In the face of ambiguity: intrinsic brain organization in development predicts one's bias toward positivity or negativity.

Exacerbated negativity bias, including in responses to ambiguity, represents a common phenotype of internalizing disorders. Individuals differ in their propensity toward positive or negative appraisals of ambiguity. This variability constitutes one's valence bias, a stable construct linked to mental health. Evidence suggests an initial negativity in response to ambiguity that updates via regulatory processes to support a more positive bias. Previous work implicates the amygdala and prefrontal cortex, and regions of the cingulo-opercular system, in this regulatory process. Nonetheless, the neurodevelopmental origins of valence bias remain unclear. The current study tests whether intrinsic brain organization predicts valence bias among 119 children and adolescents (6 to 17 years). Using whole-brain resting-state functional connectivity, a machine-learning model predicted valence bias (r = 0.20, P = 0.03), as did a model restricted to amygdala and cingulo-opercular system features (r = 0.19, P = 0.04). Disrupting connectivity revealed additional intra-system (e.g. fronto-parietal) and inter-system (e.g. amygdala to cingulo-opercular) connectivity important for prediction. The results highlight top-down control systems and bottom-up perceptual processes that influence valence bias in development. Thus, intrinsic brain organization informs the neurodevelopmental origins of valence bias, and directs future work aimed at explicating related internalizing symptomology.

Concussion-Related Disruptions to Hub Connectivity in the Default Mode Network Are Related to Symptoms and Cognition.

Concussions present with a myriad of symptomatic and cognitive concerns; however, the relationship between these functional disruptions and the underlying changes in the brain are not yet well understood. Hubs, or brain regions that are connected to many different functional networks, may be specifically disrupted after concussion. Given the implications in concussion research, we quantified hub disruption within the default mode network (DMN) and between the DMN and other brain networks. We collected resting-state functional magnetic resonance imaging data from collegiate student-athletes (n = 44) at three time points: baseline (before beginning their athletic season), acute post-injury (approximately 48h after a diagnosed concussion), and recovery (after starting return-to-play progression, but before returning to contact). We used self-reported symptoms and computerized cognitive assessments collected across similar time points to link these functional connectivity changes to clinical outcomes. Concussion resulted in increased connectivity between regions within the DMN compared with baseline and recovery, and this post-injury connectivity was more positively related to symptoms and more negatively related to visual memory performance compared with baseline and recovery. Further, concussion led to decreased connectivity between DMN hubs and visual network non-hubs relative to baseline and recovery, and this post-injury connectivity was more negatively related to somatic symptoms and more positively related to visual memory performance compared with baseline and recovery. Relationships between functional connectivity, symptoms, and cognition were not significantly different at baseline versus recovery. These results highlight a unique relationship between self-reported symptoms, visual memory performance, and acute functional connectivity changes involving DMN hubs after concussion in athletes. This may provide evidence for a disrupted balance of within- and between-network communication highlighting possible network inefficiencies after concussion. These results aid in our understanding of the pathophysiological disruptions after concussion and inform our understanding of the associations between disruptions in brain connectivity and specific clinical presentations acutely post-injury.

Brain activity associated with taste stimulation: A mechanism for neuroplastic change?

PURPOSE: Neuroplasticity may be enhanced by increasing brain activation and bloodflow in neural regions relevant to the target behavior. We administered precisely formulated and dosed taste stimuli to determine whether the associated brain activity patterns included areas that underlie swallowing control. METHODS: Five taste stimuli (unflavored, sour, sweet-sour, lemon, and orange suspensions) were administered in timing-regulated and temperature-controlled 3 mL doses via a customized pump/tubing system to 21 healthy adults during functional magnetic resonance imaging (fMRI). Whole-brain analyses of fMRI data assessed main effects of taste stimulation as well as differential effects of taste profile. RESULTS: Differences in brain activity associated with taste stimulation overall as well as specific stimulus type were observed in key taste and swallowing regions including the orbitofrontal cortex, insula, cingulate, and pre- and postcentral gyri. Overall, taste stimulation elicited increased activation in swallowing-related brain regions compared to unflavored trials. Different patterns of blood oxygen level-dependent (BOLD) signal were noted by taste profile. For most areas, sweet-sour and sour trials elicited increases in BOLD compared to unflavored trials within that region, whereas lemon and orange trials yielded reductions in BOLD. This was despite identical concentrations of citric acid and sweetener in the lemon, orange, and sweet-sour solutions. CONCLUSIONS: These results suggest that neural activity in swallowing-relevant regions can be amplified with taste stimuli and may be differentially affected by specific properties within very similar taste profiles. These findings provide critical foundational information for interpreting disparities in previous studies of taste effects on brain activity and swallowing function, defining optimal stimuli to increase brain activity in swallowing-relevant regions, and harnessing taste to enhance neuroplasticity and recovery for persons with swallowing disorders.

Constructing neural network models from brain data reveals representational transformations linked to adaptive behavior.

The human ability to adaptively implement a wide variety of tasks is thought to emerge from the dynamic transformation of cognitive information. We hypothesized that these transformations are implemented via conjunctive activations in "conjunction hubs"-brain regions that selectively integrate sensory, cognitive, and motor activations. We used recent advances in using functional connectivity to map the flow of activity between brain regions to construct a task-performing neural network model from fMRI data during a cognitive control task. We verified the importance of conjunction hubs in cognitive computations by simulating neural activity flow over this empirically-estimated functional connectivity model. These empirically-specified simulations produced above-chance task performance (motor responses) by integrating sensory and task rule activations in conjunction hubs. These findings reveal the role of conjunction hubs in supporting flexible cognitive computations, while demonstrating the feasibility of using empirically-estimated neural network models to gain insight into cognitive computations in the human brain.

Global connectivity fingerprints predict the domain generality of multiple-demand regions.

A set of distributed cognitive control networks are known to contribute to diverse cognitive demands, yet it is unclear how these networks gain this domain-general capacity. We hypothesized that this capacity is largely due to the particular organization of the human brain's intrinsic network architecture. Specifically, we tested the possibility that each brain region's domain generality is reflected in its level of global (hub-like) intrinsic connectivity as well as its particular global connectivity pattern ("connectivity fingerprint"). Consistent with prior work, we found that cognitive control networks exhibited domain generality as they represented diverse task context information covering sensory, motor response, and logic rule domains. Supporting our hypothesis, we found that the level of global intrinsic connectivity (estimated with resting-state functional magnetic resonance imaging [fMRI]) was correlated with domain generality during tasks. Further, using a novel information fingerprint mapping approach, we found that each cognitive control region's unique rule response profile("information fingerprint") could be predicted based on its unique intrinsic connectivity fingerprint and the information content in regions outside cognitive control networks. Together, these results suggest that the human brain's intrinsic network architecture supports its ability to represent diverse cognitive task information largely via the location of multiple-demand regions within the brain's global network organization.

A Prospective Evaluation of Intraoperative Indocyanine Green Fluorescence Angiography for Soft Tissue Sarcomas.

INTRODUCTION: Postoperative wound complications after resection of soft-tissue sarcomas are challenging. Indocyanine green (ICG) angiography has previously been used to predict wound complications, but not for soft-tissue sarcomas. We aimed to evaluate whether this technology could help lower wound complications after soft-tissue sarcoma resections. MATERIALS AND METHODS: We conducted a prospective study from 10/2017 to 9/2019 using ICG angiography during sarcoma resection surgery. Rates of wound complications were compared with a historical control consisting of surgeries before utilization of ICG angiography. RESULTS: A total of 88 patients were included in the study. We found significantly lower rates of infection (11.8% versus 38%; P = 0.03) and wound dehiscence (11.8% versus 42.3%; P = 0.02) in the ICG angiography cohort compared with the historical controls. CONCLUSION: ICG angiography use during soft-tissue sarcoma resections is promising technology and warrants further investigation to help reduce postoperative complications.

Intraoperative Indocyanine Green Fluorescence Angiography Is Sensitive for Predicting Postoperative Wound Complications in Soft-Tissue Sarcoma Surgery.

INTRODUCTION: Indocyanine green (ICG) angiography is a novel technology that has been predictive of postoperative wound complications. It is unknown whether this technology can successfully predict complications after sarcoma resection. In this study, we aimed to evaluate the sensitivity and specificity of ICG angiography in predicting postoperative wound complications after soft-tissue sarcoma resection. METHODS: A prospective cohort study of 23 patients was performed beginning October 2017 at our institution. Patients who underwent soft-tissue sarcoma resection were included. After tumor resection and wound closure, evaluation of tissue perfusion in skin edges was performed with ICG angiography. Wound complications were recorded in the postoperative follow-up. RESULTS: Eight patients developed postoperative wound complications. Six patients were predicted to have wound complications on the final ICG scans. The accuracy of ICG angiography was dependent on the anatomic location, with improved accuracy in the lower extremity. ICG angiography had a sensitivity of 50%, a specificity and a positive predictive value of 100%, and a negative predictive value of 70% for wound complications after soft-tissue sarcoma resections located in the lower extremity. CONCLUSION: ICG angiography has a high predictive value in the lower extremity for postoperative wound complications. LEVEL OF EVIDENCE: Level III, Diagnostic.

Flexible Coordinator and Switcher Hubs for Adaptive Task Control.

Functional connectivity (FC) studies have identified at least two large-scale neural systems that constitute cognitive control networks, the frontoparietal network (FPN) and cingulo-opercular network (CON). Control networks are thought to support goal-directed cognition and behavior. It was previously shown that the FPN flexibly shifts its global connectivity pattern according to task goal, consistent with a "flexible hub" mechanism for cognitive control. Our aim was to build on this finding to develop a functional cartography (a multimetric profile) of control networks in terms of dynamic network properties. We quantified network properties in (male and female) humans using a high-control-demand cognitive paradigm involving switching among 64 task sets. We hypothesized that cognitive control is enacted by the FPN and CON via distinct but complementary roles reflected in network dynamics. Consistent with a flexible "coordinator" mechanism, FPN connections were varied across tasks, while maintaining within-network connectivity to aid cross-region coordination. Consistent with a flexible "switcher" mechanism, CON regions switched to other networks in a task-dependent manner, driven primarily by reduced within-network connections to other CON regions. This pattern of results suggests FPN acts as a dynamic, global coordinator of goal-relevant information, while CON transiently disbands to lend processing resources to other goal-relevant networks. This cartography of network dynamics reveals a dissociation between two prominent cognitive control networks, suggesting complementary mechanisms underlying goal-directed cognition.SIGNIFICANCE STATEMENT Cognitive control supports a variety of behaviors requiring flexible cognition, such as rapidly switching between tasks. Furthermore, cognitive control is negatively impacted in a variety of mental illnesses. We used tools from network science to characterize the implementation of cognitive control by large-scale brain systems. This revealed that two systems, the frontoparietal (FPN) and cingulo-opercular (CON) networks, have distinct but complementary roles in controlling global network reconfigurations. The FPN exhibited properties of a flexible coordinator (orchestrating task changes), while CON acted as a flexible switcher (switching specific regions to other systems to lend processing resources). These findings reveal an underlying distinction in cognitive processes that may be applicable to clinical, educational, and machine learning work targeting cognitive flexibility.

Neural Bases of Phonological and Semantic Processing in Early Childhood.

During the early period of reading development, children gain phonological (letter-to-sound mapping) and semantic knowledge (storage and retrieval of word meaning). Their reading ability changes rapidly, accompanied by learning-induced brain plasticity as they learn to read. This study aims at identifying the neural bases of phonological and semantic processing in early childhood by using a combination of univariate and multivariate pattern analysis. Nineteen typically developing children between the age of five and seven performed visual word-level phonological (rhyming) and semantic (related meaning) judgment tasks during functional magnetic resonance imaging scans. Our multivariate analysis showed that young children with good reading ability have already recruited the left hemispheric regions in the brain for phonological processing, including the inferior frontal gyrus (IFG), superior and middle temporal gyrus, and fusiform gyrus. In addition, our multivariate results suggested that different sub-regions of the left IFG were recruited for the two tasks. Our results suggested the left lateralization of frontotemporal regions for phonological processing and semantic processing. In addition, we observed bilateral activations of parietal regions for semantic processing during early childhood. Our findings indicate that the neural bases of reading have already begun to be shaped in early childhood for typically developing children, which can be used as a control baseline for comparison of children at risk for reading difficulties.

Midterm Outcomes of Ultrasound-guided Local Treatment for Infrapatellar Saphenous Neuroma Following Total Knee Arthroplasty.

BACKGROUND:  While total knee arthroplasty (TKA) is a reliable treatment for advanced knee arthritis, up to 19% of patients after TKA remain dissatisfied, especially with residual pain. A less known source of medial knee pain following TKA is infrapatellar saphenous neuroma. Ultrasound-guided local treatment with hydrodissection and corticosteroid injection is an effective short-term solution. Our primary aim was to evaluate the durability of local treatment by comparing numeric pain scores for medial knee pain after TKA at pretreatment, one month following treatment, and midterm follow-up. A secondary aim was to identify associations of patient characteristics with degree of change in numeric pain score.  Methods: Retrospective chart review was performed to identify patients who had symptomatic infrapatellar saphenous neuroma following TKA and were treated with ultrasound-guided local treatment by hydrodissection and corticosteroid injection between January 1, 2012, and January 1, 2016. Those with follow-up less than three years were excluded. Patients who were unable to return for midterm follow-up were called. Numeric pain scores for the medial knee were recorded. Patient demographics, medical history, revision TKA status, number of prior knee surgeries, narcotic use, psychiatric disorders, and current tobacco use were also collected. RESULTS: Of 32 identified patients, 29 (7 men, 22 women, median age 65.9 years) elected to participate in this study with a mean (SD) follow-up of 4.6 (0.8) years. The median (range) pretreatment pain score was 9 (5-10). After local treatment, the median (range) numeric pain score was significantly lower at both one-month and midterm follow-up (5; P<0.001). The initial response to treatment was durable given that the difference between one-month and midterm follow-up scores was not significant (P=0.47). Advanced age was associated with less overall pain relief from pretreatment to midterm follow-up, while female sex, history of fibromyalgia, and TKA revision prior to treatment were associated with worsening pain from one-month to midterm follow-up (P<0.05).  Conclusions: Patients who underwent ultrasound-guided local treatment with hydrodissection and corticosteroid injection for painful postoperative infrapatellar saphenous neuroma following TKA experienced significant numeric pain score reduction. Pain relief remained consistent from 1onemonth to midterm follow-up.  Level of Evidence: Level IV, Case Series.

Global connectivity of the fronto-parietal cognitive control network is related to depression symptoms in the general population.

We all vary in our mental health, even among people not meeting diagnostic criteria for mental illness. Understanding this individual variability may reveal factors driving the risk for mental illness, as well as factors driving subclinical problems that still adversely affect quality of life. To better understand the large-scale brain network mechanisms underlying this variability, we examined the relationship between mental health symptoms and resting-state functional connectivity patterns in cognitive control systems. One such system is the fronto-parietal cognitive control network (FPN). Changes in FPN connectivity may impact mental health by disrupting the ability to regulate symptoms in a goal-directed manner. Here we test the hypothesis that FPN dysconnectivity relates to mental health symptoms even among individuals who do not meet formal diagnostic criteria but may exhibit meaningful symptom variation. We found that depression symptoms severity negatively correlated with between-network global connectivity (BGC) of the FPN. This suggests that decreased connectivity between the FPN and the rest of the brain is related to increased depression symptoms in the general population. These findings complement previous clinical studies to support the hypothesis that global FPN connectivity contributes to the regulation of mental health symptoms across both health and disease.

Task activations produce spurious but systematic inflation of task functional connectivity estimates.

Most neuroscientific studies have focused on task-evoked activations (activity amplitudes at specific brain locations), providing limited insight into the functional relationships between separate brain locations. Task-state functional connectivity (FC) - statistical association between brain activity time series during task performance - moves beyond task-evoked activations by quantifying functional interactions during tasks. However, many task-state FC studies do not remove the first-order effect of task-evoked activations prior to estimating task-state FC. It has been argued that this results in the ambiguous inference "likely active or interacting during the task", rather than the intended inference "likely interacting during the task". Utilizing a neural mass computational model, we verified that task-evoked activations substantially and inappropriately inflate task-state FC estimates, especially in functional MRI (fMRI) data. Various methods attempting to address this problem have been developed, yet the efficacies of these approaches have not been systematically assessed. We found that most standard approaches for fitting and removing mean task-evoked activations were unable to correct these inflated correlations. In contrast, methods that flexibly fit mean task-evoked response shapes effectively corrected the inflated correlations without reducing effects of interest. Results with empirical fMRI data confirmed the model's predictions, revealing activation-induced task-state FC inflation for both Pearson correlation and psychophysiological interaction (PPI) approaches. These results demonstrate that removal of mean task-evoked activations using an approach that flexibly models task-evoked response shape is an important preprocessing step for valid estimation of task-state FC.

Genetic Taster Status as a Mediator of Neural Activity and Swallowing Mechanics in Healthy Adults.

As part of a larger study examining relationships between taste properties and swallowing, we assessed the influence of genetic taster status (GTS) on measures of brain activity and swallowing physiology during taste stimulation in healthy men and women. Twenty-one participants underwent videofluoroscopic swallowing study (VFSS) and functional magnetic resonance imaging (fMRI) during trials of high-intensity taste stimuli. The precisely formulated mixtures included sour, sweet-sour, lemon, and orange taste profiles and unflavored controls. Swallowing physiology was characterized via computational analysis of swallowing mechanics plus other kinematic and temporal measures, all extracted from VFSS recordings. Whole-brain analysis of fMRI data assessed blood oxygen responses to neural activity associated with taste stimulation. Swallowing morphometry, kinematics, temporal measures, and neuroimaging analysis revealed differential responses by GTS. Supertasters exhibited increased amplitude of most pharyngeal movements, and decreased activity in the primary somatosensory cortex compared to nontasters and midtasters. These preliminary findings suggest baseline differences in swallowing physiology and the associated neural underpinnings associated with GTS. Given the potential implications for dysphagia risk and recovery patterns, GTS should be included as a relevant variable in future research regarding swallowing function and dysfunction.

Surgical Complications Associated With Atypical Femur Fractures Attributed to Bisphosphonate Use.

Complications of atypical femur fractures (AFFs) are common. AFFs often receive the same treatment as other femoral fractures; however, there appears to be a higher rate of adverse outcomes. Nine patients sustained a total of 13 AFFs, had documented bisphosphonate use before fracture, and had surgery between 2006 and 2012. Complications included continued pain, surgical revision, nonunion, malunion, deformity, or heterotopic ossification. The overall complication rate was 33.3%, with four of the 12 surgeries performed at this institution resulting in one nonunion and three minor complications. None of the primary fixations required revision. There was a higher complication rate for AFFs when compared with non-bisphosphonate-related intramedullary nail femur fracture fixations. This cohort demonstrated a lower rate of major complications compared to the literature. Using a reamed, statically locked nail, halting bisphosphonate medication, and allowing early weight bearing is a safe and efficacious method to treat atypical femur fractures. (Journal of Surgical Orthopaedic Advances 27(1):14-20, 2018).

Cognitive task information is transferred between brain regions via resting-state network topology.

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach-information transfer mapping-to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here, we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

Corrigendum: Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning.

[This corrects the article on p. 348 in vol. 7, PMID: 27014154.].

Activity flow over resting-state networks shapes cognitive task activations.

Resting-state functional connectivity (FC) has helped reveal the intrinsic network organization of the human brain, yet its relevance to cognitive task activations has been unclear. Uncertainty remains despite evidence that resting-state FC patterns are highly similar to cognitive task activation patterns. Identifying the distributed processes that shape localized cognitive task activations may help reveal why resting-state FC is so strongly related to cognitive task activations. We found that estimating task-evoked activity flow (the spread of activation amplitudes) over resting-state FC networks allowed prediction of cognitive task activations in a large-scale neural network model. Applying this insight to empirical functional MRI data, we found that cognitive task activations can be predicted in held-out brain regions (and held-out individuals) via estimated activity flow over resting-state FC networks. This suggests that task-evoked activity flow over intrinsic networks is a large-scale mechanism explaining the relevance of resting-state FC to cognitive task activations.

Integrated Brain Network Architecture Supports Cognitive Task Performance.

Spontaneous fluctuations in neural activity and connectivity are thought to support cognition and behavior. In this issue of Neuron, Shine et al. (2016) describe a possible mechanism responsible for fluctuations in the human brain's network architecture that are related to rapid shifts in cognitive state.

Higher Intelligence Is Associated with Less Task-Related Brain Network Reconfiguration.

UNLABELLED: The human brain is able to exceed modern computers on multiple computational demands (e.g., language, planning) using a small fraction of the energy. The mystery of how the brain can be so efficient is compounded by recent evidence that all brain regions are constantly active as they interact in so-called resting-state networks (RSNs). To investigate the brain's ability to process complex cognitive demands efficiently, we compared functional connectivity (FC) during rest and multiple highly distinct tasks. We found previously that RSNs are present during a wide variety of tasks and that tasks only minimally modify FC patterns throughout the brain. Here, we tested the hypothesis that, although subtle, these task-evoked FC updates from rest nonetheless contribute strongly to behavioral performance. One might expect that larger changes in FC reflect optimization of networks for the task at hand, improving behavioral performance. Alternatively, smaller changes in FC could reflect optimization for efficient (i.e., small) network updates, reducing processing demands to improve behavioral performance. We found across three task domains that high-performing individuals exhibited more efficient brain connectivity updates in the form of smaller changes in functional network architecture between rest and task. These smaller changes suggest that individuals with an optimized intrinsic network configuration for domain-general task performance experience more efficient network updates generally. Confirming this, network update efficiency correlated with general intelligence. The brain's reconfiguration efficiency therefore appears to be a key feature contributing to both its network dynamics and general cognitive ability. SIGNIFICANCE STATEMENT: The brain's network configuration varies based on current task demands. For example, functional brain connections are organized in one way when one is resting quietly but in another way if one is asked to make a decision. We found that the efficiency of these updates in brain network organization is positively related to general intelligence, the ability to perform a wide variety of cognitively challenging tasks well. Specifically, we found that brain network configuration at rest was already closer to a wide variety of task configurations in intelligent individuals. This suggests that the ability to modify network connectivity efficiently when task demands change is a hallmark of high intelligence.

Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning.

Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into "primary" and "secondary" psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional "fearlessness," while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths.