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BACKGROUND/OBJECTIVES: This study aimed to investigate the acute effects of a single session of a VR exergame (Beat Saber) and a VR nature video (Ireland 4K) on attentional performance, using the Flanker and Attentional Blink (AB) tasks. The objective was to assess whether these VR interventions could enhance attentional control, as measured by improvements in response times and accuracy. METHODS: A total of 39 psychology students, aged 19-25, were randomly assigned to one of three groups: VR exergame, VR nature video, or control. Participants completed the Flanker and AB tasks before and after the intervention. A repeated measures design was employed to analyze changes in response times and accuracy across pre- and post-test sessions. RESULTS: The study revealed significant improvements in response times and accuracy across all groups in the post-test measures, indicating a strong training effect. In the AB task, shorter stimulus onset asynchrony (SOA) led to decreased accuracy and slower response times, emphasizing the difficulty in processing closely spaced targets. The interaction between Type and Group in response times for target stimuli suggested that the intervention types differentially influenced processing speed in specific conditions. CONCLUSIONS: The findings suggest that while brief VR interventions did not produce significant differences between groups, the training effect observed highlights the influence of task-specific factors such as SOA and target presence. Further research is needed to explore whether longer or repeated VR sessions, as well as the optimization of task-specific parameters, might lead to more pronounced cognitive benefits.
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The episodic flanker task is an episodic version of the Eriksen and Eriksen (Perception & Psychophysics, 16 (1), 143-149, 1974) perceptual flanker task, showing the same compatibility and distance effects. Subjects are presented with a list followed by a probe display in which one item is cued. The task, to indicate whether the probed letter appeared in the same position in the memory list, requires focusing attention on a single item in memory. The probe display contains flanking items to be ignored. They are same as the memory list or different. Same flankers are compatible with "yes" responses and incompatible with "no" responses. Different flankers are incompatible with "yes" responses and compatible with "no" responses. Previously, we presented multiple flankers in the probe, allowing a global matching strategy. Here, we report two episodic flanker experiments with just one flanker in the probe to encourage focusing sharply on the target. We found flanker compatibility effects in both experiments when a single flanker appeared immediately adjacent to the target. Experiment 2 varied the distance between the flanker and the target in the probe and the memory list and found the compatibility effect in response time only when the flanker was immediately adjacent to the target in both the probe and the memory list. The effect in accuracy also appeared when the flanker was two positions away in both the probe and the memory list. These results show that attention is focused sharply on elements of a memory structure during retrieval, suggesting that memory retrieval is perceptual attention turned inward.
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Perception of color as a task-relevant stimulus can affect cognition and behavior in the flanker task; however, it remains unclear whether it has the same impact when it is a task-irrelevant stimulus dimension. To this end, we applied four-letter flanker tasks with or without colored (red/blue) to 23 healthy young adults, while recording the event-related potentials (ERPs) and behavioral performance. The flanker task included four kinds of color types: non-color letter (NC), all color letter (AC), flanker color letter (FC), and target color letter (TC), each flanker task included congruent and incongruent conditions. The behavioral data demonstrated the classic conflict effect across all color types of flanker tasks in both reaction times (RTs) and accuracy, the significant interaction and main effect of color type factors were only observed in accuracy. The ERP results showed significant interaction between conflict factor (congruent, incongruent) and color type (NC, AC, FC, and TC), and the color type factor enhanced the fronto-central P2 (180-200 ms), descended the fronto-centro-parietal N2b (260-320 ms), and increased the fronto-central P3b (360-520 ms). The fronto-central P2 and the fronto-central P3b were larger for TC than NC, AC, and FC in the congruent condition, while the fronto-central P3b was smaller for NC than AC, FC, and TC in the incongruent condition. Furthermore, the fronto-centro-parietal N2b was decreased successively in NC, AC, FC, and TC in both congruent and incongruent conditions. Overall, our findings suggested that the task-irrelevant stimuli dimension of color can capture some attentional resources and is affected by the location of color (target/flanker) and the type of task trial (congruent/incongruent) in the flanker task.
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Percepción de Color , Electroencefalografía , Potenciales Evocados , Tiempo de Reacción , Humanos , Masculino , Percepción de Color/fisiología , Femenino , Adulto Joven , Tiempo de Reacción/fisiología , Potenciales Evocados/fisiología , Adulto , Estimulación Luminosa/métodos , Desempeño Psicomotor/fisiología , Conflicto Psicológico , Encéfalo/fisiologíaRESUMEN
Hoarding disorder (HD) and obsessive-compulsive disorder (OCD) are highly comorbid and genetically related, but their similarities and differences at the neural level are not well characterized. The present study examined the time-frequency information contained in stimulus-related EEG data as participants worked on a visual flanker task. Three groups were included: participants diagnosed with HD (N = 33), OCD (N = 26), and healthy controls (N = 35). Permutation-controlled mass-univariate analyses found no differences between groups in terms of the magnitude of the oscillatory responses. Differences between groups were found selectively for phase-based measures (phase-locking across trials and across sensors) in time ranges well after those consistent with initial visuocortical processes, in the alpha (10 Hz) as well as theta and beta frequency bands, centered around 6 Hz and 15 Hz, respectively. Specifically, HD showed attenuated phase locking in theta and alpha compared to OCD and HC, while OCD showed heightened inter-site phase locking in alpha/beta. Including age as a covariate attenuated, but did not eliminate, the group differences. These findings point to signatures of cortical dynamics and cortical communication task processing that are unique to HD, and which are specifically present during higher-order visual cognition such as stimulus-response mapping, response selection, and action monitoring.
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Electroencefalografía , Trastorno de Acumulación , Trastorno Obsesivo Compulsivo , Humanos , Masculino , Trastorno Obsesivo Compulsivo/fisiopatología , Femenino , Adulto , Trastorno de Acumulación/fisiopatología , Trastorno de Acumulación/diagnóstico , Persona de Mediana Edad , Encéfalo/fisiopatología , Ondas Encefálicas/fisiología , Adulto Joven , Estimulación Luminosa/métodos , Mapeo EncefálicoRESUMEN
In psychophysiology, an interesting question is how to estimate the reliability of event-related potentials collected by means of the Eriksen Flanker Task or similar tests. A special problem presents itself if the data represent neurological reactions that are associated with some responses (in case of the Flanker Task, responding incorrectly on a trial) but not others (like when providing a correct response), inherently resulting in unequal numbers of observations per subject. The general trend in reliability research here is to use generalizability theory and Bayesian estimation. We show that a new approach based on classical test theory and frequentist estimation can do the job as well and in a simpler way, and even provides additional insight to matters that were unsolved in the generalizability method approach. One of our contributions is the definition of a single, overall reliability coefficient for an entire group of subjects with unequal numbers of observations. Both methods have slightly different objectives. We argue in favor of the classical approach but without rejecting the generalizability approach.
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In the flanker task, the behavioral performance for incompatible stimuli is worse in the mostly compatible (rare) condition than in the equiprobable condition. Furthermore, incompatible stimuli evoke visual mismatch negativity (VMMN) when comparing the rare and equiprobable conditions. Compatible and incompatible stimuli differ in terms of their shape and type. This study aimed to examine whether VMMN evoked by rare incompatible stimuli were associated with the shape or type of the stimulus. In a modified version of the flanker task, stimuli were manipulated by two shapes (typical or peculiar) and two types (compatible or incompatible): typical compatible stimuli (< < < < < and > > > > >), typical incompatible stimuli (> > < > > and < < > < <), peculiar compatible stimuli (+ < < < + and + > > > +), and peculiar incompatible stimuli (+ > < > + and + < > < +). In the rare condition, typical incompatible, peculiar compatible, and peculiar incompatible stimuli were presented with a probability of 10%, whereas all the stimuli were presented equally in the equiprobable condition. Right posterior negativity from 200 to 250 ms was significantly more negative in the rare condition than in the equiprobable condition for typical and peculiar incompatible stimuli; however, this difference was not observed for peculiar compatible stimuli. VMMN was significantly more negative for typical and peculiar incompatible stimuli than for peculiar compatible stimuli, and was not significantly different between typical and peculiar incompatible stimuli. These findings suggest that VMMN for incompatible stimuli is associated with the type rather than the shape of the stimulus.
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Electroencefalografía , Estimulación Luminosa , Tiempo de Reacción , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiología , Potenciales Evocados Visuales/fisiología , Percepción Visual/fisiología , Desempeño Psicomotor/fisiologíaRESUMEN
The error-related negativity (ERN) and error positivity (Pe) are components of the event-related potential following an error that are potential mechanistic biomarkers of obsessive-compulsive disorder (OCD). The study examined the ERN, Pe, flanker task accuracy, and clinical measures in 105 OCD cases and 105 matched healthy controls (HC) ages 8-18 years. Higher flanker task accuracy in all participants was associated with an increased ERN amplitude and increased difference between Pe and correct positivity amplitudes (ΔPe). Compared to HC, OCD cases had an increased ERN but decreased ΔPe and flanker task accuracy. Those differences were also significant in tic-related and non-tic-related OCD cases compared to HC. A lower ΔPe was associated in cases with an earlier age at OCD symptom onset. The results support the hypothesis that OCD involves defects in an error monitoring system and suggest a reduced ΔPe may compromise error signaling and cause uncertainty about the correctness of a response.
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Autistic people may have a less focused spotlight of spatial selective attention than non-autistic people, meaning that distracting stimuli are less effectively suppressed. Previous studies using the flanker task have supported this suggestion with observations of increased congruency effects in autistic participants. However, findings across studies have been mixed, mainly based on research in children and on response time measures, which may be influenced by differences in response strategy between autistic and non-autistic people rather than differences in selective attention. In this pre-registered study, 153 autistic and 147 non-autistic adults completed an online flanker task. The aims of this study were to test whether increased congruency effects replicate in autistic adults and to extend previous work by fitting a computational model of spatial selective attention on the flanker task to the data. Congruency effects were increased in the autistic group. The modelling revealed that the interference time from the foils was increased in the autistic group. This suggests that the activation of the foils was increased, meaning suppression was less effective for autistic participants. There were also differences in non-interference parameters between the groups. The estimate of response caution was increased in the autistic group and the estimate of perceptual efficiency was decreased. Together these findings suggest inefficient suppression, response strategy and perceptual processing all contribute to differences in performance on the flanker task between autistic and non-autistic people.
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Several studies have shown that parafoveal processing is essential in reading development. In this study, we explore the effect of transposing and substituting inner and outer letters in a flanker lexical decision task administered to 78 children and 65 adults. The results show a significant interaction between the Group factor and the Flanker factor, suggesting differences in the effects of flankers for children and adults. In the case of adults, transposed and substituted letters generated benefit of the same magnitude in comparison with the unrelated condition, but of lesser magnitude than the Identity condition. In the case of children, the results show facilitation for the transposed conditions of the same magnitude as the Identity condition. However, the substitution conditions failed to generate any benefit in comparison with the unrelated condition. The results for the adults are in line with the predictions of the open bigram model, whereas the results for the children are explained through a developmental perspective of the dual-route architecture and open bigram framework.
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Adolescents face constant exams and often experience severe test anxiety. Previous studies suggested that test anxiety impairs individuals' inhibitory control. Neurophysiological evidence suggests that anxiety interferes with the recruitment of the prefrontal region of the brain, which modulates top-down attentional control during the completion of inhibitory control tasks. However, there is little neurophysiological evidence regarding how test anxiety impairs inhibitory control in adolescents. This study used the flanker task to measure individuals' inhibitory control ability, and both event-related potential and electroencephalography indicators were used to measure neurophysiological processes. The results showed that increased trait test anxiety was significantly negatively correlated with theta power oscillation, while adolescents performed both incongruent and congruent trials. This finding suggests that trait test anxiety adolescents are less able to exert greater effort to complete the inhibitory control task and show impoverished top-down attentional control resources.
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Electroencefalografía , Ansiedad ante los Exámenes , Humanos , Adolescente , Encéfalo/fisiología , Potenciales Evocados/fisiología , AnsiedadRESUMEN
Research has confirmed that individuals with social anxiety (SA) show an attentional bias towards threat-related stimuli. However, the extent to which this attentional bias depends on top-down cognitive control processes remains controversial. The present study investigated the effect of working memory (WM) load on selective attention to emotional faces in both high social anxiety (HSA) and low social anxiety (LSA) groups by manipulating WM load through the inclusion of forward counting in multiples of two (low load) or backward counting in multiples of seven (high load) within a modified flanker task. In the flanker task, emotional faces (angry, happy, or neutral faces) were used as targets and distractors. A total of 70 participants (34 HSA participants; 36 LSA participants) completed the flanker task in the laboratory. The results showed that the HSA individuals performed worse when responding to angry targets. Relative to LSA individuals, HSA individuals showed interference from angry distractors in the flanker task, resulting in significantly lower accuracy in identifying angry targets compared to happy targets. These results were unaffected by the manipulation of WM load. The findings imply HSA individuals have impaired attentional control, and that their threat-related attentional bias relies more on the bottom-up automatic attentional process.
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Atención , Expresión Facial , Memoria a Corto Plazo , Humanos , Memoria a Corto Plazo/fisiología , Femenino , Masculino , Adulto , Adulto Joven , Atención/fisiología , Emociones/fisiología , Ansiedad , Sesgo Atencional/fisiología , Reconocimiento Facial/fisiología , Fobia SocialRESUMEN
The error-related negativity (ERN) and error positivity (Pe) are components of the event-related potential following an error that are potential mechanistic biomarkers of obsessive-compulsive disorder (OCD). The study examined the ERN, Pe, flanker task accuracy, and clinical measures in 105 OCD cases and 105 matched healthy controls (HC), ages 8 to 18 years, with 21 cases having a tic disorder history. Higher flanker task accuracy in all participants was associated with an increased ERN amplitude and increased difference between Pe and correct positivity amplitudes (ΔPe). Compared to HC, OCD cases had an increased ERN but decreased flanker task accuracy and ΔPe. Those differences were also significant in tic-related and non-tic-related OCD cases compared to HC. A lower ΔPe was associated in OCD cases with an earlier age at OCD symptom onset. The results support the hypothesis that OCD involves defects in an error monitoring system and suggest a reduced ΔPe may compromise error signaling and cause uncertainty about the correctness of a response.
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The flanker task (Eriksen & Eriksen, Perception & Psychophysics, 16(1), 143-149, 1974) has been highly influential and widely used in studies of visual attention. Its simplicity has made it popular to include it in experimental software packages and online platforms. The spacing flanker task (SFT), in which the distance between the target and flankers varies, is useful for studying the distribution of attention across space as well as inhibitory control. Use of the SFT requires that the viewing environment (e.g., stimulus size and viewing distance) be controlled, which is a challenge for online delivery. We implement and evaluate an online version of the SFT that includes two calibration pretests to provide the necessary control. Test-retest and split-half reliability of the online version was compared with a laboratory version on measures of inhibitory control and measures of the distribution of attention across space. Analyses show that the online SFT is comparable to laboratory testing on all measures. Results also identify two measures with good test-retest reliability that hold promise for studying performance in the SFT: the mean flanker effect (ICC = 0.745) and RTs on incongruent trials across distances (ICC = 0.65-0.71).
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Atención , Inhibición Psicológica , Percepción Espacial , Humanos , Atención/fisiología , Reproducibilidad de los Resultados , Percepción Espacial/fisiología , Femenino , Masculino , Adulto Joven , Adulto , Tiempo de Reacción/fisiología , AdolescenteRESUMEN
Cardiorespiratory fitness is known to protect against cognitive decline in older adults. Specifically, it has been shown that physical activity and fitness are beneficial for executive functions that are crucial for independent living up to old age. In this study, 115 individuals aged 80 years and older underwent a cardiorespiratory fitness assessment using the two-minute step test and had their electroencephalogram recorded during a colored flanker task in order to measure executive function performance. Cardiorespiratory fitness was related to quicker responses during the flanker task. A mediation analysis was carried out to determine whether these positive effects were mediated through event-related potentials (N1, N2, or P3) or motor-related cortical potentials (MRCP). Cardiorespiratory fitness was related to better visual discriminative processing as indicated by larger occipital N1 amplitudes. In addition, fitness was associated with larger MRCP amplitudes, which are a correlate of the response generation process. Fitness was not found to have a significant effect on fronto-central N2 or parietal P3, which are thought to capture cognitive control processes such as conflict detection and response inhibition. Moreover, all effects reported were present in all three flanker trial conditions (congruent, neutral, and incongruent). Thus, these results indicate that the quicker response times in fitter people were related to visual processing and motor response generation rather than cognitive control.
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Capacidad Cardiovascular , Humanos , Cognición/fisiología , Potenciales Evocados/fisiología , Función Ejecutiva/fisiología , Tiempo de Reacción/fisiología , Anciano de 80 o más AñosRESUMEN
The ability to identify and resolve conflicts between standard, well-trained behaviors and behaviors required by the current context is an essential feature of cognitive control. To date, no consensus has been reached on the brain mechanisms involved in exerting such control: while some studies identified diverse patterns of activity across different conflicts, other studies reported common resources across conflict tasks or even across simple tasks devoid of the conflict component. The latter reports attributed the entire activity observed in the presence of conflict to longer time spent on the task (i.e., to the so-called time-on-task effects). Here, we used an extended Multi-Source Interference Task (MSIT) which combines Simon and flanker types of interference to determine shared and conflict-specific mechanisms of conflict resolution in fMRI and their separability from the time-on-task effects. Large portions of the activity in the dorsal attention network and decreases of activity in the default mode network were shared across the tasks and scaled in parallel with increasing reaction times. Importantly, the activity in the sensory and sensorimotor cortices, as well as in the posterior medial frontal cortex (pMFC) - a key region implicated in conflict processing - could not be exhaustively explained by the time-on-task effects.
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Encéfalo , Conflicto Psicológico , Humanos , Encéfalo/diagnóstico por imagen , Tiempo de Reacción , Lóbulo Frontal , Mapeo EncefálicoRESUMEN
A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2 *-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.
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Ácido Glutámico , Imagen por Resonancia Magnética , Humanos , Ácido Glutámico/metabolismo , Imagen por Resonancia Magnética/métodos , Glutamina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Cognición , AguaRESUMEN
While the survival rate of very preterm (VPT) infants has increased in the last decades, they are still at risk of developing long-term neurodevelopmental impairments, especially regarding self-regulatory abilities, and goal-directed behaviors. These skills rely on executive functions (EFs), an umbrella term encompassing the core capacities for inhibition, shifting, and working memory. Existing comprehensive tests are time-consuming and therefore not suitable for all pediatric neuropsychological assessments. The Flanker task is an experimental computer game having the advantage to last less than ten minutes while giving multiple EFs measures. Here, we tested the potency of this task in thirty-one VPT children aged 8-10 years during their clinical assessment. First, we found that VPT children performed in the norm for most clinical tests (i.e., WISC-V, BRIEF, and NEPSY) except for the CPT-3 where they were slower with more omission errors, which could indicate inattentiveness. Second, some Flanker task scores were correlated with standardized clinical testing without resisting to multiple comparisons correction. Finally, compared to full-term children, VPT children showed poorer performance in global EFs measure and lower accuracy in the Flanker task. These findings suggest that this child-friendly version of the Flanker task demonstrated a reasonable sensitivity in capturing EFs with good discrimination between VPT and term children despite VPT children's mild difficulties. It may represent a promising tool for neuropsychological assessments and be suitable as a screening test, providing further validating larger studies. Moreover, while VPT schoolchildren globally display normal intelligence, subtle difficulties that seem to relate to EFs are observed.
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Selective attention might be space-, feature-, and/or object-based. Clear support for the involvement of an object-based mechanism is rather scarce, possibly because the predictions of models from these different classes often overlap. Yet, only object-based models can account for a larger congruency effect (CE) in the Eriksen flanker task when flankers are more (vs. less) strongly grouped to the target, but spacing and other response-irrelevant features of target and flankers are held constant. Exactly this was observed by Kramer and Jacobson (1991). So far, this theoretically relevant finding has not been replicated closely. We replicated the finding in two web-based experiments. Specifically, CEs were larger when flanker lines were connected to the central target line (vs. to outer neutral lines). We also successfully fitted the Diffusion Model for Conflict tasks (DMC) to the experimental data. Critically, diffusion modeling (DMC) and distributional analyses (delta functions) revealed that object membership primarily affected target processing strength rather than strength or timing of flanker processing. This challenges the prominent attentional spreading (sensory enhancement) account of object-based selective attention and motivates an alternative target attenuation account.
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Atención , Humanos , Tiempo de ReacciónRESUMEN
ACL injuries are common among athletes playing team sports. The impact of divided attention during team sports on landing mechanics is unclear. Twenty-one healthy females jumped at a 60° angle to their right and performed a second jump to their right or left at a 60° angle. The direction of the second jump was shown before movement (baseline) or mid-flight of the first jump (dual task). The signal for the dual-task conditions showed five arrows and the middle one indicated the jump direction (Flanker paradigm). The other arrows pointed in the same (congruent) or the opposite (incongruent) direction as the middle arrow. Results indicated larger initial and peak knee flexion angles, smaller peak knee valgus moments, and smaller vertical and posterior GRFs during baseline right jumps compared to other conditions. Peak posterior GRF was increased in the incongruent condition compared to the congruent condition during left jumps. Performance was decreased with longer stance times for the dual task compared to the baseline in both jump directions. Further, the incongruent condition had a longer stance time than the congruent condition during left jumps. More research focusing on decision-making with more challenging visual stimuli mimicking dynamic team sports is merited.
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BACKGROUND AND HYPOTHESES: Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. STUDY DESIGN: Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. STUDY RESULTS: We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. CONCLUSION: FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.