Specialized late cingulo-opercular network activation elucidates the mechanisms underlying decisions about ambiguity.

Cortical task control networks, including the cingulo-opercular (CO) network play a key role in decision-making across a variety of functional domains. In particular, the CO network functions in a performance reporting capacity that supports successful task performance, especially in response to errors and ambiguity. In two studies testing the contribution of the CO network to ambiguity processing, we presented a valence bias task in which masked clearly and ambiguously valenced emotional expressions were slowly revealed over several seconds. This slow reveal task design provides a window into the decision-making mechanisms as they unfold over the course of a trial. In the main study, the slow reveal task was administered to 32 young adults in the fMRI environment and BOLD time courses were extracted from regions of interest in three control networks. In a follow-up study, the task was administered to a larger, online sample (n = 81) using a more extended slow reveal design with additional unmasking frames. Positive judgments of surprised faces were uniquely accompanied by slower response times and strong, late activation in the CO network. These results support the initial negativity hypothesis, which posits that the default response to ambiguity is negative and positive judgments are associated with a more effortful controlled process, and additionally suggest that this controlled process is mediated by the CO network. Moreover, ambiguous trials were characterized by a second CO response at the end of the trial, firmly placing CO function late in the decision-making process.

In search of a human self-regulation system.

The capacity for self-regulation allows people to control their thoughts, behaviors, emotions, and desires. In spite of this impressive ability, failures of self-regulation are common and contribute to numerous societal problems, from obesity to drug addiction. Such failures frequently occur following exposure to highly tempting cues, during negative moods, or after self-regulatory resources have been depleted. Here we review the available neuroscientific evidence regarding self-regulation and its failures. At its core, self-regulation involves a critical balance between the strength of an impulse and an individual's ability to inhibit the desired behavior. Although neuroimaging and patient studies provide consistent evidence regarding the reward aspects of impulses and desires, the neural mechanisms that underlie the capacity for control have eluded consensus, with various executive control regions implicated in different studies. We outline the necessary properties for a self-regulation control system and suggest that the use of resting-state functional connectivity analyses may be useful for understanding how people regulate their behavior and why they sometimes fail in their attempts.

Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

BACKGROUND: Prior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal-striatal-thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset. METHODS: In this study, unmedicated female patients with OCD (ages 8-21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN. RESULTS: Functional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other. CONCLUSIONS: Our findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

Hypoconnectivity within the cingulo-opercular network in patients with mild cognitive impairment in Chinese communities.

INTRODUCTION: At rest, the brain's higher cognitive systems engage in correlated activity patterns, forming networks. With mild cognitive impairment (MCI), it is essential to understand how functional connectivity within and between resting-state networks changes. This study used resting-state functional connectivity to identify significant differences within and between the cingulo-opercular network (CON) and default mode network (DMN). METHODS: We assessed cognitive function in patients using the Chinese version of the Alzheimer's disease assessment scale-Cognitive subscale (ADAS-Cog). A group of MCI subjects (ages 60-83 years, n = 45) was compared to age-matched healthy controls (n = 70). Resting-state functional connectivity was used to determine functional connectivity strength within and between the CON and DMN. RESULTS: Compared to healthy controls, the MCI group showed significantly lower functional connectivity within the CON (F = 10.76, df = 1, p = 0.001, FDR adjusted p = 0.003). Additionally, the MCI group displayed no distinct differences in functional connectivity within DMN (F = 0.162, df = 1, p = 0.688, FDR adjusted p = 0.688) and between CON and DMN (F = 2.270, df = 1, p = 0.135, FDR adjusted p = 0.262). Moreover, we found no correlation between ADAS-Cog and within- or between-connectivity metrics among subjects with MCI. CONCLUSIONS: Our findings indicate that specific patterns of hypoconnectivity within CON circuitry may characterize MCI relative to healthy controls. This work improves our understanding of network dysfunction underlying MCI and could inform more targeted treatment.

A pilot randomized sham controlled trial of bilateral iTBS for depression and executive function in older adults.

INTRODUCTION: Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD. METHODS: Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target. RESULTS: A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post-intervention change in mean Montgomery-Asberg-depression scores was not different between iTBS or sham, p = 0.33. No significant group-by-time interaction for Montgomery-Asberg Depression rating scale scores (F 3, 44  = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F 1, 14  = 0.02, p = 0.88), Dimensional-change-card-sort scores F 1, 14  = 0.25, p = 0.63, and working memory scores (F 1, 14  = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F 1, 14  = 0.36, p = 0.56). No significant difference in the effect-of-time between the two groups was found on FC within the Cingulo-opercular-network (F 1, 14  = 0, p = 0.98). CONCLUSION: Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement.

Exploring the Lifelong Changes of Interaction between Cingulo-Opercular Network and Other Cognitive Control Related Functional Networks Based on Multiple Connectivity Indices.

BACKGROUND: The cingulo-opercular network (CON) has been proposed to play a central role in cognitive control. The lifetime change mechanism of its integrity and interaction with other cognitive control-related functional networks (CCRNs) is closely associated with developing cognitive control behaviors but needs further elucidation. METHODS: The resting-state functional magnetic resonance imaging data were recorded from 207 subjects, who were divided into three age groups: age 4-20, 21-59, and 60-85 years old. For each group, multiple indices (cross-correlation, total independence, and Granger causality) within CON and between CON and other cognitive control-related functional networks (dorsal attention network, DAN; central executive network, CEN; default mode network, DMN) were calculated and correlated with age to yield maps that delineated the changing pattern of CON-related interaction. RESULTS: We found three main results. (1) The connectivity indices within the CON and between CON and the other three CCRNs showed significant enhancement from childhood to early adulthood (age 4-20 years), (2) mild attenuation within CON from early adulthood to middle age (age 21-59 years), and (3) significant attenuation within CON and between CON and DMN in the elder group (age 60-85 years). CONCLUSIONS: The results indicated the prominently increased integrity of within-CON and CON-CCRNs communication, mildly weakened within-CON communication, and significantly attenuated within-CON and CON-DMN communication, characterizing distinct changing patterns of CON-interaction at three different stages that covered a life-long span.

Modular reconfiguration of an auditory control brain network supports adaptive listening behavior.

Speech comprehension in noisy, multitalker situations poses a challenge. Successful behavioral adaptation to a listening challenge often requires stronger engagement of auditory spatial attention and context-dependent semantic predictions. Human listeners differ substantially in the degree to which they adapt behaviorally and can listen successfully under such circumstances. How cortical networks embody this adaptation, particularly at the individual level, is currently unknown. We here explain this adaptation from reconfiguration of brain networks for a challenging listening task (i.e., a linguistic variant of the Posner paradigm with concurrent speech) in an age-varying sample of n = 49 healthy adults undergoing resting-state and task fMRI. We here provide evidence for the hypothesis that more successful listeners exhibit stronger task-specific reconfiguration (hence, better adaptation) of brain networks. From rest to task, brain networks become reconfigured toward more localized cortical processing characterized by higher topological segregation. This reconfiguration is dominated by the functional division of an auditory and a cingulo-opercular module and the emergence of a conjoined auditory and ventral attention module along bilateral middle and posterior temporal cortices. Supporting our hypothesis, the degree to which modularity of this frontotemporal auditory control network is increased relative to resting state predicts individuals' listening success in states of divided and selective attention. Our findings elucidate how fine-tuned cortical communication dynamics shape selection and comprehension of speech. Our results highlight modularity of the auditory control network as a key organizational principle in cortical implementation of auditory spatial attention in challenging listening situations.

Visual processing speed is linked to functional connectivity between right frontoparietal and visual networks.

Visual information processing requires an efficient visual attention system. The neural theory of visual attention (TVA) proposes that visual processing speed depends on the coordinated activity between frontoparietal and occipital brain areas. Previous research has shown that the coordinated activity between (i.e., functional connectivity and "inter-FC") cingulo-opercular (COn) and right-frontoparietal (RFPn) networks is linked to visual processing speed. However, how inter-FC of COn and RFPn with visual networks links to visual processing speed has not been directly addressed yet. Forty-eight healthy adult participants (27 females) underwent resting-state (rs-)fMRI and performed a whole-report psychophysical task. To obtain inter-FC, we analyzed the entire frequency range available in our rs-fMRI data (i.e., 0.01-0.4 Hz) to avoid discarding neural information. Following previous approaches, we analyzed the data across frequency bins (Hz): Slow-5 (0.01-0.027), Slow-4 (0.027-0.073), Slow-3 (0.073-0.198), and Slow-2 (0.198-0.4). We used the mathematical TVA framework to estimate an individual, latent-level visual processing speed parameter. We found that visual processing speed was negatively associated with inter-FC between RFPn and visual networks in Slow-5 and Slow-2, with no corresponding significant association for inter-FC between COn and visual networks. These results provide the first empirical evidence that links inter-FC between RFPn and visual networks with the visual processing speed parameter. These findings suggest that direct connectivity between occipital and right frontoparietal, but not frontoinsular, regions support visual processing speed.

Distinct and temporally associated neural mechanisms underlying concurrent, postsuccess, and posterror cognitive controls: Evidence from a stop-signal task.

Cognitive control is built upon the interactions of multiple brain regions. It is currently unclear whether the involved regions are temporally separable in relation to different cognitive processes and how these regions are temporally associated in relation to different task performances. Here, using stop-signal task data acquired from 119 healthy participants, we showed that concurrent and poststop cognitive controls were associated with temporally distinct but interrelated neural mechanisms. Specifically, concurrent cognitive control activated regions in the cingulo-opercular network (including the dorsal anterior cingulate cortex [dACC], insula, and thalamus), together with superior temporal gyrus, secondary motor areas, and visual cortex; while regions in the fronto-parietal network (including the lateral prefrontal cortex [lPFC] and inferior parietal lobule) and cerebellum were only activated during poststop cognitive control. The associations of activities between concurrent and poststop regions were dependent on task performance, with the most notable difference in the cerebellum. Importantly, while concurrent and poststop signals were significantly correlated during successful cognitive control, concurrent activations during erroneous trials were only correlated with posterror activations in the fronto-parietal network but not cerebellum. Instead, the cerebellar activation during posterror cognitive control was likely to be driven secondarily by posterror activation in the lPFC. Further, a dynamic causal modeling analysis demonstrated that postsuccess cognitive control was associated with inhibitory connectivity from the lPFC to cerebellum, while excitatory connectivity from the lPFC to cerebellum was present during posterror cognitive control. Overall, these findings suggest dissociable but temporally related neural mechanisms underlying concurrent, postsuccess, and posterror cognitive control processes in healthy individuals.

Age differences in functional network reconfiguration with working memory training.

Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task-related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default-mode network for younger adults, it enhanced efficiency within a task-specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default-mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between-network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age-related trajectories in functional network reorganization with WM training.

Neural modelling of the semantic predictability gain under challenging listening conditions.

When speech intelligibility is reduced, listeners exploit constraints posed by semantic context to facilitate comprehension. The left angular gyrus (AG) has been argued to drive this semantic predictability gain. Taking a network perspective, we ask how the connectivity within language-specific and domain-general networks flexibly adapts to the predictability and intelligibility of speech. During continuous functional magnetic resonance imaging (fMRI), participants repeated sentences, which varied in semantic predictability of the final word and in acoustic intelligibility. At the neural level, highly predictable sentences led to stronger activation of left-hemispheric semantic regions including subregions of the AG (PGa, PGp) and posterior middle temporal gyrus when speech became more intelligible. The behavioural predictability gain of single participants mapped onto the same regions but was complemented by increased activity in frontal and medial regions. Effective connectivity from PGa to PGp increased for more intelligible sentences. In contrast, inhibitory influence from pre-supplementary motor area to left insula was strongest when predictability and intelligibility of sentences were either lowest or highest. This interactive effect was negatively correlated with the behavioural predictability gain. Together, these results suggest that successful comprehension in noisy listening conditions relies on an interplay of semantic regions and concurrent inhibition of cognitive control regions when semantic cues are available.

Overt speech critically changes lateralization index and did not allow determination of hemispheric dominance for language: an fMRI study.

BACKGROUND: Pre-surgical mapping of language using functional MRI aimed principally to determine the dominant hemisphere. This mapping is currently performed using covert linguistic task in way to avoid motion artefacts potentially biasing the results. However, overt task is closer to natural speaking, allows a control on the performance of the task, and may be easier to perform for stressed patients and children. However, overt task, by activating phonological areas on both hemispheres and areas involved in pitch prosody control in the non-dominant hemisphere, is expected to modify the determination of the dominant hemisphere by the calculation of the lateralization index (LI). OBJECTIVE: Here, we analyzed the modifications in the LI and the interactions between cognitive networks during covert and overt speech task. METHODS: Thirty-three volunteers participated in this study, all but four were right-handed. They performed three functional sessions consisting of (1) covert and (2) overt generation of a short sentence semantically linked with an audibly presented word, from which we estimated the "Covert" and "Overt" contrasts, and a (3) resting-state session. The resting-state session was submitted to spatial independent component analysis to identify language network at rest (LANG), cingulo-opercular network (CO), and ventral attention network (VAN). The LI was calculated using the bootstrapping method. RESULTS: The LI of the LANG was the most left-lateralized (0.66 ± 0.38). The LI shifted from a moderate leftward lateralization for the Covert contrast (0.32 ± 0.38) to a right lateralization for the Overt contrast (- 0.13 ± 0.30). The LI significantly differed from each other. This rightward shift was due to the recruitment of right hemispheric temporal areas together with the nodes of the CO. CONCLUSION: Analyzing the overt speech by fMRI allowed improvement in the physiological knowledge regarding the coordinated activity of the intrinsic connectivity networks. However, the rightward shift of the LI in this condition did not provide the basic information on the hemispheric language dominance. Overt linguistic task cannot be recommended for clinical purpose when determining hemispheric dominance for language.

Alertness Training Increases Visual Processing Speed in Healthy Older Adults.

In this study, we investigated whether alertness training in healthy older adults increases visual processing speed (VPS) and whether functional connectivity in the cingulo-opercular network predicts training gain. Using the theory of visual attention, we derived quantitative estimates of VPS before and after training. In Study 1, 75 healthy older adults participated in alertness training, active-control training, or no training (n = 25 each). A significant Group × Session interaction indicated an increase in VPS in the alertness-training group but not in the control group, despite VPS not differing significantly between groups before training. In Study 2, 29 healthy older adults underwent resting-state functional MRI and then participated in alertness training. Pretraining functional connectivity in the cingulo-opercular network correlated with the individual training-induced change in VPS. In conclusion, results indicate that alertness training improves visual processing in older adults and that functional connectivity in the cingulo-opercular network provides a neural marker for predicting individual training gain.

Prestimulus Activity in the Cingulo-Opercular Network Predicts Memory for Naturalistic Episodic Experience.

Human memory is strongly influenced by brain states occurring before an event, yet we know little about the underlying mechanisms. We found that activity in the cingulo-opercular network (including bilateral anterior insula [aI] and anterior prefrontal cortex [aPFC]) seconds before an event begins can predict whether this event will subsequently be remembered. We then tested how activity in the cingulo-opercular network shapes memory performance. Our findings indicate that prestimulus cingulo-opercular activity affects memory performance by opposingly modulating subsequent activity in two sets of regions previously linked to encoding and retrieval of episodic information. Specifically, higher prestimulus cingulo-opercular activity was associated with a subsequent increase in activity in temporal regions previously linked to encoding and with a subsequent reduction in activity within a set of regions thought to play a role in retrieval and self-referential processing. Together, these findings suggest that prestimulus attentional states modulate memory for real-life events by enhancing encoding and possibly by dampening interference from competing memory substrates.

The functional hierarchy of the task-positive networks indicates a core control system of top-down regulation in visual attention.

The cingulo-opercular network (CON), dorsal attention network (DAN), and ventral attention network (VAN) are prominently activated during attention tasks. The function of these task-positive networks and their interplay mechanisms in attention is one of the central issues in understanding how the human brain manipulates attention to better adapt to the external environment. This study aimed to clarify the CON, DAN, and VAN's functional hierarchy by assessing causal interactions. Functional magnetic resonance imaging (fMRI) data from human participants performing a visual-spatial attention task and correlating Granger causal influences with behavioral performance revealed that CON exerts behavior-enhancing influences upon DAN and VAN, indicating a higher level of CON in top-down attention control. By contrast, the VAN exerts a behavior-degrading influence on CON, indicating external disruption of the CON's control set.

Transient and Sustained Control Mechanisms Supporting Novel Instructed Behavior.

The success of humans in novel environments is partially supported by our ability to implement new task procedures via instructions. This complex skill has been associated with the activity of control-related brain areas. Current models link fronto-parietal and cingulo-opercular networks with transient and sustained modes of cognitive control, based on observations during repetitive task settings or rest. The current study extends this dual model to novel instructed tasks. We employed a mixed design and an instruction-following task to extract phasic and tonic brain signals associated with the encoding and implementation of novel verbal rules. We also performed a representation similarity analysis to capture consistency in task-set encoding within trial epochs. Our findings show that both networks are involved while following novel instructions: transiently, during the implementation of the instruction, and in a sustained fashion, across novel trials blocks. Moreover, the multivariate results showed that task representations in the cingulo-opercular network were more stable than in the fronto-parietal one. Our data extend the dual model of cognitive control to novel demanding situations, highlighting the high flexibility of control-related regions in adopting different temporal profiles.

The neural architecture of executive functions is established by middle childhood.

Executive functions (EFs) are regulatory cognitive processes that support goal-directed thoughts and behaviors and that involve two primary networks of functional brain activity in adulthood: the fronto-parietal and cingulo-opercular networks. The current study assessed whether the same networks identified in adulthood underlie child EFs. Using task-based fMRI data from a diverse sample of N = 117 children and early adolescents (M age = 10.17 years), we assessed the extent to which neural activity was shared across switching, updating, and inhibition domains, and whether these patterns were qualitatively consistent with adult EF-related activity. Brain regions that were consistently engaged across switching, updating, and inhibition tasks closely corresponded to the cingulo-opercular and fronto-parietal networks identified in studies of adults. Isolating brain activity during more demanding task periods highlighted contributions of the dorsal anterior cingulate and anterior insular regions of the cingulo-opercular network. Results were independent of age and time-on-task effects. These results indicate that the two core brain networks that support EFs are in place by middle childhood, in agreement with resting-state findings of adultlike brain network organization. Improvement in EFs from middle childhood to adulthood, therefore, are likely due to quantitative changes in activity within these networks, rather than qualitative changes in the organization of the networks themselves. Improved knowledge of how the brain's functional organization supports EF in childhood has critical implications for understanding the maturation of cognitive abilities.

The strength of alpha and gamma oscillations predicts behavioral switch costs.

Cognitive flexibility is often examined using task-switch paradigms, whereby individuals either switch between tasks or repeat the same task on successive trials. The behavioral costs of switching in terms of accuracy and reaction time are well-known, but the oscillatory dynamics underlying such costs are poorly understood. Herein, we examined 25 healthy adults who performed a task-switching paradigm during magnetoencephalography (MEG). All MEG data were transformed into the time-frequency domain and significant oscillatory responses were imaged separately per condition (i.e., switch, repeat) using a beamformer. To determine the impact of task-switching on the neural dynamics, the resulting images were examined using paired-samples t-tests. Whole-brain correlations were also computed using the switch-related difference images (switch - repeat) and the switch-related behavioral data (i.e., switch costs). Our key results indicated stronger decreases in alpha and beta activity, and greater increases in gamma activity in nodes of the cingulo-opercular and fronto-parietal networks during switch relative to repeat trials. In addition, behavioral switch costs were positively correlated with switch-related differences in right frontal and inferior parietal alpha activity, and negatively correlated with switch effects in anterior cingulate and right temporoparietal gamma activity. In other words, participants who had a greater decrease in alpha or increase in gamma in these respective regions had smaller behavioral switch costs, which suggests that these oscillations are critical to supporting cognitive flexibility. In sum, we provide novel data linking switch effects and gamma oscillations, and employed a whole-brain approach to directly link switch-related oscillatory differences with switch-related performance differences.

Phasic alerting effects on visual processing speed are associated with intrinsic functional connectivity in the cingulo-opercular network.

Phasic alertness refers to short-lived increases in the brain's "state of readiness", and thus to optimized performance following warning cues. Parametric modelling of whole report task performance based on the computational theory of visual attention (TVA) has demonstrated that visual processing speed is increased in such cue compared to no-cue conditions. Furthermore, with respect to the underlying neural mechanisms, individual visual processing speed has been related to intrinsic functional connectivity (iFC) within the cingulo-opercular network, suggesting that this network's iFC is relevant for the tonic maintenance of an appropriate readiness or alertness state. In the present study, we asked whether iFC in the cingulo-opercular network is also related to the individual ability to actively profit from warning cues, i.e. to the degree of phasic alerting. We obtained resting-state functional magnetic resonance imaging (rs-fMRI) data from 32 healthy young participants and combined an independent component analysis of rs-fMRI time courses and dual regression approach to determine iFC in the cingulo-opercular network. In a separate behavioural testing session, we parametrically assessed the effects of auditory phasic alerting cues on visual processing speed in a TVA-based whole report paradigm. A voxel-wise multiple regression revealed that higher individual phasic alerting effects on visual processing speed were significantly associated with lower iFC in the cingulo-opercular network, with a peak in the left superior orbital gyrus. As phasic alertness was neither related to iFC in other attention-relevant, auditory, or visual networks nor associated with any inter-network connectivity pattern, the results suggest that the individual profit in visual processing speed gained from phasic alerting is primarily associated with iFC in the cingulo-opercular network.

Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control.

The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N = 1586, behavioral total N = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4ß2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence p = 1.33 * 10-5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities.SIGNIFICANCE STATEMENT The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes and is dysregulated in several neuropsychiatric disorders. Despite this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show the impact of a common polymorphism of the high-affinity nicotinic receptor α4ß2 that is consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance and higher behavioral alertness performance than both homozygous groups. This gene-brain-behavior relationship informs about the biological basis of interindividual differences in cognitive control.