White matter and latency of visual evoked potentials during maturation: a miniature pig model of adolescent development.

BACKGROUND: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period. METHODS: Eight SinclairTM minipigs (Sus scrofa domestica) were evaluated four times during weeks 14-28 (40, 28 and 28 days apart) of adolescence using monocular visual stimulation (1Hz)-evoked potentials and diffusion MRI (dMRI) of WM. The latency for the pre-positive 30 ms (PP30), positive 30 ms (P30) and negative 50 ms (N50) components of the flash visual evoked potentials (fVEPs) and their interhemispheric latency (IL) were recorded in the frontal, central and occipital areas during ten 60-second stimulations for each eye. The dMRI imaging protocol consisted of fifteen b-shells (b = 0-3500s/mm2) with 32 directions/shell, providing measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axonal water fraction (AWF), and the permeability-diffusivity index (PDI). RESULTS: Significant reductions (p < 0.05) in the latency and IL of fVEP measurements paralleled significant rises in FA, KA, AWF and PDI over the same period. The longitudinal latency changes in fVEPs were primarily associated with whole-brain changes in diffusion parameters, while fVEP IL changes were related to maturation of the corpus callosum. CONCLUSIONS: Good agreement between reduction in the latency of fVEPs and maturation of cerebral WM was interpreted as evidence for ongoing myelination and confirmation of the minipig as a viable research platform. Adolescent development in minipigs can be studied using human neuroimaging and neurophysiological protocols and followed up with more invasive assays to investigate key neurodevelopmental hypotheses in psychiatry.

Preoperative electroencephalographic alpha-power changes with eyes opening are associated with postoperative attention impairment and inattention-related delirium severity.

BACKGROUND: In the eyes-closed, awake condition, EEG oscillatory power in the alpha band (7-13 Hz) dominates human spectral activity. With eyes open, however, EEG alpha power substantially decreases. Less alpha attenuation with eyes opening has been associated with inattention; thus, we analysed whether reduced preoperative alpha attenuation with eyes opening is associated with postoperative inattention, a delirium-defining feature. METHODS: Preoperative awake 32-channel EEG was recorded with eyes open and eyes closed in 71 non-neurological, noncardiac surgery patients aged ≥ 60 years. Inattention and other delirium features were assessed before surgery and twice daily after surgery until discharge. Eyes-opening EEG alpha-attenuation magnitude was analysed for associations with postoperative inattention, primarily, and with delirium severity, secondarily, using multivariate age- and Mini-Mental Status Examination (MMSE)-adjusted logistic and proportional-odds regression analyses. RESULTS: Preoperative alpha attenuation with eyes opening was inversely associated with postoperative inattention (odds ratio [OR] 0.73, 95% confidence interval [CI]: 0.57, 0.94; P=0.038). Sensitivity analyses showed an inverse relationship between alpha-attenuation magnitude and inattention chronicity, defined as 'never', 'newly', or 'chronically' inattentive (OR 0.76, 95% CI: 0.62, 0.93; P=0.019). In addition, preoperative alpha-attenuation magnitude was inversely associated with postoperative delirium severity (OR 0.79, 95% CI: 0.65, 0.95; P=0.040), predominantly as a result of the inattention feature. CONCLUSIONS: Preoperative awake, resting, EEG alpha attenuation with eyes opening might represent a neural biomarker for risk of postoperative attentional impairment. Further, eyes-opening alpha attenuation could provide insight into the neural mechanisms underlying postoperative inattention risk.

Electrical brain activations in young children during a probabilistic reward-learning task are associated with behavioral strategy.

Both adults and children learn through feedback which events and choices in the environment are associated with higher probability of reward. This probability reward-learning ability is thought to be supported by the development of fronto-striatal reward circuits. Recent developmental studies have applied computational models of reward learning to investigate such learning in children. However, there has been limited development of task tools capable of measuring the cascade of neural reward-learning processes in children. Using a child-version of a probabilistic reward-learning task while recording event-related-potential (ERP) measures of electrical brain activity, this study examined key processes of reward learning in preadolescents (n=30), namely: (1) reward-feedback sensitivity, as measured by the early reward-related frontal ERP positivity, (2) rapid attentional shifting of processing toward favored visual stimuli, as measured by the N2pc component, and (3) longer-latency attention-related responses to reward feedback as a function of behavior strategies (i.e., Win-Stay-Lose-Shift), as measured by the central-parietal P300. Consistent with our prior work in adults, the behavioral findings indicate that preadolescents could learn stimulus-reward outcome associations, but at varying levels of performance. Neurally, poor preadolescent learners (those with slower learning rates) showed greater reward-related positivity amplitudes relative to good learners, suggesting greater reward sensitivity. We also found attention shifting towards to-be-chosen stimuli, as evidenced by the N2pc, but not to more highly rewarded stimuli. Lastly, we found an effect of behavioral learning strategies (i.e., Win-Stay-Lose-Shift) on the feedback-locked P300 over the parietal cortex. These findings provide novel insights into the key neural processes underlying reinforcement learning in preadolescents.

EEG pre-burst suppression: characterization and inverse association with preoperative cognitive function in older adults.

The most common complication in older surgical patients is postoperative delirium (POD). POD is associated with preoperative cognitive impairment and longer durations of intraoperative burst suppression (BSup) - electroencephalography (EEG) with repeated periods of suppression (very low-voltage brain activity). However, BSup has modest sensitivity for predicting POD. We hypothesized that a brain state of lowered EEG power immediately precedes BSup, which we have termed "pre-burst suppression" (preBSup). Further, we hypothesized that even patients without BSup experience these preBSup transient reductions in EEG power, and that preBSup (like BSup) would be associated with preoperative cognitive function and delirium risk. Data included 83 32-channel intraoperative EEG recordings of the first hour of surgery from 2 prospective cohort studies of patients ≥age 60 scheduled for ≥2-h non-cardiac, non-neurologic surgery under general anesthesia (maintained with a potent inhaled anesthetic or a propofol infusion). Among patients with BSup, we defined preBSup as the difference in 3-35 Hz power (dB) during the 1-s preceding BSup relative to the average 3-35 Hz power of their intraoperative EEG recording. We then recorded the percentage of time that each patient spent in preBSup, including those without BSup. Next, we characterized the association between percentage of time in preBSup and (1) percentage of time in BSup, (2) preoperative cognitive function, and (3) POD incidence. The percentage of time in preBSup and BSup were correlated (Spearman's ρ [95% CI]: 0.52 [0.34, 0.66], p < 0.001). The percentage of time in BSup, preBSup, or their combination were each inversely associated with preoperative cognitive function (ß [95% CI]: -0.10 [-0.19, -0.01], p = 0.024; -0.04 [-0.06, -0.01], p = 0.009; -0.04 [-0.06, -0.01], p = 0.003, respectively). Consistent with prior literature, BSup was significantly associated with POD (odds ratio [95% CI]: 1.34 [1.01, 1.78], p = 0.043), though this association did not hold for preBSup (odds ratio [95% CI]: 1.04 [0.95, 1.14], p = 0.421). While all patients had ≥1 preBSup instance, only 20.5% of patients had ≥1 BSup instance. These exploratory findings suggest that future studies are warranted to further study the extent to which preBSup, even in the absence of BSup, can identify patients with impaired preoperative cognition and/or POD risk.

Neural retrieval processes occur more rapidly for visual mental images that were previously encoded with high-vividness.

Visual mental imagery refers to our ability to experience visual images in the absence of sensory stimulation. Studies have shown that visual mental imagery can improve episodic memory. However, we have limited understanding of the neural mechanisms underlying this improvement. Using electroencephalography, we examined the neural processes associated with the retrieval of previously generated visual mental images, focusing on how the vividness at generation can modulate retrieval processes. Participants viewed word stimuli referring to common objects, forming a visual mental image of each word and rating the vividness of the mental image. This was followed by a surprise old/new recognition task. We compared retrieval performance for items rated as high- versus low-vividness at encoding. High-vividness items were retrieved with faster reaction times and higher confidence ratings in the memory judgment. While controlling for confidence, neural measures indicated that high-vividness items produced an earlier decrease in alpha-band activity at retrieval compared with low-vividness items, suggesting an earlier memory reinstatement. Even when low-vividness items were remembered with high confidence, they were not retrieved as quickly as high-vividness items. These results indicate that when highly vivid mental images are encoded, the speed of their retrieval occurs more rapidly, relative to low-vivid items.

Neurophysiological signatures of approximate number system acuity in preschoolers.

BACKGROUND: A hallmark of the approximate number system (ANS) is ratio dependence. Previous work identified specific event-related potentials (ERPs) that are modulated by numerical ratio throughout the lifespan. In adults, ERP ratio dependence was correlated with the precision of the numerical judgments with individuals who make more precise judgments showing larger ratio-dependent ERP effects. The current study evaluated if this relationship generalizes to preschoolers. METHOD: ERPs were recorded from 56 4.5 to 5.5-year-olds while they compared the numerosity of two sequentially presented dot arrays. Nonverbal numerical precision, often called ANS acuity, was assessed using a similar behavioral task. RESULTS: Only children with high ANS acuity exhibited a P2p ratio-dependent effect onsetting ∼250 ms after the presentation of the comparison dot array. Furthermore, P2p amplitude positively correlated with ANS acuity across tasks. CONCLUSION: Results demonstrate developmental continuity between preschool years and adulthood in the neural basis of the ANS.

The influence of imagery vividness and internally-directed attention on the neural mechanisms underlying the encoding of visual mental images into episodic memory.

Attention can be directed externally toward sensory information or internally toward self-generated information. Using electroencephalography (EEG), we investigated the attentional processes underlying the formation and encoding of self-generated mental images into episodic memory. Participants viewed flickering words referring to common objects and were tasked with forming visual mental images of the objects and rating their vividness. Subsequent memory for the presented object words was assessed using an old-new recognition task. Internally-directed attention during image generation was indexed as a reduction in steady-state visual evoked potentials (SSVEPs), oscillatory EEG responses at the frequency of a flickering stimulus. The results yielded 3 main findings. First, SSVEP power driven by the flickering word stimuli decreased as subjects directed attention internally to form the corresponding mental image. Second, SSVEP power returned to pre-imagery baseline more slowly for low- than high-vividness later remembered items, suggesting that longer internally-directed attention is required to generate subsequently remembered low-vividness images. Finally, the event-related-potential difference due to memory was more sustained for subsequently remembered low- versus high-vividness items, suggesting that additional conceptual processing may have been needed to remember the low-vividness visual images. Taken together, the results clarify the neural mechanisms supporting the encoding of self-generated information.

Prestimulus oscillatory brain activity interacts with evoked recurrent processing to facilitate conscious visual perception.

We investigated whether prestimulus alpha-band oscillatory activity and stimulus-elicited recurrent processing interact to facilitate conscious visual perception. Participants tried to perceive a visual stimulus that was perceptually masked through object substitution masking (OSM). We showed that attenuated prestimulus alpha power was associated with greater negative-polarity stimulus-evoked ERP activity that resembled the visual awareness negativity (VAN), previously argued to reflect recurrent processing related to conscious perception. This effect, however, was not associated with better perception. Instead, when prestimulus alpha power was elevated, a preferred prestimulus alpha phase was associated with a greater VAN-like negativity, which was then associated with better cue perception. Cue perception was worse when prestimulus alpha power was elevated but the stimulus occurred at a nonoptimal prestimulus alpha phase and the VAN-like negativity was low. Our findings suggest that prestimulus alpha activity at a specific phase enables temporally selective recurrent processing that facilitates conscious perception in OSM.

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.

Reward magnitude enhances early attentional processing of auditory stimuli.

Reward associations are known to shape the brain's processing of visual stimuli, but relatively less is known about how reward associations impact the processing of auditory stimuli. We leveraged the high-temporal resolution of electroencephalography (EEG) and event-related potentials (ERPs) to investigate the influence of low- and high-magnitude stimulus-reward associations in an auditory oddball task. We associated fast, correct detection of certain auditory target stimuli with larger monetary rewards, and other auditory targets with smaller rewards. We found enhanced attentional processing of the more highly rewarded target stimuli, as evidenced by faster behavioral detection of those stimuli compared with lower-rewarded stimuli. Neurally, higher-reward associations enhanced the early sensory processing of auditory targets. Targets associated with higher-magnitude rewards had higher amplitude N1 and mismatch negativity (MMN) ERP components than targets associated with lower-magnitude rewards. Reward did not impact the latency of these early components. Higher-reward magnitude also decreased the latency and increased the amplitude of the longer-latency P3 component, suggesting that reward also can enhance the final processing stages of auditory target stimuli. These results provide insight into how the sensory and attentional neural processing of auditory stimuli is modulated by stimulus-reward associations and the magnitude of those associations, with higher-magnitude reward associations yielding enhanced auditory processing at both early and late stages compared with lower-magnitude reward associations.

Electroencephalogram-Based Complexity Measures as Predictors of Post-operative Neurocognitive Dysfunction.

Physiologic signals such as the electroencephalogram (EEG) demonstrate irregular behaviors due to the interaction of multiple control processes operating over different time scales. The complexity of this behavior can be quantified using multi-scale entropy (MSE). High physiologic complexity denotes health, and a loss of complexity can predict adverse outcomes. Since postoperative delirium is particularly hard to predict, we investigated whether the complexity of preoperative and intraoperative frontal EEG signals could predict postoperative delirium and its endophenotype, inattention. To calculate MSE, the sample entropy of EEG recordings was computed at different time scales, then plotted against scale; complexity is the total area under the curve. MSE of frontal EEG recordings was computed in 50 patients ≥ age 60 before and during surgery. Average MSE was higher intra-operatively than pre-operatively (p = 0.0003). However, intraoperative EEG MSE was lower than preoperative MSE at smaller scales, but higher at larger scales (interaction p < 0.001), creating a crossover point where, by definition, preoperative, and intraoperative MSE curves met. Overall, EEG complexity was not associated with delirium or attention. In 42/50 patients with single crossover points, the scale at which the intraoperative and preoperative entropy curves crossed showed an inverse relationship with delirium-severity score change (Spearman ρ = -0.31, p = 0.054). Thus, average EEG complexity increases intra-operatively in older adults, but is scale dependent. The scale at which preoperative and intraoperative complexity is equal (i.e., the crossover point) may predict delirium. Future studies should assess whether the crossover point represents changes in neural control mechanisms that predispose patients to postoperative delirium.

The Impact of Error-Consequence Severity on Cue Processing in Importance-Biased Prospective Memory.

Prospective memory (PM) enables people to remember to complete important tasks in the future. Failing to do so can result in consequences of varying severity. Here, we investigated how PM error-consequence severity impacts the neural processing of relevant cues for triggering PM and the ramification of that processing on the associated prospective task performance. Participants role-played a cafeteria worker serving lunches to fictitious students and had to remember to deliver an alternative lunch to students (as PM cues) who would otherwise experience a moderate or severe aversive reaction. Scalp-recorded, event-related potential (ERP) measures showed that the early-latency frontal positivity, reflecting the perception-based neural responses to previously learned stimuli, did not differ between the severe versus moderate PM cues. In contrast, the longer-latency parietal positivity, thought to reflect full PM cue recognition and post-retrieval processes, was elicited earlier by the severe than the moderate PM cues. This faster instantiation of the parietal positivity to the severe-consequence PM cues was then followed by faster and more accurate behavioral responses. These findings indicate how the relative importance of a PM can be neurally instantiated in the form of enhanced and faster PM-cue recognition and processing and culminate into better PM.

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.

Context-Dependent Modulation of Early Visual Cortical Responses to Numerical and Nonnumerical Magnitudes.

Whether and how the brain encodes discrete numerical magnitude differently from continuous nonnumerical magnitude is hotly debated. In a previous set of studies, we orthogonally varied numerical (numerosity) and nonnumerical (size and spacing) dimensions of dot arrays and demonstrated a strong modulation of early visual evoked potentials (VEPs) by numerosity and not by nonnumerical dimensions. Although very little is known about the brain's response to systematic changes in continuous dimensions of a dot array, some authors intuit that the visual processing stream must be more sensitive to continuous magnitude information than to numerosity. To address this possibility, we measured VEPs of participants viewing dot arrays that changed exclusively in one nonnumerical magnitude dimension at a time (size or spacing) while holding numerosity constant and compared this to a condition where numerosity was changed while holding size and spacing constant. We found reliable but small neural sensitivity to exclusive changes in size and spacing; however, exclusively changing numerosity elicited a much more robust modulation of the VEPs. Together with previous work, these findings suggest that sensitivity to magnitude dimensions in early visual cortex is context dependent: The brain is moderately sensitive to changes in size and spacing when numerosity is held constant, but sensitivity to these continuous variables diminishes to a negligible level when numerosity is allowed to vary at the same time. Neurophysiological explanations for the encoding and context dependency of numerical and nonnumerical magnitudes are proposed within the framework of neuronal normalization.

Disruptions of Sustained Spatial Attention Can Be Resistant to the Distractor's Prior Reward Associations.

Attention can be involuntarily biased toward reward-associated distractors (value-driven attentional capture, VDAC). Yet past work has primarily demonstrated this distraction phenomenon during a particular set of circumstances: transient attentional orienting to potentially relevant stimuli occurring in our visual environment. Consequently, it is not well-understood if reward-based attentional capture can occur under other circumstances, such as during sustained visuospatial attention. Using EEG, we investigated whether associating transient distractors with reward value would increase their distractibility and lead to greater decrements in concurrent sustained spatial attention directed elsewhere. Human participants learned to associate three differently colored, laterally presented squares with rewards of varying magnitude (zero, small, and large). These colored squares were then periodically reintroduced as distractors at the same lateral locations during a demanding sustained-attention rapid-serial-visual-presentation (RSVP) task at the midline. Behavioral and neural evidence indicated that participants had successfully learned and maintained the reward associations to the distractors. During the RSVP task, consistent with prior work, we found that the distractors generated dips in the instantaneous amplitude of the steady-state visual evoked potentials (SSVEPs) elicited by the midline RSVP stimuli, indicating that the distractors were indeed transiently disrupting sustained spatial attention. Contrary to our hypotheses, however, the magnitude of this dip did not differ by the magnitude of the distractor's reward associations. These results indicate that while sustained spatial attention can be impaired by the introduction of distractors at another location, the main distraction process is resistant to the distractors' reward associations, thus providing evidence of an important boundary condition to value-driven attentional capture.

Diminished Feedback Evaluation and Knowledge Updating Underlying Age-Related Differences in Choice Behavior During Feedback Learning.

In our daily lives, we continuously evaluate feedback information, update our knowledge, and adapt our behavior in order to reach desired goals. This ability to learn from feedback information, however, declines with age. Previous research has indicated that certain higher-level learning processes, such as feedback evaluation, integration of feedback information, and updating of knowledge, seem to be affected by age, and recent studies have shown how the adaption of choice behavior following feedback can differ with age. The neural mechanisms underlying this age-related change in choice behavior during learning, however, remain unclear. The aim of this study is therefore to investigate the relation between learning-related neural processes and choice behavior during feedback learning in two age groups. Behavioral and fMRI data were collected, while a group of young (age 18-30) and older (age 60-75) adults performed a probabilistic learning task consisting of 10 blocks of 20 trials each. On each trial, the participants chose between a house and a face, after which they received visual feedback (loss vs. gain). In each block, either the house or the face image had a higher probability of yielding a reward (62.5 vs. 37.5%). Participants were instructed to try to maximize their gains. Our results showed that less successful learning in older adults, as indicated by a lower learning rate, corresponded with a higher tendency to switch to the other stimulus option, and with a reduced adaptation of this switch choice behavior following positive feedback. At the neural level, activation following positive and negative feedback was found to be less distinctive in the older adults, due to a smaller feedback-evaluation response to positive feedback in this group. Furthermore, whereas young adults displayed increased levels of knowledge updating prior to adapting choice behavior, we did not find this effect in older adults. Together, our results suggest that diminished learning performance with age corresponds with diminished evaluation of positive feedback and reduced knowledge updating related to changes in choice behavior, indicating how such differences in feedback processing at the trial level in older adults might lead to reduced learning performance across trials.

Caffeine Boosts Preparatory Attention for Reward-related Stimulus Information.

The intake of caffeine and the prospect of reward have both been associated with increased arousal, enhanced attention, and improved behavioral performance on cognitive tasks, but how they interact to exert these effects is not well understood. To investigate this question, we had participants engage in a two-session cued-reward cognitive task while we recorded their electrical brain activity using scalp electroencephalography. The cue indicated whether monetary reward could be received for fast and accurate responses to a color-word Stroop stimulus that followed. Before each session, participants ingested decaffeinated coffee with either caffeine (3-mg/kg bodyweight) or placebo (3-mg/kg bodyweight lactose). The behavioral results showed that both caffeine and reward-prospect improved response accuracy and speed. In the brain, reward-prospect resulted in an enlarged frontocentral slow wave (contingent negative variation, or CNV) and reduced posterior alpha power (indicating increased cortical activity) before stimulus presentation, both neural markers for preparatory attention. Moreover, the CNV enhancement for reward-prospect trials was considerably more pronounced in the caffeine condition as compared to the placebo condition. These interactive neural enhancements due to caffeine and reward-prospect were mainly visible in preparatory attention activity triggered by the cue (CNV). In addition, some interactive neural enhancements in the processing of the Stroop target stimulus that followed were also observed. The results suggest that caffeine facilitates the neural processes underlying attentional preparation and stimulus processing, especially for task-relevant information.

The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. OBJECTIVE: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. METHODS: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. CONCLUSION: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

Physical Salience and Value-Driven Salience Operate through Different Neural Mechanisms to Enhance Attentional Selection.

Previous studies have indicated that both increased physical salience and increased reward-value salience of a target improve behavioral measures of attentional selection. It is unclear, however, whether these two forms of salience interact with attentional networks through similar or different neural mechanisms, and what such differences might be. We examined this question by separately manipulating both the value-driven and physical salience of targets in a visual search task while recording response times (RTs) and event-related potentials, focusing on the attentional-orienting-sensitive N2pc event-related potential component. Human participants of both sexes searched arrays for targets of either a high-physical-salience color or one of two low-physical-salience colors across three experimental phases. The first phase ("baseline") offered no rewards. RT and N2pc latencies were shorter for high-physical-salience targets, indicating faster attentional orienting. In the second phase ("equal-reward"), a low monetary reward was given for fast correct responses for all target types. This reward context improved overall performance, similarly shortening RTs and enhancing N2pc amplitudes for all target types, but with no change in N2pc latencies. In the third phase ("selective-reward"), the reward rate was made selectively higher for one of the two low-physical-salience colors, resulting in their RTs becoming as fast as the high-physical-salience targets. Despite the equally fast RTs, the N2pc's for these low-physical-salience, high-value targets remained later than for high-physical-salience targets, instead eliciting significantly larger N2pc's. These results suggest that enhanced physical salience leads to faster attentional orienting, but value-driven salience to stronger attentional orienting, underscoring the utilization of different underlying mechanisms.SIGNIFICANCE STATEMENT Associating relevant target stimuli with reward value can enhance their salience, facilitating their attentional selection. This value-driven salience improves behavioral performance, similar to the effects of physical salience. Recent theories, however, suggest that these forms of salience are intrinsically different, although the neural mechanisms underlying any such differences remain unclear. This study addressed this issue by manipulating the physical and value-related salience of targets in a visual search task, comparing their effects on several attention-sensitive neural-activity measures. Our findings show that, whereas physical salience accelerates the speed of attentional selection, value-driven salience selectively enhances its strength. These findings shed new insights into the theoretical and neural underpinnings of value-driven salience and its effects on attention and behavior.