Neural Dynamics of Context-sensitive Adjustments in Cognitive Flexibility.

To adaptively interact with the uncertainties of daily life, we must match our level of cognitive flexibility to situations that place different demands on our ability to focus on the current task while remaining sensitive to cues that signal other, more urgent tasks. Such cognitive-flexibility adjustments in response to changing contextual demands (metaflexibility) have been observed in cued task-switching paradigms, where the performance cost incurred by switching versus repeating tasks (switch cost) scales inversely with the proportion of switches (PS) within a block of trials. However, the neural underpinnings of these adjustments in cognitive flexibility are not well understood. Here, we recorded 64-channel EEG measures of electrical brain activity as participants switched between letter and digit categorization tasks in varying PS contexts, from which we extracted ERPs elicited by the task cue and EEG alpha-power differences during both the cue-to-target interval and the resting precue period. The temporal resolution of EEG/ERPs allowed us to test whether contextual adjustments in cognitive flexibility are mediated by tonic changes in processing mode, or by changes in phasic, task-cue-triggered processes. We observed reliable modulation of behavioral switch cost by PS context that were mirrored in both cue-evoked ERP and time-frequency effects, but not in blockwide precue EEG changes. These results indicate that different levels of cognitive flexibility are instantiated in response to the presentation of task cues, rather than by being maintained as a tonic neural-activity state difference between low- and high-switch contexts.

Effects of category learning strategies on recognition memory.

Extant research has shown that previously acquired categorical knowledge affects recognition memory, and that differences in category learning strategies impact classification accuracy. However, it is unknown whether different learning strategies also have downstream effects on subsequent recognition memory. The present study investigates the effect of two unidimensional rule-based category learning strategies - learning (a) with or without explicit instruction, and (b) with or without supervision - on subsequent recognition memory. Our findings suggest that acquiring categorical knowledge increased both hits (Experiments 1 and 2) and false-alarms (Experiment 1) for category-congruent items regardless of the particular strategy employed in initially learning these categories. There were, however, small processing speed advantages during recognition memory for both explicit instruction and supervised practice relative to neither (Experiment 2). We discuss these findings in the context of how prior knowledge influences recognition memory, and in relation to similar findings showing schematic effects on episodic memory.

Neural Dynamics of Conflict Control in Working Memory.

Attention and working memory (WM) have classically been considered as two separate cognitive functions, but more recent theories have conceptualized them as operating on shared representations and being distinguished primarily by whether attention is directed internally (WM) or externally (attention, traditionally defined). Supporting this idea, a recent behavioral study documented a "WM Stroop effect," showing that maintaining a color word in WM impacts perceptual color-naming performance to the same degree as presenting the color word externally in the classic Stroop task. Here, we employed ERPs to examine the neural processes underlying this WM Stroop task compared to those in the classic Stroop and in a WM-control task. Based on the assumption that holding a color word in WM would (pre-)activate the same color representation as by externally presenting that color word, we hypothesized that the neural cascade of conflict-control processes would occur more rapidly in the WM Stroop than in the classic Stroop task. Our behavioral results replicated equivalent interference behavioral effects for the WM and classic Stroop tasks. Importantly, however, the ERP signatures of conflict detection and resolution displayed substantially shorter latencies in the WM Stroop task. Moreover, delay-period conflict in the WM Stroop task, but not in the WM control task, impacted the ERP and performance measures for the WM probe stimuli. Together, these findings provide new insights into how the brain processes conflict between internal representations and external stimuli, and they support the view of shared representations between internally held WM content and attentional processing of external stimuli.

Contextual Adaptation of Cognitive Flexibility is driven by Task- and Item-Level Learning.

Adaptive behavior requires finding, and adjusting, an optimal tradeoff between focusing on a current task-set (cognitive stability) and updating that task-set when the environment changes (cognitive flexibility). Such dynamic adjustments of cognitive flexibility are observed in cued task-switching paradigms, where switch costs tend to decrease as the proportion of switch trials over blocks increases. However, the learning mechanisms underlying this phenomenon, here referred to as the list-wide proportion switch effect (LWPSE), are currently unknown. We addressed this question across four behavioral experiments. Experiment 1 replicated the basic LWPSE reported in previous studies. Having participants switch between three instead of two tasks, Experiment 2 demonstrated that the LWPSE is preserved even when the specific alternate task to switch to cannot be anticipated. Experiments 3a and 3b tested for the generalization of list-wide switch-readiness to an unbiased "transfer task," presented equally often as switch and repeat trials, by intermixing the transfer task with biased tasks. Despite the list-wide bias, the LWPSE was only found for biased tasks, suggesting that the modulations of switch costs are task set and/or task stimulus (item)-specific. To evaluate these two possibilities, Experiment 4 employed biased versus unbiased stimuli within biased task sets and found switch-cost modulations for both stimuli sets. These results establish how people adapt their stability-flexibility tradeoff to different contexts. Specifically, our findings show that people learn to associate context-appropriate levels of switch readiness with switch-predictive cues, provided by task sets as well as specific task stimuli.

Insights into control over cognitive flexibility from studies of task-switching.

Cognitive flexibility denotes the ability to disengage from a current task and shift one's focus to a different activity. An individual's level of flexibility is not fixed; rather, people adapt their readiness to switch tasks to changing circumstances. We here review recent studies in the task-switching literature that have produced new insights into the contextual factors that drive this adaptation of flexibility, as well as proposals regarding the underlying cognitive mechanisms and learning processes. A fast-growing literature suggests that there are several different means of learning the need for, and implementing, changes in one's level of flexibility. These, in turn, have distinct consequences for the degree to which adjustments in cognitive flexibility are transferrable to new stimuli and tasks.

Quantification of surface-localized and total oxytocin receptor in myometrial smooth muscle cells.

Oxytocin acts through the oxytocin receptor (OXTR) to modulate uterine contractility. We previously identified OXTR genetic variants and showed that, in HEK293T cells, two of the OXTR protein variants localized to the cell surface less than wild-type OXTR. Here, we sought to measure OXTR in the more native human myometrial smooth muscle cell (HMSMC) line on both the cell-surface and across the whole cell, and used CRISPR editing to add an HA tag to the endogenous OXTR gene for anti-HA measurement. Quantitative flow cytometry revealed that these cells possessed 55,000 ± 3200 total OXTRs and 4900 ± 390 cell-surface OXTRs per cell. To identify any differential wild-type versus variant localization, we transiently transfected HMSMCs to exogenously express wild-type or variant OXTR with HA and green fluorescent protein tags. Total protein expression of wild-type OXTR and all tested variants were similar. However, the two variants with lower surface localization in HEK293T cells also presented lower surface localization in HMSMCs. Overall, we confirm the differential surface localization of variant OXTR in a more native cell type, and further demonstrate that the quantitative flow cytometry technique is adaptable to whole-cell measurements.

Task sets define boundaries of learned cognitive flexibility in list-wide proportion switch manipulations.

Different contexts in daily life often require varying levels of cognitive flexibility. Previous research has shown that people adapt their level of flexibility to match changing contextual demands for task switching in cued-switching paradigms that vary the proportion of switch trials within lists of trials. Specifically, the behavioral costs of switching as opposed to repeating tasks scale inversely with the proportion of switches-a finding referred to as the list-wide proportion switch (LWPS) effect. Previous research found that flexibility adaptations transferred across stimuli, but were specifically tied to task sets, rather than block-wide changes in flexibility state. In the current study, we conducted additional tests of the hypothesis that flexibility learning is task specific in the LWPS paradigm. In Experiments 1 and 2, we used trial-unique stimuli and unbiased task cues to control for associative learning tied to stimulus or cue features. Experiment 3 further tested whether task-specific learning occurred even for tasks performed on integrated features of the same stimuli. Across these three experiments, we found robust task-specific flexibility learning, which transferred across novel stimuli and unbiased cues and occurred regardless of stimulus-feature overlap between tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.

Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.

Intragenic EGFR::EGFR.E1E8 Fusion (EGFRvIII) in 4331 Solid Tumors.

Epidermal growth factor receptor variant III (EGFRvIII, the deletion of exons 2-7) is a recurrent intragenic EGFR::EGFR.E1E8 fusion that occurs in high-grade gliomas. The presence of EGFRvIII in other solid tumors has not been well characterized. We retrospectively reviewed advanced malignant solid tumor cases tested by a custom hybrid capture 610-gene next-generation sequencing platform from 2021 to 2022. EGFRvIII was identified in 17 of 4331 (0.4%) cases, including 16 of 238 (7%) brain tumors and 1/301 (0.3%) breast tumors. EGFRvIII-positive brain tumors were all glioblastoma IDH-wildtype, most with concurrent TERT promoter mutation (14 of 16), EGFR amplification (13 of 16), and EGFR mutation (8 of 16). The only EGFRvIII-positive breast lesion was a sarcomatoid neoplasm in a young female patient. A separate breast case tested outside our institution with reported EGFRvIII was noted in a young female patient with a malignant phyllodes tumor with stromal overgrowth. Microscopically, both EGFRvIII-positive breast tumors showed high-grade sarcomatoid morphology with brisk mitotic activity. In summary, EGFRvIII is rare, occurring primarily in glioblastoma and rarely in breast sarcomatoid neoplasm, with no instances identified in other tumor types in our series. This select group of patients may benefit from chemotherapy and/or targeted anti-EGFR therapy.

Characterizing academic performance in pediatric acute lymphoblastic leukemia with population-based achievement tests.

BACKGROUND: Recent shifts from radiation to chemotherapy-based treatment for acute lymphoblastic leukemia (ALL) have contributed to reduced long-term morbidity. Despite this, ALL survivors remain at increased risk for long-term cognitive impairments. AIM: To identify demographic and treatment factors associated with school performance in pediatric survivors of ALL. METHODS: We collected standardized test scores for reading, math, and science obtained in a school setting from grades 3-11 in 63 ALL survivors (46.0% boys). Most participants were assessed across multiple grades (median number of grades n = 5, range 1-7), and 269 observations were considered in the analyses. Treatment exposures were extracted from medical records. Socio-economic status was estimated using participation in free/reduced lunch programs at school. Mixed effects linear regression models were conducted to determine factors associated with school performance. RESULTS: ALL survivors' scores were comparable to state norms on reading, math, and science performances. On multivariable analysis, participation in free/reduced lunch programs was significantly associated with lower reading scores (ß = -12.52; 95% CI -22.26:-2.77, p = .01). Exposure to radiation during treatment was also associated with lower reading test scores (ß = -30.81, 95% CI -52.00:-9.62, p = .01). No significant associations between demographics and treatment parameters were observed for math and science test scores. CONCLUSIONS: We utilized population-based achievement tests conducted from grades 3-11 to characterize school performance in ALL survivors. Our results imply that survivors with low socio-economic status and those exposed to radiation during treatment could benefit from early monitoring and intervention to maximize academic success.

Selective contributions of executive function ability to the P3.

The P3 component (P300, P3b) is considered to be an effective index of attention and categorization processes when elicited in a visual oddball task, specifically reflecting the selection of a rare target item among frequent non-targets. Researchers have proposed that target categorization is guided by representations of target features held in working memory (WM), thus guiding attention and categorization processes to distinguish targets from non-targets. Although WM is theorized to have visuospatial, verbal and executive function components, most studies do not investigate how these WM components contribute to the P3. This study uses an individual differences approach to determine whether correlations between WM capabilities and P3 amplitudes indicate a common underlying cognitive construct. Participants (n = 140) completed an 80/20 visual oddball task to elicit the P3 as well as independent visual working memory (VWM), spatial working memory (SPWM), and executive function (task switching (TS) and digit symbol substitution (DSS)) tests. Results indicated that measures of executive function, DSS and TS, but not VWM or SPWM ability, correlated with and predicted faster task response times and greater P3 amplitudes. RT and WM measures were not correlated with P3 fractional area latencies. These results support context updating theory. Executive function WM availability, whether as a property of the participant's processing system or based on task demands, plays a functional role in the P3 and an important role in efficient visual categorization and goal-directed learning.

Minimal impact of consolidation on learned switch-readiness.

Adaptive behavior is characterized by our ability to create, maintain, and update (or switch) rules by which we categorize and respond to stimuli across changing contexts (cognitive flexibility). Recent research suggests that people can link the control process of task-switching to contextual cues through associative learning, whereby the behavioral cost of switching is reduced for contexts that require frequent switching. One example is the listwide proportion switch (LWPS) effect, denoting smaller switch costs in blocks of trials where switching is more frequent. However, the conditions that govern such learned cognitive flexibility are poorly understood. One major unanswered question is whether this type of learning benefits from memory consolidation effects. To address this question, we manipulated whether task-sets and/or specific task stimuli were more frequently linked with task-switching (vs. repeating), and ran participants over two experimental sessions, separated by a 24-hr delay. We expected that consolidation would facilitate learned cognitive flexibility, resulting in a greater reduction of switch costs with increasing task-switch likelihood on Session 2 compared with Session 1. Across two experiments, we observed robust LWPS effects in both sessions. However, we found little evidence for effects of consolidation on learned cognitive flexibility: The magnitude of the LWPS effect did not change from Session 1 to 2. Altogether our results suggest that people reliably and quickly acquire task-set and stimulus-based switch associations, but this form of control learning-unlike many instances of reward-based learning-does not benefit from long-term memory consolidation. Possible reasons for these findings are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm.

BACKGROUND: Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. RESEARCH QUESTION: Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)? STUDY DESIGN AND METHODS: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. RESULTS: Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment. INTERPRETATION: The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.

The Longitudinal Immune Response to Coronavirus Disease 2019: Chasing the Cytokine Storm.

The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.

Neuromechanical control of the isolated upper airway of mice.

We characterized the passive structural and active neuromuscular control of pharyngeal collapsibility in mice and hypothesized that pharyngeal collapsibility, which is elevated by anatomic loads, is reduced by active neuromuscular responses to airflow obstruction. To address this hypothesis, we examined the dynamic control of upper airway function in the isolated upper airway of anesthetized C57BL/6J mice. Pressures were lowered downstream and upstream to the upper airway to induce inspiratory airflow limitation and critical closure of the upper airway, respectively. After hyperventilating the mice to central apnea, we demonstrated a critical closing pressure (Pcrit) of -6.2 +/- 1.1 cmH(2)O under passive conditions that was unaltered by the state of lung inflation. After a period of central apnea, lower airway occlusion led to progressive increases in phasic genioglossal electromyographic activity (EMG(GG)), and in maximal inspiratory airflow (Vi(max)) through the isolated upper airway, particularly as the nasal pressure was lowered toward the passive Pcrit level. Moreover, the active Pcrit fell during inspiration by 8.2 +/- 1.4 cmH(2)O relative to the passive condition (P < 0.0005). We conclude that upper airway collapsibility (passive Pcrit) in the C57BL/6J mouse is similar to that in the anesthetized canine, feline, and sleeping human upper airway, and that collapsibility falls markedly under active conditions. Active EMG(GG) and Vi(max) responses dissociated at higher upstream pressure levels, suggesting a decrease in the mechanical efficiency of upper airway dilators. Our findings in mice imply that anatomic and neuromuscular factors interact dynamically to modulate upper airway function, and provide a novel approach to modeling the impact of genetic and environmental factors in inbred murine strains.

Dissociable processing of emotional and neutral body movements revealed by µ-alpha and beta rhythms.

Both when actions are executed and observed, electroencephalography (EEG) has shown reduced alpha-band (8-12 Hz) oscillations over sensorimotor cortex. This 'µ-alpha' suppression is thought to reflect mental simulation of action, which has been argued to support internal representation of others' emotional states. Despite the proposed role of simulation in emotion perception, little is known about the effect of emotional content on µ-suppression. We recorded high-density EEG while participants viewed point-light displays of emotional vs neutral body movements in 'coherent' biologically plausible and 'scrambled' configurations. Although coherent relative to scrambled stimuli elicited µ-alpha suppression, the comparison of emotional and neutral movement, controlling for basic visual input, revealed suppression effects in both alpha and beta bands. Whereas alpha-band activity reflected reduced power for emotional stimuli in central and occipital sensors, beta power at frontocentral sites was driven by enhancement for neutral relative to emotional actions. A median-split by autism-spectrum quotient score revealed weaker µ-alpha suppression and beta enhancement in participants with autistic tendencies, suggesting that sensorimotor simulation may be differentially engaged depending on social capabilities. Consistent with theories of embodied emotion, these data support a link between simulation and social perception while more firmly connecting emotional processing to the activity of sensorimotor systems.