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Cited by 698Neural and Behavioral Psychology StudiesCognitive Functions and MemoryNeurotransmitter Receptor Influence on Behavior

Cognitive and behavioural flexibility: Neural mechanisms and clinical considerations

Open access
Uddin, Lucina Q.·2021·Nature Reviews Neuroscience
DOI 10.1038/s41583-021-00428-wPMC PMC7856857
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Abstract

Cognitive and behavioural flexibility permit the appropriate adjustment of thoughts and behaviours in response to changing environmental demands. Brain mechanisms enabling flexibility have been examined using non-invasive neuroimaging and behavioural approaches in humans alongside pharmacological and lesion studies in animals. This work has identified large-scale functional brain networks encompassing lateral and orbital frontoparietal, midcingulo-insular and frontostriatal regions that support flexibility across the lifespan. Flexibility can be compromised in early-life neurodevelopmental disorders, clinical conditions that emerge during adolescence and late-life dementias. We critically evaluate evidence for the enhancement of flexibility through cognitive training, physical activity and bilingual experience. Flexibility is critical for the optimal adaptation of thoughts and actions under changing circumstances. In this Review, Uddin summarizes research that has identified cognitive processes and neural systems supporting flexibility and discusses ways to improve flexibility across the lifespan.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes human neuroimaging and animal work on cognitive and behavioural flexibility, emphasizing distributed frontoparietal, midcingulo-insular, and frontostriatal systems across the lifespan. It argues that flexibility deficits cut across neurodevelopmental, adolescent-onset, and late-life disorders, while evidence for enhancing flexibility through training, exercise, and bilingualism remains mixed.

Key findings

  • Flexibility is supported by large-scale functional networks: a lateral frontoparietal network (including dorsolateral prefrontal cortex, inferior frontal junction, and inferior parietal lobule), a midcingulo-insular network (including anterior insula and anterior midcingulate cortex), and frontostriatal circuits. The inferior frontal junction is engaged during updating of task representations and flexible item selection, with connectivity strength related to individual task performance.
  • Flexibility follows an inverted U-shaped lifespan trajectory, peaking between the second and third decades and declining in later life. Brain signal variability generally decreases from ages 6 to 85 across most regions, except the anterior insula, which increases; higher variability has been linked to better performance in some older adults.
  • Flexibility deficits appear transdiagnostically in autism spectrum disorder, ADHD, mood and anxiety disorders, obsessive–compulsive disorder, schizophrenia, Alzheimer disease, and Parkinson disease. The review’s table links manifestations such as restricted/repetitive behaviours, repetitive negative thinking, cognitive rigidity, and compulsions to putative substrates including frontostriatal, orbitofrontal, midcingulo-insular, and frontoparietal systems.
  • Intervention evidence is mixed: cognitive training often produces narrow short-term transfer; a game-based flexibility training study reported reading comprehension gains only at 6-week follow-up; a randomized controlled trial of working memory and cognitive flexibility training in autism did not show differential improvement; “Unstuck and On Target” improved classroom behaviour, flexibility, and problem-solving in autism; exercise alone showed little or no executive function benefit; bilingual advantages were inconsistent but observed in lower socio-economic status children and as possible cognitive reserve.

Methods

  • Narrative critical review, not a primary empirical study. It synthesizes non-invasive human neuroimaging and behavioural paradigms (including task-switching, set-shifting, Wisconsin Card Sorting Test, and reversal learning) alongside animal lesion, pharmacological, and behavioural studies.
  • The review spans typical development, adulthood, ageing, and clinical conditions, and evaluates cognitive training, physical activity, and bilingualism as potential flexibility interventions.
  • Main analysis is qualitative synthesis and critical evaluation; no systematic search strategy, meta-analysis, or primary sample is described.

Limitations

  • The paper states measurement problems: laboratory/performance-based measures and self- or informant-report measures are only weakly correlated, and construct validity versus ecological validity remains a challenge. It calls for standardized, transdiagnostic, age-normed assessments.
  • The paper states that intervention evidence is mixed, bilingualism findings lack consensus, and no interventional studies have yet shown that training changes brain network dynamics supporting flexibility. Cholinergic contributions are complicated by co-release of other neurotransmitters.
  • Evident from the text: as a narrative review, it does not report a systematic search, formal effect sizes, or risk-of-bias assessment, and conclusions draw on heterogeneous paradigms, populations, and study designs.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41583-021-00428-w

Cites

148 of 148 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 107 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Neurosynth analysis of the terms shifting, updating, and inhibition shows highly overlapping activation maps in lateral frontoparietal and midcingulo-insular regions.

    “Entering the terms describing the latent variables comprising executive function into Neurosynth reveals that the brain maps associated with these interrelated cognitive constructs are highly overlapping7 (Fig. 1a).”
    • Also stated in: § Cognitive flexibility in humans · plain
      “Neurosynth reveals that brain imaging studies including the terms ‘shifting’, ‘updating’ and ‘inhibition’ report highly overlapping patterns of activation in lateral frontoparietal and midcingulo-insular brain regions”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Miyake, A. et al. The unity and diversity of executive functions and their contributions to complex ‘frontal lobe’ tasks: a latent variable analysis. Cogn. Psychol. 41, 49–100 (2000). source

      Not checked in the free run.

    • cites [29] Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C. & Wager, T. D. Large-scale automated synthesis of human functional neuroimaging data. Nat. Methods 8, 665–670 (2011). source

      Not checked in the free run.

  • Premisecitation

    Large-scale functional brain networks that include lateral and orbital frontoparietal, midcingulo-insular, and frontostriatal regions support flexibility throughout life.

    “This work has identified large-scale functional brain networks encompassing lateral and orbital frontoparietal, midcingulo-insular and frontostriatal regions that support flexibility across the lifespan.”
    • Also stated in: § Cognitive flexibility in humans · boosted
      “A large body of literature on human functional neuroimaging studies using task-switching and set-shifting paradigms points to a central role for the lateral frontoparietal network (L-FPN) and the midcingulo-insular network (M-CIN) in supporting executive function and cognitive flexibility20,30.”
    • Also stated in: § Behavioural flexibility in animals · hedged
      “These findings have led to the proposal that the lateral PFC is necessary for shifting of responding between abstract perceptual dimensions, whereas the OFC and associated corticostriatal loops are necessary for shifting of responding between different stimuli with specific associations with reinforcement36.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Dajani, D. R. & Uddin, L. Q. Demystifying cognitive flexibility: Implications for clinical and developmental neuroscience. Trends Neurosci. 38, 571–578 (2015). source

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    • cites [30] Seeley, W. W. et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J. Neurosci. 27, 2349–2356 (2007). source

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    • cites [36] Robbins, T. W. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 917–932 (2007). source

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  • Premisecitation

    In a flexible item-selection task, the inferior frontal junction is engaged first and then recruits other lateral frontoparietal and midcingulo-insular regions through functional connectivity.

    “During a task requiring flexible selection of items based on different stimulus dimensions, participants initially directly engaged the IFJ, leading to recruitment of other L-FPN and M-CIN regions, including the dlPFC, IPL, anterior midcingulate cortex and AI via functional connections33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Dajani, D. R. et al. Measuring cognitive flexibility with the flexible item selection task: from MRI adaptation to individual connectome mapping. J. Cogn. Neurosci. 32, 1026–1045 (2020). This functional neuroimaging study in humans demonstrates that flexible item selection directly engages the left IFJ, which influences activity in other cortical and subcortical brain regions supporting cognitive flexibility. source

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  • Interpretationreasoning

    The shared lateral frontoparietal and striatal involvement in flexibility and creativity suggests these constructs may have common neural substrates.

    “The overlap in lateral frontoparietal and striatal involvement for both flexibility and creativity points to potential shared neural substrates for these related constructs.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Wisconsin Card Sorting Test performance is strongly associated with shifting.

    “Performance on the WCST is strongly related to shifting (also referred to as ‘attention switching‘ or ‘task switching’), which involves the disengagement of an irrelevant task set and subsequent active engagement of a relevant task set7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Miyake, A. et al. The unity and diversity of executive functions and their contributions to complex ‘frontal lobe’ tasks: a latent variable analysis. Cogn. Psychol. 41, 49–100 (2000). source

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  • Classified as probably not a substantial claim. 6
  • May combine two claims. 42

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reversal learning paradigms measure adaptive responding when stimulus-outcome or response-outcome contingencies change.

    “These paradigms assess the ability to respond adaptively in the face of changing stimulus–outcome or response–outcome contingencies15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Izquierdo, A., Brigman, J. L., Radke, A. K., Rudebeck, P. H. & Holmes, A. The neural basis of reversal learning: an updated perspective. Neuroscience 345, 12–26 (2017). source

      Not checked in the free run.

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    Premisecitation

    Marmosets with lateral prefrontal cortex lesions show intact reversal learning and shifting to a previously rewarded alternative but impaired extradimensional shifts.

    “Assessment of behavioural flexibility in marmoset monkeys reveals that animals with lateral PFC lesions are not impaired in reversal learning or in shifting behavioural responses to a previously rewarded alternative. These monkeys are, however, impaired with regard to extradimensional shifts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Robbins, T. W. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 917–932 (2007). source

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    Premisecitation

    Cognitive and behavioural flexibility are part of executive functions.

    “Cognitive and behavioural flexibility fall under the broader category of executive functions, or processes necessary for the control of goal-directed behaviour7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Miyake, A. et al. The unity and diversity of executive functions and their contributions to complex ‘frontal lobe’ tasks: a latent variable analysis. Cogn. Psychol. 41, 49–100 (2000). source

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    Interpretationcitation

    The RDoC framework could produce a revised diagnostic classification that is more biologically grounded.

    “This framework may lead to a revised diagnostic nosology that is more firmly grounded in biology17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Saggar, M. & Uddin, L. Q. Pushing the boundaries of psychiatric neuroimaging to ground diagnosis in biology. eNeuro https://doi.org/10.1523/ENEURO.0384-19.2019 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Laboratory and neuropsychological measures of flexibility have high construct validity but do not always match real-world flexible behaviour reported by self- or informant-report questionnaires.

    “laboratory-based measures and neuropsychological tests have high construct validity but may not always converge with real-world flexible behaviours as indexed using self-report or informant-report questionnaires, which typically have greater ecological validity21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Dang, J., King, K. M. & Inzlicht, M. Why are self-report and behavioral measures weakly correlated? Trends Cogn. Sci. 24, 267–269 (2020). source

      Not checked in the free run.

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    Premisecitation

    Flexibility promotes academic achievement and employment success.

    “Developmental and lifespan research suggests that flexibility promotes academic achievement, employment success2, successful transitioning to adulthood3 and other optimal life outcomes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Diamond, A. & Lee, K. Interventions shown to aid executive function development in children 4 to 12 years old. Science 333, 959–964 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Executive functions consist of three latent factors-shifting, updating, and inhibition-that are moderately correlated yet separable.

    “executive functions are postulated to comprise three latent variables, described as mental set-shifting (‘shifting’), information updating and monitoring in working memory (‘updating’) and inhibition of prepotent responses (‘inhibition’), that are moderately correlated with one another, yet clearly separable7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Miyake, A. et al. The unity and diversity of executive functions and their contributions to complex ‘frontal lobe’ tasks: a latent variable analysis. Cogn. Psychol. 41, 49–100 (2000). source

      Not checked in the free run.

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    Premisecitation

    People with frontal lobe damage and children under 4 years often keep using previously learned sorting rules and struggle to switch to new ones.

    “Individuals with frontal lobe damage and children younger than 4 years tend to persist in sorting cards according to previously learned rules and have difficulty flexibly switching to new sorting rules143.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Grant, D. A. & Berg, E. A. Wisconsin Card Sorting Test. PsycTESTS Dataset https://doi.org/10.1037/t31298-000 (2014). source

      Not checked in the free run.

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    Premisecitation

    Cognitive flexibility develops over a long inverted U-shaped course, peaks in the second or third decade, and declines in later life.

    “Cognitive flexibility follows a protracted, inverted U-shaped developmental trajectory from early childhood through adolescence and adulthood, peaking between the second and third decades of life, and declining in late life19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Cepeda, N. J., Kramer, A. F. & Gonzalez de Sather, J. C. M. Changes in executive control across the life span: examination of task-switching performance. Dev. Psychol. 37, 715–730 (2001). source

      Not checked in the free run.

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    Premisecitation

    Functional network topography supporting cognitive flexibility varies considerably between individuals, and connectivity strength among selected regions is related to task performance differences.

    “Considerable individual variability in functional network topography supporting cognitive flexibility was observed, and the strength of functional connectivity between selected brain regions was related to individual differences in task performance (Fig. 1b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Dajani, D. R. et al. Measuring cognitive flexibility with the flexible item selection task: from MRI adaptation to individual connectome mapping. J. Cogn. Neurosci. 32, 1026–1045 (2020). This functional neuroimaging study in humans demonstrates that flexible item selection directly engages the left IFJ, which influences activity in other cortical and subcortical brain regions supporting cognitive flexibility. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    People with higher Wisconsin Card Sorting Test scores show more episodes of frequently occurring brain states and fewer episodes of infrequent states previously linked to low vigilance and arousal.

    “Individuals who score higher on the WCST exhibit more episodes of more frequently occurring brain states, and fewer episodes of less frequently occurring brain states that have previously been associated with low vigilance and arousal44 (Fig. 2c).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Nomi, J. S. et al. Chronnectomic patterns and neural flexibility underlie executive function. Neuroimage 147, 861–871 (2017). This dynamic functional connectivity analysis demonstrates that individuals with the propensity to exhibit whole-brain dynamics characterized by attenuated correlations between brain regions and greater functional connectivity variability perform better on the WCST, a test of cognitive flexibility. source

      Not checked in the free run.

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    Premisecitation

    In younger adults, executive function correlates with efficient midcingulo-insular dynamics, while in older adults it correlates with efficient medial frontoparietal dynamics.

    “In younger adults, executive function ability is correlated with efficiency in brain dynamics of the M-CIN, whereas for older adults this ability is associated with efficiency in the M-FPN52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Ezaki, T., Sakaki, M., Watanabe, T. & Masuda, N. Age-related changes in the ease of dynamical transitions in human brain activity. Hum. Brain Mapp. 39, 2673–2688 (2018). source

      Not checked in the free run.

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    Premisecitation

    From childhood to mid-adulthood, brain signal variability rises with age and correlates negatively with reaction-time variability and positively with accuracy.

    “Between childhood and mid-adulthood, brain signal variability increases with age, shows negative correlations with reaction time variability and positive correlations with accuracy57.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] McIntosh, A. R., Kovacevic, N. & Itier, R. J. Increased brain signal variability accompanies lower behavioral variability in development. PLoS Comput. Biol. 4, e1000106 (2008). source

      Not checked in the free run.

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    Premisecitation

    Younger and faster adults show greater brain variability during tasks than at rest, while older and slower adults show less difference in variability between conditions.

    “Brain variability appears to increase during task performance compared with rest in younger and faster-performing adults, whereas older and slower-performing adults exhibit less differentiation in brain variability across experimental conditions58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Garrett, D. D., Kovacevic, N., McIntosh, A. R. & Grady, C. L. The modulation of BOLD variability between cognitive states varies by age and processing speed. Cereb. Cortex 23, 684–693 (2013). This study illustrates how variability of fMRI signals differs in normal ageing, and specifically highlights the fact that older and slower-performing individuals exhibit reduced variability. source

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    Premisecitation

    Older adults with better cognitive test performance show globally coherent brain states, while poorer performers switch more often between dynamic brain states.

    “older adults performing well on a cognitive test battery were found to exhibit brain states characterized by global coherence, whereas those performing poorly exhibited greater frequency of switching between dynamic brain states51.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Cabral, J. et al. Cognitive performance in healthy older adults relates to spontaneous switching between states of functional connectivity during rest. Sci. Rep. 7, 5135 (2017). source

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    Premisecitation

    Inactivating the dorsomedial striatum impairs reversal learning and strategy switching and prevents maintaining newly selected choice patterns.

    “Dorsomedial striatal inactivation impairs both reversal learning and strategy switching, resulting in an inability to maintain new choice patterns once they are selected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Ragozzino, M. E. The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann. NY Acad. Sci. 1121, 355–375 (2007). This review summarizes work in rodents delineating limbic, orbitofrontal and striatal contributions to behavioural flexibility. source

      Not checked in the free run.

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    Premisecitation

    Monkeys with orbitofrontal cortex lesions are impaired in reversal learning but not in extradimensional shifts.

    “Monkeys with orbitofrontal cortex (OFC) lesions show the opposite behaviour: impairment in reversal learning but no deficits in extradimensional shifts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Robbins, T. W. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 917–932 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The lateral prefrontal cortex is proposed to be required for shifting between abstract perceptual dimensions, while the orbitofrontal cortex and related corticostriatal loops are required for shifting between stimuli with specific reinforcement associations.

    “These findings have led to the proposal that the lateral PFC is necessary for shifting of responding between abstract perceptual dimensions, whereas the OFC and associated corticostriatal loops are necessary for shifting of responding between different stimuli with specific associations with reinforcement36.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Robbins, T. W. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 917–932 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, reversal learning is easier than extradimensional shifting, yet fMRI shows neuroanatomy similar to that in animals.

    “For humans, reversal learning is much easier to perform than extradimensional shifts, but similar neuroanatomy to that seen in animals has been observed using fMRI39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Hampshire, A. & Owen, A. M. Fractionating attentional control using event-related fMRI. Cereb. Cortex 16, 1679–1689 (2006). source

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    Interpretationcitation

    Higher variability may reflect a wider repertoire of metastable brain states and transitions that support optimal responses.

    “The suggestion is that higher variability might reflect a broader repertoire of metastable brain states and transitions between them to enable optimal responses57.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] McIntosh, A. R., Kovacevic, N. & Itier, R. J. Increased brain signal variability accompanies lower behavioral variability in development. PLoS Comput. Biol. 4, e1000106 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Children with ASD, ADHD, or comorbid ASD and ADHD may all show flexibility deficits, but the nature and severity can differ across and within these disorders.

    “Although children with ASD, ADHD or co-morbid ASD and ADHD may all exhibit flexibility deficits, the nature and severity of these issues can differ across and even within these disorders.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    How easily individuals transition between brain states differs between younger and older adults and is associated with executive function measured by the D-KEFS.

    “Ease of transitions between brain states distinguishes younger from older individuals, and is further linked with executive function indexed by the D-KEFS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Cabral, J. et al. Cognitive performance in healthy older adults relates to spontaneous switching between states of functional connectivity during rest. Sci. Rep. 7, 5135 (2017). source

      Not checked in the free run.

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    Premisecitation

    From ages 6 to 85, BOLD variability declines linearly in most brain regions, but the anterior insula shows the opposite trend.

    “Across the age range from 6 to 85 years, BOLD signal variability decreases linearly across most of the brain, with the exception of the AI, a critical M-CIN node involved in flexibility, which shows the opposite pattern60 (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Nomi, J. S., Bolt, T. S., Ezie, C., Uddin, L. Q. & Heller, A. S. Moment-to-moment BOLD Signal variability reflects regional changes in neural flexibility across the lifespan. J. Neurosci. https://doi.org/10.1523/JNEUROSCI.3408-16.2017 (2017). source

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    Premisecitation

    Higher-order association cortex regions show high functional flexibility, and frontal and parietal regions show separable age-related changes across life.

    “Brain regions in higher-order association cortices exhibit high levels of functional flexibility, with dissociable age-related changes observed in frontal and parietal regions across the lifespan53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Yin, D. et al. Dissociable changes of frontal and parietal cortices in inherent functional flexibility across the human life span. J. Neurosci. 36, 10060–10074 (2016). source

      Not checked in the free run.

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    Premisecitation

    Executive function and flexibility impairments are seen across many forms of psychopathology and may act as transdiagnostic intermediate phenotypes.

    “Executive function impairments broadly, and flexibility impairments specifically, are observed across many forms of psychopathology and may serve as transdiagnostic intermediate phenotypes63.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Snyder, H. R., Miyake, A. & Hankin, B. L. Advancing understanding of executive function impairments and psychopathology: bridging the gap between clinical and cognitive approaches. Front. Psychol. 6, 328 (2015). source

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    Premisecitation

    The vast majority of children with comorbid ASD and ADHD exhibit executive function impairments, though not all children with ASD alone do.

    “Even though not all children with a primary diagnosis of ASD exhibit executive dysfunction78, the vast majority of children with co-morbid ASD and ADHD do exhibit executive function impairments65.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Baez, A. C. et al. Parsing heterogeneity of executive function in typically and atypically developing children: a conceptual replication and exploration of social function. J. Autism Dev. Disord. https://doi.org/10.1007/s10803-019-04290-9 (2019). source

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    • cites [65] Dajani, D. R., Llabre, M. M., Nebel, M. B., Mostofsky, S. H. & Uddin, L. Q. Heterogeneity of executive functions among comorbid neurodevelopmental disorders. Sci. Rep. 6, 36566 (2016). source

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    Premisecitation

    ADHD diagnostic criteria include inattention, hyperactivity, and impulsivity, which can be viewed as manifestations of distractibility or excessive flexibility.

    “Diagnostic criteria for ADHD include inattention, hyperactivity and impulsivity69, which can be thought of as manifestations of distractibility or too much flexibility.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). (American Psychiatric Association Publishing, 2013). source

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    Premisecitation

    Brain circuitry supporting cognitive control is still developing during adolescence, partly due to differential development of limbic and executive control systems.

    “Brain circuitry supporting cognitive control is still undergoing development during adolescence87, in part owing to differential development of limbic and executive control systems88.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Luna, B., Paulsen, D. J., Padmanabhan, A. & Geier, C. The teenage brain: cognitive control and motivation. Curr. Dir. Psychol. Sci. 22, 94–100 (2013). source

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    • cites [88] Casey, B. J., Jones, R. & Hare, T. The adolescent brain. The year in cognitive neuroscience. Ann. NY Acad. Sci. 11, 84–94 (2008).

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  • May combine two claims.

    Premisenone given

    Executive function and flexibility deficits are observed in normal ageing and can be exacerbated in later-life neurological disorders.

    “While executive function and flexibility deficits are observed in normal ageing, these issues can be further exacerbated in neurological disorders that affect later life.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Older adults show reduced efficiency of lateral prefrontal control regions and compensate for age-related task-switching declines by relying on enhanced frontotemporal connectivity compared with younger adults.

    “Older adults exhibit reduced efficiency of lateral prefrontal control regions, and compensate for age-related declines in task-switching performance by relying on enhanced frontotemporal connectivity compared with younger adults97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Hakun, J. G., Zhu, Z., Johnson, N. F. & Gold, B. T. Evidence for reduced efficiency and successful compensation in older adults during task switching. Cortex 64, 352–362 (2015). source

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    Premisecitation

    A recent meta-analysis of fMRI studies of executive function in ageing shows that the IFJ is recruited to different degrees in younger versus older adults, and functional connectivity between the IFJ and other executive function-related regions decreases with age.

    “A recent meta-analysis of fMRI studies of executive function in ageing reveals that the IFJ is recruited to a different degree in younger versus older adults. Furthermore, decreased functional connectivity between the IFJ and other executive function-related brain regions is observed with increasing age99.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Heckner, M. K. et al. The aging brain and executive functions revisited: implications from meta-analytic and functional connectivity evidence. J. Cogn. Neurosci. 1–36 (2020). source

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    Premisecitation

    Restricted and repetitive behaviours in ASD can include stereotyped movements, insistence on sameness, and circumscribed or perseverative interests.

    “Restricted and repetitive behaviours (RRBs), considered core deficits in ASD, can include stereotyped movements, insistence on sameness, and circumscribed or perseverative interests69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). (American Psychiatric Association Publishing, 2013). source

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    Premisecitation

    Transdiagnostic executive function subtypes have been identified using community detection algorithms, and children in an inflexibility subtype failed to modulate parietal activation with increasing executive task demands.

    “For example, transdiagnostic executive function subtypes have been identified with use of community detection algorithms, and children within the subtype characterized by inflexibility showed a failure to modulate parietal lobe activation in response to increasing executive task demands82.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Vaidya, C. J. et al. Data-driven identification of subtypes of executive function across typical development, attention deficit hyperactivity disorder, and autism spectrum disorders. J. Child. Psychol. Psychiatry 61, 51–61 (2020). source

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    Premisecitation

    Adolescents learn faster from negative reward prediction errors than adults and recruit the right AI more during probabilistic reversal learning.

    “These asymmetries are evident in studies demonstrating that adolescents learn faster from negative reward prediction errors than adults, and recruit the right AI to a greater degree during probabilistic reversal learning89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Hauser, T. U., Iannaccone, R., Walitza, S., Brandeis, D. & Brem, S. Cognitive flexibility in adolescence: neural and behavioral mechanisms of reward prediction error processing in adaptive decision making during development. Neuroimage 104, 347–354 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    OCD is an adolescent-onset disorder characterized by severe flexibility impairments.

    “Another adolescent-onset disorder characterized by severe flexibility impairments is OCD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Schizophrenia emerges in late adolescence and is associated with reduced cognitive flexibility, often with frontal lobe hypometabolism.

    “Schizophrenia is another condition emerging during late adolescence that is associated with reduced cognitive flexibility, often accompanied by frontal lobe hypometabolism94.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Weinberger, D. R. Schizophrenia and the frontal lobe. Trends Neurosci. 11, 367–370 (1988). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Standardized informant-report assessments targeting flexible behaviours in autism have been developed, such as the Flexibility Scale, which reveals factors related to routines/rituals, transitions/change, special interests, social flexibility, and generativity.

    “Standardized informant-report assessments specifically targeting flexible behaviours in autism have been developed, such as the Flexibility Scale, which reveals factors related to routines/rituals, transitions/change, special interests, social flexibility and generativity86.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Strang, J. F. et al. The Flexibility Scale: development and preliminary validation of a cognitive flexibility measure in children with autism spectrum disorders. J. Autism Dev. Disord. 47, 2502–2518 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Broad executive dysfunction in ASD across domains and more specific flexibility impairments, typically assessed with the WCST, are confirmed by early work and meta-analyses.

    “Early work in developmental psychopathology66 and recent meta-analyses confirm broad executive dysfunction in ASD across domains67 as well as more specific impairments in flexibility, typically assessed with the WCST64,68.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [66] Pennington, B. F. & Ozonoff, S. Executive functions and developmental psychopathology. J. Child. Psychol. Psychiatry 37, 51–87 (1996). source

      Not checked in the free run.

    • cites [67] Demetriou, E. A. et al. Autism spectrum disorders: a meta-analysis of executive function. Mol. Psychiatry 23, 1198–1204 (2018). source

      Not checked in the free run.

    • cites [64] Lai, C. L. E. et al. Meta-analysis of neuropsychological measures of executive functioning in children and adolescents with high-functioning autism spectrum disorder. Autism Res. 10, 911–939 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Children with ADHD have difficulty with attentional focus and high moment-to-moment behavioural variability.

    “While ASD is characterized by difficulty in flexibly adapting to changes in routines, children with ADHD have difficulty with attentional focus and exhibit high levels of variability in moment-to-moment behaviours73.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Kuntsi, J. & Klein, C. Intraindividual variability in ADHD and its implications for research of causal links. Curr. Top. Behav. Neurosci. 9, 67–91 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Worry and rumination may reflect the same underlying construct of repetitive negative thinking, which is likely a product of inflexible thinking and difficulty engaging L-FPN executive control systems for emotion regulation.

    “Worry and rumination may reflect the same underlying construct of repetitive negative thinking, which is likely a product of inflexible thinking and difficulty engaging the L-FPN executive control systems in the service of emotion regulation90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Burrows, C. A., Timpano, K. R. & Uddin, L. Q. Putative brain networks underlying repetitive negative thinking and comorbid internalizing problems in autism. Clin. Psychol. Sci. 5, 522–536 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Individuals with schizophrenia perform worse than individuals with OCD on the WCST, suggesting different subsystems within basal-corticofrontal circuits are involved.

    “Individuals with schizophrenia perform worse than individuals with OCD on the WCST, suggesting the involvement of different subsystems within basal–corticofrontal circuits in these two disorders95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Cavallaro, R. et al. Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study. Biol. Psychiatry 54, 437–443 (2003). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Methylphenidate, a psychostimulant influencing dopamine and noradrenaline activity, has long been used to treat ADHD and other developmental disorders.

    “Methylphenidate, a psychostimulant influencing dopamine and noradrenaline activity, has long been used to treat ADHD and other developmental disorders109.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Martino, A. D., Di Martino, A., Melis, G., Cianchetti, C. & Zuddas, A. Methylphenidate for pervasive developmental disorders: safety and efficacy of acute single dose test and ongoing therapy: an open-pilot study. J. Child. Adolesc. Psychopharmacol. 14, 207–218 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dysexecutive syndrome, involving working memory, cognitive flexibility, and inhibitory control impairment, is seen in progressive dementia due to Alzheimer disease and is accompanied by frontoparietal hypometabolism on PET.

    “Dysexecuitve syndrome, which involves impairment of working memory, cognitive flexibility and inhibitory control, is seen in progressive dementia syndrome due to Alzheimer disease. This syndrome is accompanied by frontoparietal hypometabolism as demonstrated by positron emission tomography104.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Townley, R. A. et al. Progressive dysexecutive syndrome due to Alzheimer’s disease: a description of 55 cases and comparison to other phenotypes. Brain Commun. https://doi.org/10.1093/braincomms/fcaa068 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Flexibility reductions can be associated with adaptive or healthy traits, and the required level of flexibility can fluctuate with context.

    “While we focus on maladaptive outcomes associated with flexibility deficits here, flexibility reductions can also be associated with adaptive or healthy traits, and the level of flexibility required can fluctuate depending on the context.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In Parkinson disease, cognitive impairments such as slowed thinking and cognitive inflexibility parallel motor impairments, suggesting reduced flexibility might be an appropriate reaction to a world experienced as more stationary.

    “In Parkinson disease, cognitive impairments such as slowed thinking and cognitive inflexibility parallel motor impairments102, suggesting that reduced flexibility might be an appropriate reaction to a world that is experienced as more stationary.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Robbins, T. W. & Cools, R. Cognitive deficits in Parkinson’s disease: a cognitive neuroscience perspective. Mov. Disord. 29, 597–607 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Evidence from rhesus monkeys given therapeutic doses of methylphenidate suggests the drug can impair task-switching performance, indicating improved attention may come at the expense of flexibility.

    “There is some evidence from studies of rhesus monkeys given therapeutic doses of methylphenidate that the drug can impair task-switching performance. This indicates that the improved ability to focus attention may come at the expense of hindering flexibility110.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Rajala, A. Z., Populin, L. C. & Jenison, R. L. Methylphenidate affects task-switching and neural signaling in non-human primates. Psychopharmacology 237, 1533–1543 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Different aspects of cognitive flexibility may be impaired across neurological disorders; frontoparietal changes affecting set-shifting characterize ALS, while frontostriatal changes affecting rule inference are seen in primary dystonia and Parkinson disease.

    “Across neurological disorders, different aspects of cognitive flexibility may be impaired. For example, frontoparietal changes affecting set-shifting ability characterize patients with amyotrophic lateral sclerosis, whereas frontostriatal changes affecting rule inference are seen in primary dystonia and Parkinson disease103.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Lange, F., Seer, C. & Kopp, B. Cognitive flexibility in neurological disorders: cognitive components and event-related potentials. Neurosci. Biobehav. Rev. 83, 496–507 (2017). source

      Not checked in the free run.

47 of 47

  • The paper relies on this without support.

    Cognitive and behavioural flexibility are impaired in autism spectrum disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, and dementias.

    “Cognitive and behavioural flexibility are compromised in clinical conditions affecting early life such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD); those that emerge in adolescence, including schizophrenia and mood disorders; and dementias with later-life onset.”

  • The paper relies on this without support.

    Many of these clinical conditions share flexibility deficits.

    “While many of these conditions share flexibility deficits, the heterogeneous nature, severity and patterns of co-morbid symptoms complicate efforts to develop treatment strategies for enhancing flexibility.”

  • The paper relies on this without support.

    The heterogeneity, severity, and co-morbidity of these conditions make it difficult to develop treatments to enhance flexibility.

    “While many of these conditions share flexibility deficits, the heterogeneous nature, severity and patterns of co-morbid symptoms complicate efforts to develop treatment strategies for enhancing flexibility.”

  • The paper relies on this without support.

    All DSM-V categories, possibly except sleep-wake disorders, include clinical conditions with compromised executive function domains.

    “All of the DSM-V categories (with the possible exception of sleep–wake disorders) include clinical conditions in which domains of executive function are compromised; this raises the question of the extent to which the construct of flexibility has discriminative value.”

  • The paper relies on this without support.

    In several disorders with documented flexibility deficits, these impairments can be observed while basic perceptual and motor performance remains unchanged.

    “In several of the disorders in which flexibility deficits have been documented, these impairments can be observed even while performance on basic perceptual and motor tasks remains unaltered.”

  • The authors state this as an assumption.

    The common behavioural manifestations of cognitive inflexibility across ASD and ADHD should be reflected in shared neural substrates.

    “Although it is hypothesized that the common behavioural manifestations of cognitive inflexibility across ASD and ADHD should be reflected in shared neural substrates, few assessments of brain circuitry supporting flexibility across these disorders have been conducted.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mechanisms underlying cognitive flexibility overlap anatomically with those of updating working memory to some extent, but likely also depend on some specialized circuitry.

    “Thus, mechanisms underlying cognitive flexibility overlap anatomically with those of updating working memory to some extent, but likely also depend on some specialized circuitry [90].”

    From The role of prefrontal cortex in cognitive control and executive function (2022) · cites this paper as [90]

    In ‘Neural substrates of flexibility > Cognitive flexibility in humans’ (page unavailable), the paper reports highly overlapping activation patterns for shifting (flexibility) and updating (working memory). ‘Components of flexibility’ describes shifting and updating as separable executive functions, but the cited passages do not establish specialized circuitry for flexibility relative to working-memory updating. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Recent neuroimaging studies support dynamic functional connectivity alterations in CSTC loops that extend to associated subcortical and cortical regions, contributing to cognitive inflexibility.

    “Recent neuroimaging studies support this view, emphasizing dynamic functional connectivity alterations in CSTC loops that extend to associated subcortical and cortical regions, contributing to cognitive inflexibility (158).”

    From Neural mechanisms underlying cognitive inflexibility in obsessive-compulsive disorder: a review (2026) · cites this paper as [158]

    In “Brain dynamics supporting flexibility” (page not available), the review links time-varying functional connectivity in whole-brain and named networks to differences in cognitive flexibility. “Cognitive flexibility in humans” also describes cortical networks with subcortical nodes. The cited passages do not establish dynamic connectivity alterations specifically in CSTC loops or show that those alterations contribute to cognitive inflexibility. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

2 of the 150 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Cambridge Cognition. Intra-Extra Dimensional Set Shift (IED). https://www.cambridgecognition.com/cantab/cognitive-tests/executive-function/intra-extra-dimensional-set-shift-ied/ (2021).
  2. Casey, B. J., Jones, R. & Hare, T. The adolescent brain. The year in cognitive neuroscience. Ann. NY Acad. Sci. 11, 84–94 (2008).

Cited by

Sorted by citations

Related

Authors
Uddin, L. Q.
Affiliations
University of Miami (US)
Corresponding author
Uddin, Lucina Q.
ORCID
Uddin, Lucina Q.
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2021-02-03
Volume
22
Issue
3
Pages
167-179
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-021-00428-w
PMC
PMC7856857
OpenAlex
W3128518091
Cited by
698
References
150
Citations by year
2026: 151 · 2025: 175 · 2024: 146 · 2023: 111 · 2022: 79 · 2021: 36
FWCI
13.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Miami
  • Canadian Institute for Advanced Research
  • National Institute of Mental Health (R01MH107549)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Functions and Memory
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
cognitive flexibility, behavioral flexibility, neural mechanisms, frontoparietal network, frontostriatal circuits, neurodevelopmental disorders, dementia, cognitive training, physical activity, bilingualism
MeSH terms
Animals, Behavior, Behavioral Symptoms, Cognition, Cognition Disorders, Humans, Nerve Net, Nervous System Physiological Phenomena, Neural Pathways

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