Systematic review and meta-analysis of individual serum lipids and analysis of lipid ratios in ankylosing spondylitis and healthy control cohorts: significantly lower mean HDL-cholesterol level in ankylosing spondylitis cohorts.

OBJECTIVES: Ankylosing spondylitis (AS) is suspected to have increased risk of atherosclerosis and cardiovascular disease (CVD) mortality. This systematic review and meta-analysis aims to critically study serum lipids and lipoprotein ratios in AS compared to healthy control (HC) subjects and determine any significant difference. METHODS: English-language articles were systematically searched in PubMed, Ovid Medline, Embase (Medline records removed), and Scopus databases from 1970 to 2021. Random-effects model was used to pool results expressed as standardised mean difference (SMD) in the lipid outcomes. Lipid ratios of total ÷ HDL-C and the log10 (TG/HDL-C), i.e. atherogenic index of plasma (AIP), were analysed by histograms of differences in weighted means and weighted SDs between AS and HC exposure cohorts. RESULTS: The meta-analysis included a total of 68 articles, 47 from database search and 21 from reference reviews. Pooled Hedges' g effect size revealed no difference in mean total cholesterol, mean triglycerides, and mean LDL-C between AS and HC subjects. However, mean HDL-C was significantly (p<0.001) lower in AS than HC subjects, with pooled Hedges' g (SE) for HDL-C of -0.484 (0.092), with 95% mean CIs [-0.664, -0.305]. In comparing differencesin AS minus HC weighted means of total HDL-C ratios, 8 values in HC were below the lowest ratio in AS. CONCLUSIONS: Highly significantly lower HDL-C levels occurred in AS versus HC subjects. The lower HDL-C levels in AS than HC populations deserve further study and may be attributable to uninvestigated demographic, exercise capacity, or clinical manifestations.

Electroencephalography reveals a selective disruption of cognitive control processes in craving cigarette smokers.

Addiction to nicotine is extremely challenging to overcome, and the intense craving for the next cigarette often leads to relapse in smokers who wish to quit. To dampen the urges of craving and inhibit unwanted behaviour, smokers must harness cognitive control, which is itself impaired in addiction. It is likely that craving may interact with cognitive control, and the present study sought to test the specificity of such interactions. To this end, data from 24 smokers were gathered using EEG and behavioural measures in a craving session (following a three-hour nicotine abstention period) and a non-craving session (having just smoked). In both sessions, participants performed a task probing various facets of cognitive control (response inhibition, task switching and conflict processing). Results showed that craving smokers were less flexible with the implementation of cognitive control, with demands of task switching and incongruency yielding greater deficits under conditions of craving. Importantly, inhibitory control was not affected by craving, suggesting that the interactions of craving and cognitive control are selective. Together, these results provide evidence that smokers already exhibit specific control-related deficits after brief nicotine deprivation. This disruption of cognitive control while craving may help to explain why abstinence is so difficult to maintain.

Cortical Mechanisms of Prioritizing Selection for Rejection in Visual Search.

In visual search, the more one knows about a target, the faster one can find it. Surprisingly, target identification is also faster with knowledge about distractor-features. The latter is paradoxical, as it implies that to avoid the selection of an item, the item must somehow be selected to some degree. This conundrum has been termed the "ignoring paradox", and, to date, little is known about how the brain resolves it. Here, in data from four experiments using neuromagnetic brain recordings in male and female humans, we provide evidence that this paradox is resolved by giving distracting information priority in cortical processing. This attentional priority to distractors manifests as an enhanced early neuromagnetic index, which occurs before target-related processing, and regardless of distractor predictability. It is most pronounced on trials for which a response rapidly occurred, and is followed by a suppression of the distracting information. These observations together suggest that in visual search items cannot be ignored without first being selected.SIGNIFICANCE STATEMENT How can we ignore distracting stimuli in our environment? To do this successfully, a logical hypothesis is that as few neural resources as possible should be devoted to distractor processing. Yet, to avoid devoting resources to a distractor, the brain must somehow mark what to avoid; this is a philosophical problem, which has been termed the "ignoring paradox" or "white bear phenomenon". Here, we use MEG recordings to determine how the human brain resolves this paradox. Our data show that distractors are not only processed, they are given temporal priority, with the brain building a robust representation of the to-be-ignored items. Thus, successful suppression of distractors can only be achieved if distractors are first strongly neurally represented.

Dissociating Reward- and Attention-driven Biasing of Global Feature-based Selection in Human Visual Cortex.

Objects that promise rewards are prioritized for visual selection. The way this prioritization shapes sensory processing in visual cortex, however, is debated. It has been suggested that rewards motivate stronger attentional focusing, resulting in a modulation of sensory selection in early visual cortex. An open question is whether those reward-driven modulations would be independent of similar modulations indexing the selection of attended features that are not associated with reward. Here, we use magnetoencephalography in human observers to investigate whether the modulations indexing global color-based selection in visual cortex are separable for target- and (monetary) reward-defining colors. To assess the underlying global color-based activity modulation, we compare the event-related magnetic field response elicited by a color probe in the unattended hemifield drawn either in the target color, the reward color, both colors, or a neutral task-irrelevant color. To test whether target and reward relevance trigger separable modulations, we manipulate attention demands on target selection while keeping reward-defining experimental parameters constant. Replicating previous observations, we find that reward and target relevance produce almost indistinguishable gain modulations in ventral extratriate cortex contralateral to the unattended color probe. Importantly, increasing attention demands on target discrimination increases the response to the target-defining color, whereas the response to the rewarded color remains largely unchanged. These observations indicate that, although task relevance and reward influence the very same feature-selective area in extrastriate visual cortex, the associated modulations are largely independent.

The Rapid Capture of Attention by Rewarded Objects.

When a stimulus is associated with a reward, it becomes prioritized, and the allocation of attention to that stimulus increases. For low-level features, such as color, this reward-based allocation of attention can manifest early in time and as a faster and stronger shift of attention to targets with that color, as reflected by the N2pc (a parieto-occipital electrophysiological component peaking at ∼250 msec). It is unknown, however, if reward associations can similarly modulate attentional shifts to complex objects or object categories, or if reward-related modulation of attentional allocation to such stimuli would occur later in time or through a different mechanism. Here, we used magnetoencephalographic recordings in 24 participants to investigate how object categories with a reward association would modulate the shift of attention. On each trial, two colored squares were presented, one in a target color and the other in a distractor color, each with an embedded object. Participants searched for the target-colored square and performed a corner discrimination task. The embedded objects were from either a rewarded or non-rewarded category, and if a rewarded-category object were present within the target-colored square, participants could earn extra money for correct performance. We observed that when the target color contained an object from a rewarded versus a non-rewarded category, the neural shift of attention to the target was faster and of greater magnitude, although the rewarded objects were not relevant for correct task performance. These results suggest that reward associations of complex objects can rapidly modulate attentional allocation to a target.

Reward-associated features capture attention in the absence of awareness: Evidence from object-substitution masking.

Reward-associated visual features have been shown to capture visual attention, evidenced in faster and more accurate behavioral performance, as well as in neural responses reflecting lateralized shifts of visual attention to those features. Specifically, the contralateral N2pc event-related-potential (ERP) component that reflects attentional shifting exhibits increased amplitude in response to task-relevant targets containing a reward-associated feature. In the present study, we examined the automaticity of such reward-association effects using object-substitution masking (OSM) in conjunction with MEG measures of visual attentional shifts. In OSM, a visual-search array is presented, with the target item to be detected indicated by a surrounding mask (here, four surrounding squares). Delaying the offset of the target-surrounding four-dot mask relative to the offset of the rest of the target/distracter array disrupts the viewer's awareness of the target (masked condition), whereas simultaneous offsets do not (unmasked condition). Here we manipulated whether the color of the OSM target was or was not of a previously reward-associated color. By tracking reward-associated enhancements of behavior and the N2pc in response to masked targets containing a previously rewarded or unrewarded feature, the automaticity of attentional capture by reward could be probed. We found an enhanced N2pc response to targets containing a previously reward-associated color feature. Moreover, this enhancement of the N2pc by reward did not differ between masking conditions, nor did it differ as a function of the apparent visibility of the target within the masked condition. Overall, these results underscore the automaticity of attentional capture by reward-associated features, and demonstrate the ability of feature-based reward associations to shape attentional capture and allocation outside of perceptual awareness.

An electrophysiological marker of the desire to quit in smokers.

For many smokers, the motivational state of craving is a central feature of their dependence on nicotine, and is often at odds with a general desire to quit. How this desire to quit may influence the craving for a cigarette, however, is unclear. In the current study, we manipulated the level of craving in 24 regular smokers, and recorded EEG measures of brain activity during a rare target detection task utilizing addiction-unrelated stimuli. In response to the non-targets, we observed that smokers wanting to quit showed an enhanced late frontal activation when they were craving vs. not craving, whereas smokers not wanting to quit showed the opposite pattern of activity. A dissociation was also present in the target-related P300 response as a function of craving and desire to quit, with smokers who did not want to quit processing targets differentially between the states of craving and non-craving. The data suggest that distinct top-down control mechanisms during craving may be implemented by people who wish to quit smoking, as compared to those who do not wish to quit. This pattern of findings establishes this ERP activity as a potential biomarker that may help to differentiate people who want to quit their addiction from those who wish to continue to use their substance of choice.

An electrophysiological dissociation of craving and stimulus-dependent attentional capture in smokers.

It has been suggested that over the course of an addiction, addiction-related stimuli become highly salient in the environment, thereby capturing an addict's attention. To assess these effects neurally in smokers, and how they interact with craving, we recorded electroencephalography (EEG) in two sessions: one in which participants had just smoked (non-craving), and one in which they had abstained from smoking for 3 h (craving). In both sessions, participants performed a visual-search task in which two colored squares were presented to the left and right of fixation, with one color being the target to which they should shift attention and discriminate the locations of two missing corners. Task-irrelevant images, both smoking-related and non-smoking-related, were embedded in both squares, enabling the shift of spatial attention to the target to be examined as a function of the addiction-related image being present or absent in the target, the distractor, or both. Behaviorally, participants were slower to respond to targets containing a smoking-related image. Furthermore, when the target contained a smoking-related image, the neural responses indicated that attention had been shifted less strongly to the target; when the distractor contained a smoking-related image, the shift of attention to the contralateral target was stronger. These effects occurred independently of craving and suggest that participants were actively avoiding the smoking-related images. Together, these results provide an electrophysiological dissociation between addiction-related visual-stimulus processing and the neural activity associated with craving.

Electrophysiological evidence for the involvement of the approximate number system in preschoolers' processing of spoken number words.

Little is known about the neural underpinnings of number word comprehension in young children. Here we investigated the neural processing of these words during the crucial developmental window in which children learn their meanings and asked whether such processing relies on the Approximate Number System. ERPs were recorded as 3- to 5-year-old children heard the words one, two, three, or six while looking at pictures of 1, 2, 3, or 6 objects. The auditory number word was incongruent with the number of visual objects on half the trials and congruent on the other half. Children's number word comprehension predicted their ERP incongruency effects. Specifically, children with the least number word knowledge did not show any ERP incongruency effects, whereas those with intermediate and high number word knowledge showed an enhanced, negative polarity incongruency response (N(inc)) over centroparietal sites from 200 to 500 msec after the number word onset. This negativity was followed by an enhanced, positive polarity incongruency effect (P(inc)) that emerged bilaterally over parietal sites at about 700 msec. Moreover, children with the most number word knowledge showed ratio dependence in the P(inc) (larger for greater compared with smaller numerical mismatches), a hallmark of the Approximate Number System. Importantly, a similar modulation of the P(inc) from 700 to 800 msec was found in children with intermediate number word knowledge. These results provide the first neural correlates of spoken number word comprehension in preschoolers and are consistent with the view that children map number words onto approximate number representations before they fully master the verbal count list.

Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes.

The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer between donor and recipient cells, has recently been identified in a wide range of cell types. Intercellular mitochondrial transfer has also been observed between different types of cancer stem cells (CSCs) and their neighboring cells, including brain CSCs and astrocytes. CSC mitochondrial transfer significantly enhances overall tumor progression by reprogramming neighboring cells. Despite the urgent need to investigate this newly identified phenomenon, mitochondrial transfer in the central nervous system remains largely uncharacterized. In this study, we found evidence of intercellular mitochondrial transfer from human NSCs and from brain CSCs, also known as brain tumor-initiating cells (BTICs), to astrocytes in co-culture experiments. Both NSC and BTIC mitochondria triggered similar transcriptome changes upon transplantation into the recipient astrocytes. In contrast to NSCs, the transplanted mitochondria from BTICs had a significant proliferative effect on the recipient astrocytes. This study forms the basis for mechanistically deciphering the impact of intercellular mitochondrial transfer on recipient astrocytes, which will potentially provide us with new insights into the mechanisms of mitochondrial retrograde signaling.

The rapid distraction of attentional resources toward the source of incongruent stimulus input during multisensory conflict.

Neuroimaging work on multisensory conflict suggests that the relevant modality receives enhanced processing in the face of incongruency. However, the degree of stimulus processing in the irrelevant modality and the temporal cascade of the attentional modulations in either the relevant or irrelevant modalities are unknown. Here, we employed an audiovisual conflict paradigm with a sensory probe in the task-irrelevant modality (vision) to gauge the attentional allocation to that modality. ERPs were recorded as participants attended to and discriminated spoken auditory letters while ignoring simultaneous bilateral visual letter stimuli that were either fully congruent, fully incongruent, or partially incongruent (one side incongruent, one congruent) with the auditory stimulation. Half of the audiovisual letter stimuli were followed 500-700 msec later by a bilateral visual probe stimulus. As expected, ERPs to the audiovisual stimuli showed an incongruency ERP effect (fully incongruent versus fully congruent) of an enhanced, centrally distributed, negative-polarity wave starting ∼250 msec. More critically here, the sensory ERP components to the visual probes were larger when they followed fully incongruent versus fully congruent multisensory stimuli, with these enhancements greatest on fully incongruent trials with the slowest RTs. In addition, on the slowest-response partially incongruent trials, the P2 sensory component to the visual probes was larger contralateral to the preceding incongruent visual stimulus. These data suggest that, in response to conflicting multisensory stimulus input, the initial cognitive effect is a capture of attention by the incongruent irrelevant-modality input, pulling neural processing resources toward that modality, resulting in rapid enhancement, rather than rapid suppression, of that input.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

The cross-modal spread of attention reveals differential constraints for the temporal and spatial linking of visual and auditory stimulus events.

The integration of multisensory information has been shown to be guided by spatial and temporal proximity, as well as to be influenced by attention. Here we used neural measures of the multisensory spread of attention to investigate the spatial and temporal linking of synchronous versus near-synchronous auditory and visual events. Human participants attended selectively to one of two lateralized visual-stimulus streams while task-irrelevant tones were presented centrally. Electrophysiological measures of brain activity showed that tones occurring simultaneously or delayed by 100 ms were temporally linked to an attended visual stimulus, as reflected by robust cross-modal spreading-of-attention activity, but not when delayed by 300 ms. The neural data also indicated a ventriloquist-like spatial linking of the auditory to the attended visual stimuli, but only when occurring simultaneously. These neurophysiological results thus provide unique insight into the temporal and spatial principles of multisensory feature integration and the fundamental role attention plays in such integration.

Is conflict monitoring supramodal? Spatiotemporal dynamics of cognitive control processes in an auditory Stroop task.

The electrophysiological correlates of conflict processing and cognitive control have been well characterized for the visual modality in paradigms such as the Stroop task. Much less is known about corresponding processes in the auditory modality. Here, electroencephalographic recordings of brain activity were measured during an auditory Stroop task, using three different forms of behavioral response (overt verbal, covert verbal, and manual), that closely paralleled our previous visual Stroop study. As was expected, behavioral responses were slower and less accurate for incongruent than for congruent trials. Neurally, incongruent trials showed an enhanced fronto-central negative polarity wave (N(inc)), similar to the N450 in visual Stroop tasks, with similar variations as a function of behavioral response mode, but peaking ~150 ms earlier, followed by an enhanced positive posterior wave. In addition, sequential behavioral and neural effects were observed that supported the conflict-monitoring and cognitive adjustment hypothesis. Thus, while some aspects of the conflict detection processes, such as timing, may be modality dependent, the general mechanisms would appear to be supramodal.

Links between multisensory processing and autism.

Autism spectrum disorder is typically associated with social deficits and is often specifically linked to difficulty with processing faces and other socially relevant stimuli. Emerging research has suggested that children with autism might also have deficits in basic perceptual abilities including multisensory processing (e.g., simultaneously processing visual and auditory inputs). The current study examined the relationship between multisensory temporal processing (assessed via a simultaneity judgment task wherein participants were to report whether a visual stimulus and an auditory stimulus occurred at the same time or at different times) and self-reported symptoms of autism (assessed via the Autism Spectrum Quotient questionnaire). Data from over 100 healthy adults revealed a relationship between these two factors as multisensory timing perception correlated with symptoms of autism. Specifically, a stronger bias to perceive auditory stimuli occurring before visual stimuli as simultaneous was associated with greater levels of autistic symptoms. Additional data and analyses confirm that this relationship is specific to multisensory processing and symptoms of autism. These results provide insight into the nature of multisensory processing while also revealing a continuum over which perceptual abilities correlate with symptoms of autism and that this continuum is not just specific to clinical populations but is present within the general population.

Parallel fast and slow recurrent cortical processing mediates target and distractor selection in visual search.

Visual search has been commonly used to study the neural correlates of attentional allocation in space. Recent electrophysiological research has disentangled distractor processing from target processing, showing that these mechanisms appear to operate in parallel and show electric fields of opposite polarity. Nevertheless, the localization and exact nature of this activity is unknown. Here, using MEG in humans, we provide a spatiotemporal characterization of target and distractor processing in visual cortex. We demonstrate that source activity underlying target- and distractor-processing propagates in parallel as fast and slow sweep from higher to lower hierarchical levels in visual cortex. Importantly, the fast propagating target-related source activity bypasses intermediate levels to go directly to V1, and this V1 activity correlates with behavioral performance. These findings suggest that reentrant processing is important for both selection and attenuation of stimuli, and such processing operates in parallel feedback loops.

Controlled retrieval and selection of action-relevant knowledge mediated by partially overlapping regions in left ventrolateral prefrontal cortex.

Information from long-term memory is used to identify appropriate responses to cues in the environment. Left ventrolateral prefrontal cortex (VLPFC) has been implicated in the effortful retrieval of semantic representations, as well as in the goal-directed selection between such representations. It has also been suggested that left posterior middle temporal gyrus (pMTG) stores the rules which VLPFC accesses to guide behavior. In the present event-related fMRI study, we examined the contributions of left VLPFC and pMTG in the controlled retrieval and selection of action-relevant knowledge associated with road signs. Controlled retrieval demands were manipulated by varying how recently the sign meaning was learned, and selection demands were manipulated by varying the number of competing meanings associated with a sign. Activation in anterior VLPFC was consistent with controlled retrieval, activation in posterior VLPFC was consistent with selection, and activation in mid-VLPFC was sensitive to both manipulations. Left pMTG, while active, was not sensitive to these manipulations. These findings highlight the role of left VLPFC in accessing and maintaining goal-relevant information for the control of action.

Neurodevelopmental correlates of true and false recognition.

The Deese/Roediger-McDermott (DRM) false-memory effect has been extensively documented in psychological research. People falsely recognize critical lures or nonstudied items that are semantically associated with studied items. Behavioral research has provided evidence for age-related increases in the DRM false-recognition effect. The present event-related functional magnetic resonance imaging study was aimed at investigating neurodevelopmental changes in brain regions associated with true- and false-memory recognition in 8-year olds, 12-year olds, and adults. Relative to 8-year olds, adults correctly endorsed more studied items as "old" but also mistakenly endorsed more critical lures. Age-related increases in recollection were associated with changes in the medial temporal lobe (MTL) activation profile. Additionally, age-related increases in false alarms (FAs) to semantically related lures were associated with changes in the activation profile of left ventrolateral prefrontal cortex, a region associated with semantic processing. Additional regions exhibiting age-related changes include posterior parietal and anterior prefrontal cortices. In summary, concomitant changes in the MTL, prefrontal cortex, and parietal cortex underlie developmental increases in true and false recognition during childhood and adolescence.

A neural hallmark of auditory implicit learning is altered in older adults.

Temporal regularities in the environment are often learned implicitly. In an auditory target-detection paradigm using EEG, Jongsma and colleagues (2006) showed that the neural response to these implicit regularities results in a reduction of the P3-N2 complex. Here, we utilized the same paradigm, this time in both young and old participants, to determine if this EEG signature of implicit learning was altered with age. Behaviorally, both groups of participants showed similar benefits for the presence of temporal regularity, with faster and more accurate responses given when the auditory targets were presented in a temporally regular vs. random pattern. In the brain, the younger adults showed the expected decrease in amplitude of this complex for regular compared to irregular trials. Older adults, in contrast, showed no difference in the amplitude of the P3-N2 complex between the irregular and regular condition. These data suggest that, although auditory implicit learning may be behaviorally spared in aging, older adults are not using the same neural substrates as younger adults to achieve this.

Switching between colors and shapes on the basis of positive and negative feedback: an fMRI and EEG study on feedback-based learning.

A crucial element of testing hypotheses about rules for behavior is the use of performance feedback. In this study, we used fMRI and EEG to test the role of medial prefrontal cortex (PFC) and dorsolateral (DL) PFC in hypothesis testing using a modified intradimensional/extradimensional rule shift task. Eighteen adults were asked to infer rules about color or shape on the basis of positive and negative feedback in sets of two trials. Half of the trials involved color-to-color or shape-to-shape trials (intradimensional switches; ID) and the other half involved color-to-shape or shape-to-color trials (extradimensional switches; ED). Participants performed the task in separate fMRI and EEG sessions. ED trials were associated with reduced accuracy relative to ID trials. In addition, accuracy was reduced and response latencies increased following negative relative to positive feedback. Negative feedback resulted in increased activation in medial PFC and DLPFC, but more so for ED than ID shifts. Reduced accuracy following negative feedback correlated with increased activation in DLPFC, and increased response latencies following negative feedback correlated with increased activation in medial PFC. Additionally, around 250msec following negative performance feedback participants showed a feedback-related negative scalp potential, but this potential did not differ between ID and ED shifts. These results indicate that both medial PFC and DLPFC signal the need for performance adjustment, and both regions are sensitive to the increased demands of set shifting in hypothesis testing.