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Traditional decision-making models conceptualize humans as adaptive learners utilizing the differences between expected and actual rewards (prediction errors, PEs) to maximize outcomes, but rarely consider the influence of violations of emotional expectations (emotional PEs) and how it differs from reward PEs. Here, we conducted a fMRI experiment (n = 43) using a modified Ultimatum Game to examine how reward and emotional PEs affect punishment decisions in terms of rejecting unfair offers. Our results revealed that reward relative to emotional PEs exerted a stronger prediction to punishment decisions. On the neural level, the left dorsomedial prefrontal cortex (dmPFC) was strongly activated during reward receipt whereas the emotions engaged the bilateral anterior insula. Reward and emotional PEs were also encoded differently in brain-wide multivariate patterns, with a more sensitive neural signature observed within fronto-insular circuits for reward PE. We further identified a fronto-insular network encompassing the left anterior cingulate cortex, bilateral insula, left dmPFC and inferior frontal gyrus that encoded punishment decisions. In addition, a stronger fronto-insular pattern expression under reward PE predicted more punishment decisions. These findings underscore that reward and emotional violations interact to shape decisions in complex social interactions, while the underlying neurofunctional PEs computations are distinguishable.Reward and emotional evaluations interact to guide decisions regarding the punishment of a social norm-violating proposer, with these processes being mediated by distinct neurofunctional computation. [ABSTRACT FROM AUTHOR]

When we collaborate with others to tackle novel problems, we anticipate how they will perform their part of the task to coordinate behavior effectively. We might estimate how well someone else will perform by extrapolating from estimates of how well we ourselves would perform. This account predicts that our metacognitive model should make accurate predictions when projected onto people as good as, or worse than, us but not on those whose abilities exceed our own. We demonstrate just such a pattern and that it leads to worse coordination when working with people more skilled than ourselves. Metacognitive projection is associated with a specific activity pattern in anterior lateral prefrontal cortex (alPFC47). Manipulation of alPFC47 activity altered metacognitive projection and impaired interpersonal social coordination. By contrast, monitoring of other individuals' observable performance and outcomes is associated with a distinct pattern of activity in the posterior temporal parietal junction (TPJp). When we collaborate with others to tackle novel problems, we anticipate how they will perform their part effectively. Miyamoto et al find that metacognitive projection mediated by anterior lateral prefrontal cortex enables this social coordination. [ABSTRACT FROM AUTHOR]

Substance Use Disorder (SUD) is a medical condition where an individual compulsively misuses drugs or alcohol despite knowing the negative consequences. The anterior cingulate cortex (ACC) has been implicated in various types of SUDs, including nicotine, heroin, and alcohol use disorders. Our research aimed to investigate the effects of deep brain stimulation (DBS) in the ACC as a potential therapeutic approach for morphine use disorder. Additionally, we measured c-Fos protein expression as an indicator of neural activity in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Our findings indicate that high-frequency (130 Hz) DBS at different amperages, 150 µA and 200 µA in the ACC during the acquisition phase of morphine conditioned place preference (CPP) inhibited the rewarding properties of morphine. Furthermore, DBS at these intensities during the extinction phase facilitated the extinction and mitigated the reinstatement of morphine CPP triggered by drug priming. Morphine conditioning was associated with impaired novel object conditioning (NOR) and locomotor activity. While DBS in the acquisition and extinction phases at both intensities restored NOR memory, only DBS at 200 µA recovered locomotor activity in the open field test. Treatment with DBS at 200 µA decreased c-Fos protein expression in the NAc and PFC (compared to morphine-only group). In conclusion, our data indicate an intensity-dependent effect of ACC DBS on the acquisition, extinction, and reinstatement of morphine-induced CPP in rats. These findings suggest that ACC DBS could be a potential intervention for the treatment of morphine use disorder. [ABSTRACT FROM AUTHOR]

Cognitive models of reading assume that speech production occurs after visual and phonological processing of written words. This traditional view is at odds with more recent magnetoencephalography studies showing that the left posterior inferior frontal cortex (pIFC) classically associated with spoken production responds to print at 100–150 ms after word-onset, almost simultaneously with posterior brain regions for visual and phonological processing. Yet the theoretical significance of this fast neural response remains open to date. We used transcranial magnetic stimulation (TMS) to investigate how the left pIFC contributes to the early stage of reading. In Experiment 1, 23 adult participants (14 females) performed three different tasks about written words (oral reading, semantic judgment, and perceptual judgment) while single-pulse TMS was delivered to the left pIFC, fusiform gyrus or supramarginal gyrus at different time points (50–200 ms after word-onset). A robust double dissociation was found between tasks and stimulation sites—oral reading, but not other control tasks, was disrupted only when TMS was delivered to pIFC at 100 ms. This task-specific impact of pIFC stimulation was further corroborated in Experiment 2, which revealed another double dissociation between oral reading and picture naming. These results demonstrate that the left pIFC specifically and causally mediates rapid computation of speech motor codes at the earliest stage of reading and suggest that this fast sublexical neural pathway for pronunciation, although seemingly dormant, is fully functioning in literate adults. Our results further suggest that these left-hemisphere systems for reading overall act faster than known previously. [ABSTRACT FROM AUTHOR]

Brain oscillations in the alpha-band (8–14 Hz) have been linked to specific processes in attention and perception. In particular, decreases in posterior alpha-amplitude are thought to reflect activation of perceptually relevant brain areas for target engagement, while alpha-amplitude increases have been associated with inhibition for distractor suppression. Traditionally, these alpha-changes have been viewed as two facets of the same process. However, recent evidence calls for revisiting this interpretation. Here, we recorded MEG/EEG in 32 participants (19 females) during covert visuospatial attention shifts (spatial cues) and two control conditions (neutral cue, no-attention cue), while tracking fixational eye movements. In disagreement with a single, perceptually relevant alpha-process, we found the typical alpha-modulations contra- and ipsilateral to the attention focus to be triple dissociated in their timing, topography, and spectral features: Ipsilateral alpha-increases occurred early, over occipital sensors, at a high alpha-frequency (10–14 Hz) and were expressed during spatial attention (alpha spatial cue > neutral cue). In contrast, contralateral alpha-decreases occurred later, over parietal sensors, at a lower alpha-frequency (7–10 Hz) and were associated with attention deployment in general (alpha spatial and neutral cue < no-attention cue). Additionally, the lateralized early alpha-increases but not alpha-decreases during spatial attention coincided in time with directionally biased microsaccades. Overall, this suggests that the attention-related early alpha-increases and late alpha-decreases reflect distinct, likely reflexive versus endogenously controlled attention mechanisms. We conclude that there is more than one perceptually relevant posterior alpha-oscillation, which need to be dissociated for a detailed account of their roles in perception and attention. [ABSTRACT FROM AUTHOR]

Learning occurs across multiple timescales, with fast learning crucial for adapting to sudden environmental changes, and slow learning beneficial for extracting robust knowledge from multiple events. Here, we asked if miscalibrated fast vs slow learning can lead to maladaptive decision-making in individuals with problem gambling. We recruited participants with problem gambling (PG; N = 20; 9 female and 11 male) and a recreational gambling control group without any symptoms associated with PG (N = 20; 10 female and 10 male) from the community in Los Angeles, CA. Participants performed a decision-making task involving reward-learning and loss-avoidance while being scanned with fMRI. Using computational model fitting, we found that individuals in the PG group showed evidence for an excessive dependence on slow timescales and a reduced reliance on fast timescales during learning. fMRI data implicated the putamen, an area associated with habit, and medial prefrontal cortex (PFC) in slow loss-value encoding, with significantly more robust encoding in medial PFC in the PG group compared to controls. The PG group also exhibited stronger loss prediction error encoding in the insular cortex. These findings suggest that individuals with PG have an impaired ability to adjust their predictions following losses, manifested by a stronger influence of slow value learning. This impairment could contribute to the behavioral inflexibility of problem gamblers, particularly the persistence in gambling behavior typically observed in those individuals after incurring loss outcomes. [ABSTRACT FROM AUTHOR]

The ability to prioritize among input features according to relevance enables adaptive behaviors across the human lifespan. However, relevance often remains ambiguous, and such uncertainty increases demands for dynamic control. While both cognitive stability and flexibility decline during healthy ageing, it is unknown whether aging alters how uncertainty impacts perception and decision-making, and if so, via which neural mechanisms. Here, we assess uncertainty adjustment across the adult lifespan (N = 100; cross-sectional) via behavioral modeling and a theoretically informed set of EEG-, fMRI-, and pupil-based signatures. On the group level, older adults show a broad dampening of uncertainty adjustment relative to younger adults. At the individual level, older individuals whose modulation more closely resembled that of younger adults also exhibit better maintenance of cognitive control. Our results highlight neural mechanisms whose maintenance plausibly enables flexible task-set, perception, and decision computations across the adult lifespan. Reduced flexibility is a hallmark of cognitive ageing. Here, the authors examine EEG, fMRI and pupillometry signatures to show that older adults adapt less to variable uncertainty and identify neural mechanisms that support uncertainty adjustment in aging populations. [ABSTRACT FROM AUTHOR]

Background: The effect of varying brain ventricular volume on the cerebrospinal fluid (CSF) proteome has been discussed as possible confounding factors in comparative protein level analyses. However, the relationship between CSF volume and protein levels remains largely unexplored. Moreover, the few existing studies provide conflicting findings, indicating the need for further research. Methods: Here, we explored the association between levels of 88 pre-selected CSF proteins and ventricular volume derived from magnetic resonance imaging (MRI) measurements in 157 cognitively healthy 70-year-olds from the H70 Gothenburg Birth Cohort Studies, including individuals with and without pathological levels of Alzheimer's disease (AD) CSF markers (n = 123 and 34, respectively). Both left and right lateral, the inferior horn as well as the third and the fourth ventricular volumes were measured. Different antibody-based methods were employed for the protein measurements, with most being analyzed using a multiplex bead-based microarray technology. Furthermore, the associations between the protein levels and cortical thickness, fractional anisotropy, and mean diffusivity were assessed. Results: CSF levels of many brain-derived proteins correlated with ventricular volumes in A-T- individuals, with lower levels in individuals with larger ventricles. The strongest negative correlations with total ventricular volume were observed for neurocan (NCAN) and neurosecretory protein VGF (rho = -0.34 for both). Significant negative correlations were observed also for amyloid beta (Ab) 38, Ab40, total tau (t-tau), and phosphorylated tau (p-tau), with correlation ranging between − 0.34 and − 0.28, while no association was observed between ventricular volumes and Ab42 or neurofilament light chain (NfL). Proteins with negative correlations to ventricular volumes further demonstrated negative correlations to mean diffusivity and positive correlation to fractional anisotropy. However, only weak or no correlations were observed between the CSF protein levels and cortical thickness. A + T + individuals demonstrated higher CSF protein levels compared to A-T- individuals with the most significant differences observed for neurogranin (NRGN) and synuclein beta (SNCB). Conclusions: Our findings suggest that the levels of many brain-derived proteins in CSF may be subjected to dilution effects depending on the size of the brain ventricles in healthy individuals without AD pathology. This phenomenon could potentially contribute to the inter-individual variations observed in CSF proteomic studies. [ABSTRACT FROM AUTHOR]

Volition is conceived as a set of orchestrated executive functions, which can be characterized by features, such as reason-based and goal-directedness, driven by endogenous signals. The lateral prefrontal cortex (LPFC) has long been considered to be responsible for cognitive control and executive function, and its neurodynamics appears to be central to goal-directed cognition. In order to address both associative processes (i.e. reason-action and action-outcome) based on internal stimuli, it seems essential to consider the interconnectivity of LPFC and the anterior cingulate cortex (ACC). The critical placement of ACC as a hub mediates projection of afferent expectancy signals directly from brain structures associated with emotion, as well as internal signals from subcortical areas to the LPFC. Apparently, the two cortical areas LPFC and ACC play a pivotal role in the formation of voluntary behaviors. In this paper, we model the neurodynamics of these two neural structures and their interactions related to intentional control. We predict that the emergence of intention is the result of both feedback-based and competitive mechanisms among neural attractors. These mechanisms alter the dimensionalities of coexisting chaotic attractors to more stable, low dimensional manifolds as limit cycle attractors, which may result in the onset of a readiness potential (RP) in SMA, associated with a decision to act. [ABSTRACT FROM AUTHOR]

Background: Abnormal cognitive response to pain is consistently associated with deleterious outcomes among adolescents with depression. Highly relevant to both pain and cognition, dorsolateral prefrontal cortex (DLPFC) is important to understanding pain cognition. Our study aimed to characterize the circuit of DLPFC and the efficacy of transcranial magnetic stimulation (TMS) over DLPFC on pain cognition in adolescents with depression. Methods: Using neuroimaging data, we first compared functional connectivity (FC) of DLPFC between 60 adolescents with depression and 65 controls. The patients were then divided into add-on TMS group (N = 30) and Sertraline group (N = 30). Clinical outcome was determined using Pain Vigilance and Awareness Questionnaire (PVAQ) and Pain Catastrophizing Scale (PCS). Finally, we conducted regression analysis to assess the effect that FC of DLPFC contributes to in predicting clinical outcome. Results: FC analysis showed that compared to controls, patients displayed hyperconnection of left DLPFC - left triangular part of inferior frontal gyrus (IFG), which was significantly correlated with higher PCS total-, magnification- and helplessness-scores. Patients also showed hyperconnection of right DLPFC - right supramarginal gyrus (SMG), which was correlated with lower PCS total- and rumination- scores. After intervention, the add-on TMS group displayed significantly decreased score on PVAQ, PCS total and rumination. FC of left DLPFC - bilateral triangular part of IFG, - right SMG, as well as right DLPFC - left putamen, could predict the improvement of pain vigilance and magnification. Conclusion: Our results point to a key role of DLPFC acting as a connection linking cognitive control and pain processing in adolescents with depression. Trial registration: The study is registered in https://www.chictr.org.cn/ with a registration number ChiCTR2000039503 (date: 10.30.2020). [ABSTRACT FROM AUTHOR]

Sequential information permeates daily activities, such as when watching for the correct series of buildings to determine when to get off the bus or train. These sequences include periodicity (the spacing of the buildings), the identity of the stimuli (the kind of house), and higher-order more abstract rules that may not depend on the exact stimulus (e.g., house, house, house, business). Previously, we found that the posterior fundus of area 46 in the monkey lateral prefrontal cortex (LPFC) responds to rule changes in such abstract visual sequences. However, it is unknown if this region responds to other components of the sequence, i.e., image periodicity and identity, in isolation. Further, it is unknown if this region dissociates from other, more ventral LPFC subregions that have been associated with sequences and their components. To address these questions, we used awake functional magnetic resonance imaging in three male macaque monkeys during two no-report visual tasks. One task contained abstract visual sequences, and the other contained no visual sequences but maintained the same image periodicity and identities. We found the fundus of area 46 responded only to abstract sequence rule violations. In contrast, the ventral bank of area 46 responded to changes in image periodicity and identity, but not changes in the abstract sequence. These results suggest a functional specialization within anatomical substructures of LPFC to signal different kinds of stimulus regularities. This specialization may provide key scaffolding to identify abstract patterns and construct complex models of the world for daily living. [ABSTRACT FROM AUTHOR]

The noradrenergic system is believed to support behavioral flexibility. A possible source mediating improved flexibility are α2A adrenoceptors (α2AR) in prefrontal cortex (PFC) or the anterior cingulate cortex (ACC). We tested this hypothesis by stimulating α2ARs using Guanfacine during attentional set shifting in male nonhuman primates. We found that α2AR stimulation improved learning from errors and updating attention sets. Neural recordings in the ACC, dorsolateral PFC, and the striatum showed that α2AR stimulation selectively enhanced neural signaling of prediction errors in neurons of the ACC and the striatum, but not in dlPFC. This modulation was accompanied by enhanced encoding of attended target features and particularly apparent in putative fast-spiking interneurons, pointing to an interneuron mediated mechanism of α2AR action. These results reveal that α2A receptors are part of the causal chain of flexibly updating attention sets through an enhancement of outcomes and prediction error signaling in ACC and striatum. How noradrenergic modulation could support the flexible switching of cognitive states in primates is not fully understood. Here authors show that alpha-2A noradrenergic action causally enhances cognitive flexibility by enhancing prediction error signaling and neural coding of attended target features in anterior cingulate cortex and the anterior striatum. [ABSTRACT FROM AUTHOR]

The brain's white matter connections are thought to provide the structural basis for its functional connections between distant brain regions but how our brain selects the best structural routes for functional communications remains poorly understood. In this study, we propose a Unified Structural and Functional Connectivity (USFC) model and use an "economical assumption" to create the brain's first "traffic map" reflecting how frequently each segment of the brain structural connection is used to achieve the global functional communication system. The resulting USFC map highlights regions in the subcortical, default-mode, and salience networks as the most heavily traversed nodes and a midline frontal-caudate-thalamus-posterior cingulate-visual cortex corridor as the backbone of the whole brain connectivity system. Our results further revealed a striking negative association between structural and functional connectivity strengths in routes supporting negative functional connections, as well as significantly higher efficiency metrics and better predictive performance for cognition in the USFC connectome when compared to structural and functional ones alone. Overall, the proposed USFC model opens up a new window for integrated brain connectome modeling and provides a major leap forward in brain mapping efforts for a better understanding of the brain's fundamental communication mechanisms. Unified Structural and Functional Connectivity (USFC) model provides a novel framework for modeling the brain's integrated structural and functional pathway system and potentially opens up a new window uncovering the brain's working principles. [ABSTRACT FROM AUTHOR]

Introduction: Abnormalities in the hippocampus have been extensively reported in schizophrenia research. However, inconsistent findings exist, and how structural and functional abnormalities of the hippocampus are associated with clinical symptoms in schizophrenia, especially concerning clozapine treatment, remains uncertain. Methods: We recruited 52 patients with schizophrenia, each with an illness duration of at least 5 years, and categorized them based on clozapine treatment. T1-weighted images and resting-state functional magnetic resonance imaging scans were obtained and analyzed to perform group comparisons of the structural and functional changes in the hippocampus. Volumes of the hippocampal subregions, as well as resting-state functional connectivity maps from these areas were compared between the groups. Associations with clinical symptoms, including the severity of psychiatric symptoms and cognitive functions, were investigated. Results: The clozapine group (n=23) exhibited smaller volumes in several hippocampal subregions, including the CA1, CA4, granule cell and molecular layers of the dentate gyrus, compared to the non-clozapine group (n=29). Seven clusters with significant group differences in functional connectivity with these hippocampal subregions were identified, with six of these clusters showing increased functional connectivity in the clozapine group. The reduced volumes of the hippocampal subregions were moderately associated with the severity of negative symptoms, general intelligence, and executive function. Discussion: Patients with schizophrenia undergoing clozapine treatment exhibited smaller volumes in the hippocampal subregions, which were moderately associated with negative symptoms and cognitive functions, compared to those without clozapine treatment. [ABSTRACT FROM AUTHOR]

Investigating evolutionary changes in frontal cortex microstructure is crucial to understanding how modifications of neuron and axon distributions contribute to phylogenetic variation in cognition. In the present study, we characterized microstructural components of dorsolateral prefrontal cortex, orbitofrontal cortex, and primary motor cortex from 14 primate species using measurements of neuropil fraction and immunohistochemical markers for fast-spiking inhibitory interneurons, large pyramidal projection neuron subtypes, serotonergic innervation, and dopaminergic innervation. Results revealed that the rate of evolutionary change was similar across these microstructural variables, except for neuropil fraction, which evolves more slowly and displays the strongest correlation with brain size. We also found that neuropil fraction in orbitofrontal cortex layers V–VI was associated with cross-species variation in performance on experimental tasks that measure self-control. These findings provide insight into the evolutionary reorganization of the primate frontal cortex in relation to brain size scaling and its association with cognitive processes. [ABSTRACT FROM AUTHOR]

Regional variations in glutamate levels across the cingulate cortex, decreasing rostral to caudal, have been observed previously in healthy volunteers with proton magnetic resonance spectroscopy (1H-MRS) at 7 T. This study sought to explore cingulate cortex glutamate trends further by investigating whether a similar gradient could be detected at 3 T, the effect of sex, as well as whether individual variations gave rise to more than one regional glutamate pattern. 1H-MRS at 3 T [Phillips Elition; semi-localization by adiabatic selective refocusing, echo time (TE)/repetition time (TR) = 32/5,000] was acquired in four cingulate regions: the anterior, midanterior, midposterior, and posterior cortices, in 50 healthy participants (26 F) scanned at a fixed time of day and with controlled food intake. K-means clustering was used to characterize the presence of distinct regional patterns, which were then compared between sex and clusters. In addition, cortical thickness was compared between clusters and in relation to glutamate. Aligned with 7 T findings, we demonstrated that average glutamate levels decreased rostral to caudal in the healthy cingulate cortex. No effect of sex was found, suggesting similar resting glutamate levels in both sexes. Interestingly, the majority of participants were characterized by glutamate levels that did not significantly change across the cingulate (65%). Different regional patterns in cortical thickness between clusters offer further evidence into these distinct glutamate variations and suggest that both a neuroanatomical and a functional role may lead to these findings. This study provides a much-needed foundation for further research to determine the implications of neurotransmission patterns in health and disease. NEW & NOTEWORTHY: In a large, sex-balanced sample of healthy individuals, we demonstrate that average regional differences (rostral to caudal) in cingulate cortex glutamate exist, using optimized experimental conditions and 3 T magnetic resonance spectroscopy techniques. Results align with observations from 7 T. A novel clustering approach was introduced to determine the number of patterns for glutamate in the healthy adult brain for the first time. These findings demonstrate that regional differences are detectable at 3 T when present and suggest the occurrence of multiple glutamate metabolism patterns in the cingulate. [ABSTRACT FROM AUTHOR]

Background: The ability to relearn a lost skill is critical to motor recovery after a stroke. Previous studies indicate that stroke typically affects the processes underlying motor control and execution but not the learning of those skills. However, these studies could be confounded by the presence of significant motor impairments. Furthermore, prior research involving the upper extremity indicates that stroke survivors have an advantage in offline motor learning when compared with controls. However, this has not been examined using motor acuity tasks (i.e., tasks focusing on the quality of executed actions) that have direct functional relevance to rehabilitation. Objective: Investigate how stroke affects leg motor skill learning during walking in stroke survivors. Methods: Twenty-five participants (10 stroke; 15 controls) were recruited for this prospective, case-control study. Participants learned a novel foot-trajectory tracking task on two consecutive days while walking on a treadmill. The task necessitated greater hip and knee flexion during the swing phase of the gait. Online learning was measured by comparing tracking error at the beginning and end of each practice session, offline (rest-driven) learning was measured by comparing the end of the first practice session to the beginning of the second, and retention was measured by comparing the beginning of the first practice session to the beginning of the second. Online learning, offline learning, and retention were compared between the stroke survivors and uninjured controls. Results: Stroke survivors improved their tracking performance on the first day (p = 0.033); however, the amount of learning in stroke survivors was lower in comparison with the control group on both days (p ≤ 0.05). Interestingly, stroke survivors showed higher offline learning gains when compared with uninjured controls (p = 0.011). Conclusions: Even stroke survivors with no perceivable motor impairments have difficulty acquiring new motor skills related to walking, which may be related to the underlying neural damage caused at the time of stroke. Furthermore, stroke survivors may require longer training with adequate rest to acquire new motor skills. [ABSTRACT FROM AUTHOR]

Introduction: Abnormalities in the hippocampus have been extensively reported in schizophrenia research. However, inconsistent findings exist, and how structural and functional abnormalities of the hippocampus are associated with clinical symptoms in schizophrenia, especially concerning clozapine treatment, remains uncertain. Methods: We recruited 52 patientswith schizophrenia, eachwith an illness duration of at least 5 years, and categorized them based on clozapine treatment. T1- weighted images and resting-state functional magnetic resonance imaging scans were obtained and analyzed to perform group comparisons of the structural and functional changes in the hippocampus. Volumes of the hippocampal subregions, as well as resting-state functional connectivity maps from these areas were compared between the groups. Associations with clinical symptoms, including the severity of psychiatric symptoms and cognitive functions, were investigated. Results: The clozapine group (n=23) exhibited smaller volumes in several hippocampal subregions, including the CA1, CA4, granule cell and molecular layers of the dentate gyrus, compared to the non-clozapine group (n=29). Seven clusters with significant group differences in functional connectivity with these hippocampal subregions were identified, with six of these clusters showing increased functional connectivity in the clozapine group. The reduced volumes of the hippocampal subregions were moderately associated with the severity of negative symptoms, general intelligence, and executive function. Discussion: Patients with schizophrenia undergoing clozapine treatment exhibited smaller volumes in the hippocampal subregions, which were moderately associated with negative symptoms and cognitive functions, compared to those without clozapine treatment. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence supports the comorbidity between depression (DEP) and obesity, yet the genetic mechanisms underlying this association remain unclear. Our study explored the shared genetic architecture and causal associations of DEP with BMI. Methods: We investigated the multigene overlap and genetic correlation between DEP (N > 1.3 million) and BMI (N = 806,834) based on genome-wide association studies (GWAS) and using the bivariate causal mixture model and linkage disequilibrium score regression (LDSC). The causal association was explored by bi-directional Mendelian randomization (MR). Common risk loci were identified through cross-trait meta-analyses. Stratified LDSC and multi-marker gene annotation analyses were applied to investigate single-nucleotide polymorphisms enrichment across tissue types, cell types, and functional categories. Finally, we explored shared functional genes by Summary Data-Based Mendelian Randomization (SMR) and further detected differential expression genes (DEG) in brain tissues of individuals with depression and obesity. Results: We found a positive genetic correlation between DEP and BMI (rg = 0.19, P = 4.07 × 10−26), which was more evident in local genomic regions. Cross-trait meta-analyses identified 16 shared genetic loci, 5 of which were newly identified, and they had influence on both diseases in the same direction. MR analysis showed a bidirectional causal association between DEP and BMI, with comparable effect sizes estimated in both directions. Combined with gene expression information, we found that genetic correlations between DEP and BMI were enriched in 6 brain regions, predominantly in the nucleus accumbens and anterior cingulate cortex. Moreover, 6 specific cell types and 23 functional genes were found to have an impact on both DEP and BMI across the brain regions. Of which, NEGR1 was identified as the most significant functional gene and associated with DEP and BMI at the genome-wide significance level (P < 5 × 10−8). Compared with healthy controls, the expression levels of NEGR1 gene were significant lower in brain tissues of individuals with depression and obesity. Conclusions: Our study reveals shared genetic basis underpinnings between DEP and BMI, including genetic correlations and common genes. These insights offer novel opportunities and avenues for future research into their comorbidities. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is associated with deficits in cognitive function, thought to be related to underlying decreased hedonic experiences. Further research is needed to fully elucidate the role of functional brain activity in this relationship. In this study, we investigated the neurofunctional correlate of the interplay between cognitive function and hedonic experiences in medication-free MDD using functional near-infrared spectroscopy (fNIRS). Methods: We examine differences of brain activation corresponding to the verbal fluency test (VFT) between MDD patients and healthy controls (HCs). Fifty-six MDD patients and 35 HCs underwent fMRI scanning while performing the VFT. In exploratory analyses, cognitive performance, as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), four dimensions of hedonic processing (desire, motivation, effort, and consummatory pleasure) measured by the Dimensional Anhedonia Rating Scale (DARS), and relative changes in oxygenated hemoglobin concentration during the VFT were compared across groups. Results: Patients with MDD demonstrated impairments in sustained attention and working memory, accompanied by lower total and subscale scores on the DARS. Compared to healthy controls, MDD patients exhibited reduced activation in the prefrontal cortex (PFC) during the VFT task (t = 2.32 to 4.77, p < 0.001 to 0.02, FDR corrected). DARS motivation, desire, and total scores as well as sustained attention, were positively correlated with activation in the dorsolateral PFC and Broca's area (p < 0.05, FDR corrected). Conclusions: These findings indicate that changes in prefrontal lobe oxygenated hemoglobin levels, a region implicated in hedonic motivation and cognitive function, may serve as potential biomarkers for interventions targeting individuals with MDD. Our results corroborate the clinical consensus that the prefrontal cortex is a primary target for non-invasive neuromodulatory treatments for depression. [ABSTRACT FROM AUTHOR]

Background: Previous research has suggests that cooperative learning methods and the development of fundamental motor skills support children's cognitive development, and further studies covering various aspects are recommended. In this study, as an alternative to traditional physical education classes including fundamental motor skill activities, we investigated the impact of cooperative learning methods incorporating these skills on children's visual-motor integration and selective attention. Methods: A total of 60 boy children in the 10–11 age range were included in the study. Groups; classical method (10.95 ± 0.58age), and cooperative learning group (10.91 ± 0.42age). The study spanned a total of 24 physical education class hours. While the classical method group continued to attend physical education lessons with an FMS-based prepared program for 8 weeks, cooperative learning group participated in an FMS-based program prepared according to the cooperative learning method (40min/3days/8weeks).At the beginning and end of the study, children underwent the Bender-Gestalt test and the d2 test of attention. Results: Within-group pre-post test comparisons revealed improvement in visual-motor integration and selective attention for both the classical method and cooperative learning groups. In between-group post-test comparisons, the cooperative learning group demonstrated greater improvement in visual-motor integration and selective attention parameters compared to the classical method. Conclusion: The results support increasing the inclusion of fundamental motor skill activities in physical education classes and advocating for the use of cooperative learning methods in these classes. Enhancements in visual-motor integration and selective attention may contribute to children forming quality relationships, enjoying activities, learning stress management, and developing as a group. [ABSTRACT FROM AUTHOR]

Background: Delivering HD-tDCS on individual motor hotspot with optimal electric fields could overcome challenges of stroke heterogeneity, potentially facilitating neural activation and improving motor function for stroke survivors. However, the intervention effect of this personalized HD-tDCS has not been explored on post-stroke motor recovery. In this study, we aim to evaluate whether targeting individual motor hotspot with HD-tDCS followed by EMG-driven robotic hand training could further facilitate the upper extremity motor function for chronic stroke survivors. Methods: In this pilot randomized controlled trial, eighteen chronic stroke survivors were randomly allocated into two groups. The HDtDCS-group (n = 8) received personalized HD-tDCS using task-based fMRI to guide the stimulation on individual motor hotspot. The Sham-group (n = 10) received only sham stimulation. Both groups underwent 20 sessions of training, each session began with 20 min of HD-tDCS and was then followed by 60 min of robotic hand training. Clinical scales (Fugl-meyer Upper Extremity scale, FMAUE; Modified Ashworth Scale, MAS), and neuroimaging modalities (fMRI and EEG-EMG) were conducted before, after intervention, and at 6-month follow-up. Two-way repeated measures analysis of variance was used to compare the training effect between HDtDCS- and Sham-group. Results: HDtDCS-group demonstrated significantly better motor improvement than the Sham-group in terms of greater changes of FMAUE scores (F = 6.5, P = 0.004) and MASf (F = 3.6, P = 0.038) immediately and 6 months after the 20-session intervention. The task-based fMRI activation significantly shifted to the ipsilesional motor area in the HDtDCS-group, and this activation pattern increasingly concentrated on the motor hotspot being stimulated 6 months after training within the HDtDCS-group, whereas the increased activation is not sustainable in the Sham-group. The neuroimaging results indicate that neural plastic changes of the HDtDCS-group were guided specifically and sustained as an add-on effect of the stimulation. Conclusions: Stimulating the individual motor hotspot before robotic hand training could further enhance brain activation in motor-related regions that promote better motor recovery for chronic stroke. Trial registration: This study was retrospectively registered in ClinicalTrials.gov (ID NCT05638464). [ABSTRACT FROM AUTHOR]

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For better decisions in social interactions, humans often must understand the thinking of others and predict their actions. Since such predictions are uncertain, multiple predictions may be necessary for better decision-making. However, the neural processes and computations underlying such social decision-making remain unclear. We investigated this issue by developing a behavioral paradigm and performing functional magnetic resonance imaging and computational modeling. In our task, female and male participants were required to predict others' choices in order to make their own value-based decisions, as the outcome depended on others' choices. Results showed, to make choices, the participants mostly relied on a value difference (primary) generated from the case where others would make a likely choice, but sometimes they additionally used another value difference (secondary) from the opposite case where others make an unlikely choice. We found that the activations in the posterior cingulate cortex (PCC) correlated with the primary difference while the activations in the right dorsolateral prefrontal cortex (rdlPFC) correlated with the secondary difference. Analysis of neural coupling and temporal dynamics suggested a three-step processing network, beginning with the left amygdala signals for predictions of others' choices. Modulated by these signals, the PCC and rdlPFC reflect the respective value differences for self-decisions. Finally, the medial prefrontal cortex integrated these decision signals for a final decision. Our findings elucidate the neural process of constructing value-based decisions by predicting others and illuminate their key variables with social modulations, providing insight into the differential functional roles of these brain regions in this process. [ABSTRACT FROM AUTHOR]

Although the locus ceruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (LC-NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential and single-unit activity in multiple cortical regions associated with auditory- motor processing, including the auditory cortex, posterior parietal cortex, secondary motor cortex, anterior cingulate cortex, prefrontal cortex, and orbitofrontal cortex (OFC), in response to optogenetic activation (40 Hz and 0.5 s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillation (50-80 Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in norepinephrine levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a go/no-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing. [ABSTRACT FROM AUTHOR]

Hemispheric asymmetry is a fundamental principle in the functional architecture of the brain. It plays an important role in attention research where right hemisphere dominance is core to many attention theories. Lesion studies seem to confirm such hemispheric dominance with patients being more likely to develop left hemineglect after right hemispheric stroke than vice versa. However, the underlying concept of hemispheric dominance is still not entirely clear. Brain stimulation studies using transcranial magnetic stimulation (TMS) might be able to illuminate this concept. To examine the putative hemispheric asymmetry in spatial attention, we conducted a meta-analysis of studies applying inhibitory TMS protocols to the left or right posterior parietal cortices (PPC), assessing effects on attention biases with the landmark and line bisection task. A total of 18 studies including 222 participants from 1994 to February 2022 were identified. The analysis revealed a significant shift of the perceived midpoint towards the ipsilateral hemifield after right PPC suppression (Cohen's d = 0.52), but no significant effect after left PPC suppression (Cohen's d = 0.26), suggesting a hemispheric asymmetry even though the subgroup difference does not reach significance (p =.06). A complementary Bayesian meta-analysis revealed a high probability of at least a medium effect size after right PPC disruption versus a low probability after left PPC disruption. This is the first quantitative meta-analysis supporting right hemisphere-specific TMS-induced spatial attention deficits, mimicking hemineglect in healthy participants. We discuss the result in the light of prominent attention theories, ultimately concluding how difficult it remains to differentiate between these theories based on attentional bias scores alone. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) can markedly reduce muscle rigidity in people with Parkinson's disease (PD); however, the mechanisms mediating this effect are poorly understood. Computational modeling of DBS provides a method to estimate the relative contributions of neural pathway activations to changes in outcomes. In this study, we generated subject-specific biophysical models of GPi DBS (derived from individual 7-T MRI), including pallidal efferent, putamenal efferent, and internal capsule pathways, to investigate how activation of neural pathways contributed to changes in forearm rigidity in PD. Ten individuals (17 arms) were tested off medication under four conditions: off stimulation, on clinically optimized stimulation, and on stimulation specifically targeting the dorsal GPi or ventral GPi. Quantitative measures of forearm rigidity, with and without a contralateral activation maneuver, were obtained with a robotic manipulandum. Clinically optimized GPi DBS settings significantly reduced forearm rigidity (P < 0.001), which aligned with GPi efferent fiber activation. The model demonstrated that GPi efferent axons could be activated at any location along the GPi dorsal-ventral axis. These results provide evidence that rigidity reduction produced by GPi DBS is mediated by preferential activation of GPi efferents to the thalamus, likely leading to a reduction in excitability of the muscle stretch reflex via overdriving pallidofugal output. NEW & NOTEWORTHY: Subject-specific computational models of pallidal deep brain stimulation, in conjunction with quantitative measures of forearm rigidity, were used to examine the neural pathways mediating stimulation-induced changes in rigidity in people with Parkinson's disease. The model uniquely included internal, efferent and adjacent pathways of the basal ganglia. The results demonstrate that reductions in rigidity evoked by deep brain stimulation were principally mediated by the activation of globus pallidus internus efferent pathways. [ABSTRACT FROM AUTHOR]

Under threats, individuals exhibit freezing behavior and prepare for active coping. The ability to flexibly shift between freezing and active coping increases survival chances in animals and decreases susceptibility to mental disorders among human beings. For example, patients with psychiatric disorders, such as obsessive-compulsive disorder and posttraumatic stress disorder, often show maladaptive coping behaviors. The orbitofrontal cortex (OFC) is a critical hub to process higher cognitive functions, sensory inputs, reward learning, and decision-making. It also regulates negative emotions and its aberrant activation level often correlates with numerous mental disorders. The rodent OFC comprises different subdivisions with varying connections to cortical and subcortical regions. Among these subdivisions, the medial orbital area (MO) and the lateral orbital area (LO) have distinct functions in the regulation of fear. Here, we updated the existing rodent literature studying the function of the OFC, with a particular focus on the MO and the LO in different coping strategies of animals. By examining the role of the OFC in the mediation of defensive coping strategies, we aim to deepen the understanding of its functional importance on mental health. [ABSTRACT FROM AUTHOR]

Many daily choices are based on one's own knowledge. However, when predicting other people's behavior, we need to consider the differences between our knowledge and other people's presumed knowledge. Social agents need a mechanism to use privileged information for their own behavior but exclude it from predictions of others. Using fMRI, we investigated the neural implementation of such social and personal predictions in healthy human volunteers of both sexes by manipulating privileged and shared information. The medial frontal cortex appeared to have an important role in flexibly making decisions using privileged information for oneself or predicting others' behavior. Specifically, we show that ventromedial PFC tracked the state of the world independent of the type of decision (personal, social), whereas dorsomedial regions adjusted their frame of reference to the use of privileged or shared information. Sampling privileged evidence not available to another person also relied on specific interactions between temporoparietal junction area and frontal pole. [ABSTRACT FROM AUTHOR]

In contrast to conventional cognitive training paradigms, where learning effects are specific to trained parameters, playing action video games has been shown to produce broad enhancements in many cognitive functions. These remarkable generalizations challenge the conventional theory of generalization that learned knowledge can be immediately applied to novel situations (i.e., immediate generalization). Instead, a new "learning to learn" theory has recently been proposed, suggesting that these broad generalizations are attained because action video game players (AVGPs) can quickly acquire the statistical regularities of novel tasks in order to increase the learning rate and ultimately achieve better performance. Although enhanced learning rate has been found for several tasks, it remains unclear whether AVGPs efficiently learn task statistics and use learned task knowledge to guide learning. To address this question, we tested 34 AVGPs and 36 non-video game players (NVGPs) on a cue-response associative learning task. Importantly, unlike conventional cognitive tasks with fixed task statistics, in this task, cue-response associations either remain stable or change rapidly (i.e., are volatile) in different blocks. To complete the task, participants should not only learn the lower-level cue-response associations through explicit feedback but also actively estimate the high-level task statistics (i.e., volatility) to dynamically guide lower-level learning. Such a dual learning system is modelled using a hierarchical Bayesian learning framework, and we found that AVGPs indeed quickly extract the volatility information and use the estimated higher volatility to accelerate learning of the cue-response associations. These results provide strong evidence for the "learning to learn" theory of generalization in AVGPs. Taken together, our work highlights enhanced hierarchical learning of both task statistics and cognitive abilities as a mechanism underlying the broad enhancements associated with action video game play. [ABSTRACT FROM AUTHOR]

The ventral frontal cortex (VFC) in macaques is involved in many affective and cognitive processes and has a key role in flexibly guiding reward-based decision-making. VFC is composed of a set of anatomically distinct subdivisions that are within the orbitofrontal cortex, ventrolateral prefrontal cortex, and anterior insula. In part, because prior studies have lacked the resolution to test for differences, it is unclear if neural representations related to decision-making are dissociable across these subdivisions. Here we recorded the activity of thousands of neurons within eight anatomically defined subdivisions of VFC in male macaque monkeys performing a two-choice probabilistic task for different fruit juice outcomes. We found substantial variation in the encoding of decision variables across these eight subdivisions. Notably, ventrolateral Area 12l was unique relative to the other areas that we recorded from as the activity of single neurons integrated multiple attributes when monkeys evaluated the different choice options. Activity within Area 12o, in contrast, more closely represented reward probability and whether reward was received on a given trial. Orbitofrontal Area 11m/l contained more specific representations of the quality of the outcome that could be earned later on. We also found that reward delivery encoding was highly distributed across all VFC subdivisions, while the properties of the reward, such as its flavor, were more strongly represented in Areas 11m/l and 13m. Taken together, our work reveals the diversity of encoding within the various anatomically distinct subdivisions of VFC in primates. [ABSTRACT FROM AUTHOR]

Background: The mesocircuit model describes a complex network that includes the prefrontal cortical-striatopallidal-thalamo-cortical loop systems and is involved in the mechanism underlying consciousness in patients with disorders of consciousness (DoC). Inhibitory signals to the thalamus become hyperactive in DoC patients, leading to a loss of consciousness. Reactivating this mesocircuit system is important for recovering consciousness in these patients. We investigated how the residual integrity of the thalamo-dorsolateral prefrontal cortex tract (TDLPFCT) influences consciousness in patients with DoC. Methods: This retrospective case-control study included three groups: prolonged DoC (n = 20), stroke without DoC (n = 20), and healthy controls (n = 20). Diffusion tensor imaging (DTI) was performed at least 4 weeks after the onset. Thalamo-DLPFC tracts were reconstructed using diffusion tensor tractography, and fractional anisotropy (FA) and tract volume (TV) were measured for each hemisphere. Consciousness was assessed using the revised coma recovery scale (CRS-R) within a week of brain imaging. Results: Significant differences in DLPFCT TV were observed across all three groups, in both affected and less-affected lobes, with the DoC group showing the greatest reduction. A significant correlation was found between the TV of the less-affected TDLPFCT and CRS-R score. Conclusion: The integrity of the TDLPFCT, particularly in the less affected hemisphere, is associated with consciousness levels in patients with prolonged DoC. This finding suggests its potential importance in assessing prognosis and further developing therapeutic strategies for patients with DoC. [ABSTRACT FROM AUTHOR]

Trunk control involves integration of sensorimotor information in the brain. Individuals with chronic low back pain (cLBP) have impaired trunk control and show differences in brain structure and function in sensorimotor areas compared with healthy controls (HC). However, the relationship between brain structure and trunk control in this group is not well understood. This cross-sectional study aimed to compare seated trunk control and sensorimotor white matter (WM) structure in people with cLBP and HC and explore relationships between WM properties and trunk control in each group. Thirty-two people with cLBP and 35 HC were tested sitting on an unstable chair to isolate trunk control; performance was measured using the 95% confidence ellipse area (CEA95) of center-of-pressure tracing. A WM network between cortical sensorimotor regions of interest was derived using probabilistic tractography. WM microstructure and anatomical connectivity between cortical sensorimotor regions were assessed. A mixed-model ANOVA showed that people with cLBP had worse trunk control than HC (F = 12.96; p <.001; ηp2 =.091). There were no differences in WM microstructure or anatomical connectivity between groups (p = 0.564 to 0.940). In the cLBP group, WM microstructure was moderately correlated (|r| =.456 to.565; p ≤.009) with trunk control. Additionally, the cLBP group demonstrated stronger relationships between anatomical connectivity and trunk control (|r| =.377 to.618 p <.034) compared to the HC group. Unique to the cLBP group, WM connectivity between right somatosensory and left motor areas highlights the importance of interhemispheric information exchange for trunk control. Parietal areas associated with attention and spatial reference frames were also relevant to trunk control. These findings suggest that people with cLBP adopt a more cortically driven sensorimotor integration strategy for trunk control. Future research should replicate these findings and identify interventions to effectively modulate this strategy. [ABSTRACT FROM AUTHOR]

Adaptive behaviors require the ability to resolve conflicting information caused by the processing of incompatible sensory inputs. Prominent theories of attention have posited that early selective attention helps mitigate cognitive interference caused by conflicting sensory information by facilitating the processing of task-relevant sensory inputs and filtering out behaviorally irrelevant information. Surprisingly, many recent studies that investigated the role of early selective attention on conflict mitigation have failed to provide positive evidence. Here, we examined changes in the selectivity of early visuospatial attention in male and female human subjects performing an attention-cueing Eriksen flanker task, where they discriminated the shape of a visual target surrounded by congruent or incongruent distractors. We used the inverted encoding model to reconstruct spatial representations of visual selective attention from the topographical patterns of amplitude modulations in alpha band oscillations in scalp EEG (∼8-12 Hz). We found that the fidelity of the alpha-based spatial reconstruction was significantly higher in the incongruent compared with the congruent condition. Importantly, these conflict-related modulations in the reconstruction fidelity occurred at a much earlier time window than those of the lateralized posterior event-related potentials associated with target selection and distractor suppression processes, as well as conflict-related modulations in the frontocentral negative-going wave and midline-frontal theta oscillations (∼3-7 Hz), thought to track executive control functions. Taken together, our data suggest that conflict resolution is supported by the cascade of neural processes underlying early selective visuospatial attention and frontal executive functions that unfold over time. [ABSTRACT FROM AUTHOR]

Hand visibility affects motor control, perception, and attention, as visual information is integrated into an internal model of somatomotor control. Spontaneous brain activity, i.e., at rest, in the absence of an active task, is correlated among somatomotor regions that are jointly activated during motor tasks. Recent studies suggest that spontaneous activity patterns not only replay task activation patterns but also maintain a model of the body's and environment's statistical regularities (priors), which may be used to predict upcoming behavior. Here, we test whether spontaneous activity in the human somatomotor cortex as measured using fMRI is modulated by visual stimuli that display hands vs. non-hand stimuli and by the use/action they represent. A multivariate pattern analysis was performed to examine the similarity between spontaneous activity patterns and task-evoked patterns to the presentation of natural hands, robot hands, gloves, or control stimuli (food). In the left somatomotor cortex, we observed a stronger (multivoxel) spatial correlation between resting state activity and natural hand picture patterns compared to other stimuli. No task-rest similarity was found in the visual cortex. Spontaneous activity patterns in somatomotor brain regions code for the visual representation of human hands and their use. [ABSTRACT FROM AUTHOR]