrate the utility of open-source tracking and visualisation tools in the targeting of lung cancer.Material and methods: The study demonstrates the first deployment of the Anser electromagnetic (EM) tracking system with the CustusX image-guided interventional research platform to navigate using an endobronchial catheter to injected tumour targets. Live animal investigations validated the deployment and targeting of peripheral tumour models using an innovative tumour marking routine.Results: Novel tumour model deployment was successfully achieved at all eight target sites across two live animal investigations without pneumothorax. Virtual bronchoscopy with tracking successfully guided the tracked catheter to 2-12 mm from the target tumour site. Deployment of a novel marker was achieved at all eight sites providing a reliable measure of targeting accuracy. Targeting accuracy within 10 mm was achieved in 7/8 sites and in all cases, the virtual target distance at marker deployment was within the range subsequently measured with x-ray.Conclusions: Endobronchial targeting of peripheral airway targets is feasible using existing open-source technology. Notwithstanding the shortcomings of current commercial platforms, technological improvements in EM tracking and registration accuracy fostered by open-source technology may provide the impetus for widespread clinical uptake of electromagnetic navigation in bronchoscopy.

Distorter Characterisation Using Mutual Inductance in Electromagnetic Tracking.

Electromagnetic tracking (EMT) is playing an increasingly important role in surgical navigation, medical robotics and virtual reality development as a positional and orientation reference. Though EMT is not restricted by line-of-sight requirements, measurement errors caused by magnetic distortions in the environment remain the technology's principal shortcoming. The characterisation, reduction and compensation of these errors is a broadly researched topic, with many developed techniques relying on auxiliary tracking hardware including redundant sensor arrays, optical and inertial tracking systems. This paper describes a novel method of detecting static magnetic distortions using only the magnetic field transmitting array. An existing transmitter design is modified to enable simultaneous transmission and reception of the generated magnetic field. A mutual inductance model is developed for this transmitter design in which deviations from control measurements indicate the location, magnitude and material of the field distorter to an approximate degree. While not directly compensating for errors, this work enables users of EMT systems to optimise placement of the magnetic transmitter by characterising a distorter's effect within the tracking volume without the use of additional hardware. The discrimination capabilities of this method may also allow researchers to apply material-specific compensation techniques to minimise position error in the clinical setting.

Parsing the phonological loop: activation timing in the dorsal speech stream determines accuracy in speech reproduction.

Despite significant research and important clinical correlates, direct neural evidence for a phonological loop linking speech perception, short-term memory and production remains elusive. To investigate these processes, we acquired whole-head magnetoencephalographic (MEG) recordings from human subjects performing a variable-length syllable sequence reproduction task. The MEG sensor data were source localized using a time-frequency optimized spatially adaptive filter, and we examined the time courses of cortical oscillatory power and the correlations of oscillatory power with behavior between onset of the audio stimulus and the overt speech response. We found dissociations between time courses of behaviorally relevant activations in a network of regions falling primarily within the dorsal speech stream. In particular, verbal working memory load modulated high gamma power in both Sylvian-parietal-temporal and Broca's areas. The time courses of the correlations between high gamma power and subject performance clearly alternated between these two regions throughout the task. Our results provide the first evidence of a reverberating input-output buffer system in the dorsal stream underlying speech sensorimotor integration, consistent with recent phonological loop, competitive queuing, and speech-motor control models. These findings also shed new light on potential sources of speech dysfunction in aphasia and neuropsychiatric disorders, identifying anatomically and behaviorally dissociable activation time windows critical for successful speech reproduction.

Individual differences in uncertainty evaluation explain opposing exploratory behaviors in anxiety and apathy.

Navigating uncertain environments is a fundamental challenge for adaptive behavior, and affective states such as anxiety and apathy can profoundly influence an individual's response to uncertainty. Uncertainty encompasses both volatility and stochasticity, where volatility refers to how rapidly the environment changes and stochasticity describes outcomes resulting from random chance. This study investigates how anxiety and apathy modulate perceptions of environmental volatility and stochasticity and how these perceptions impact exploratory behavior. In a large online sample (N = 1001), participants completed a restless three-armed bandit task, and their choices were analyzed using latent state models to quantify the computational processes. We found that anxious individuals attributed uncertainty more to environmental volatility than stochasticity, leading to increased exploration, particularly after reward omission. Conversely, apathetic individuals perceived uncertainty as more stochastic than volatile, resulting in decreased exploration. The ratio of perceived volatility to stochasticity mediated the relationship between anxiety and exploratory behavior following adverse outcomes. These findings reveal distinct computational mechanisms underlying anxiety and apathy in uncertain environments. Our results provide a novel framework for understanding the cognitive and affective processes driving adaptive and potentially maladaptive behaviors under uncertainty, with implications for the characterization and treatment of neuropsychiatric disorders.