Cognitive Flexibility – Neurology

” Recent meta-analyses of neuroimaging studies of cognitive flexibility in neurotypical adults have identified a distributed network of frontoparietal regions involved in flexible switching, including high-level cortical association areas (vlPFC, dlPFC, anterior cingulate, right AI), the premotor cortex, the inferior and superior parietal cortices, the inferior temporal cortex, the occipital cortex, and subcorti- cal structures such as the caudate and thalamus [26,27]. “^​1​

” Recent meta-analyses of neuroimaging studies of cognitive flexibility in neurotypical adults have identified a distrib- uted network of frontoparietal regions involved in flexible switching, including high-level cortical association areas (vlPFC, dlPFC, anterior cingulate, right AI), the premotor cortex, the inferior and superior parietal cortices, the inferior temporal cortex, the occipital cortex, and subcorti- cal structures such as the caudate and thalamus [26,27]. Ongoing work is attempting to understand how these brain regions interact to form a coherent network to implement cognitive flexibility. “^​1​

” It is unclear wheth- er cognitive flexibility arises from neural substrates distinct from the executive control network (ECN) or from the interplay of nodes within this and other net- works. “^​1​

” Cognitive flexibility is likely to emerge from the interplay of specific nodes in the frontal and parietal cortices, all of which are necessary while each provides a relatively specific functional contri-bution. These nodes may not be specific to cognitive flexi-bility but are activated across a range of other EFs such as working memory, attention, and inhibition [27]. The neu-ral context in which these nodes operate, such as their connectivity with other nodes [41], may determine which cognitive operation is conducted. “^​1​

” The vlPFC, widely implicated in inhibitory control [20,21,29], is also consistently recruited during cognitive flexibility tasks “^​1​

” One of the most robust regions of activation across various cognitive flexibility tasks is the PPC [26]. The PPC is the site of visual attentional processing and visuomotor inte-gration “^​1​

” Other areas consistently reported in cognitive flexibility fMRI studies are the ACC and AI [27,28,34–36], which are key nodes of the salience network [24] or cingulo-opercular network “^​1​

“Young children (around 5 years of age) tend to have difficulty processing task cues efficiently to determine the relevant task [48,58,59]. Cue monitoring is also an impor- tant facet of inhibition [60] that may be subserved by the right vlPFC [29]. Developmental brain network differences between children and adults may be partially explained by improvements in cue monitoring, possibly driven by mat- uration of the right vlPFC. In support of this view, Rubia et al. [54] showed a linear increase in activation of right vlPFC from childhood to adulthood during both inhibition and switching tasks “^​1​

“The brain regions most consis- tently involved in inhibitory control are the right vlPFC [20,21], AI, and inferior frontal junction (IFJ) [22]. Recent studies have aimed to delineate the separable functional roles of these three regions in inhibitory control. Cai and colleagues [23] revealed that the rAI is particularly impor- tant for detecting behaviorally relevant events, highlight- ing its role as a node in the salience network [24]. Sebastian and colleagues [25] demonstrated that the rIFJ is impor- tant for detection of behaviorally relevant stimuli, empha- sizing its primary involvement as a possible mediator etween the dorsal and ventral attention networks. Mir- roring the Cai et al. (2014) results demonstrating the specific functional role of the right vlPFC in inhibitory control, Sebastian et al. (2015) showed that the right vlPFC is involved in response inhibition as it interacts with motor regions to update action sequences. “^​1​

” cent research has suggested that phasic LC activity, driven by outcome of task-related decisions believed to be computed in the orbito-frontal and anterior cingulate cortices, facilitates task-relevant processes in contrast to distractors to optimize task performance (Aston-Jones & Cohen, 2005). Increased tonic LC activity, particularly when associated with decreased phasic LC activity, promotes disengagement from current behaviors while facilitating exploration of other behaviors (Aston-Jones & Cohen, 2005). As would be expected by this tonic LC effect, increased alpha-1 adrenergic activity has been shown to facilitate attentional set-shifting ” ^​2​ ( locus ceruleus , assumed)

Salience Network

” The relative salience of a stimulus determines whether it will capture attention and be processed further. The sa-lience network [including the anterior insula (AI), dorsal anterior cingulate cortex (dACC), and other subcortical and limbic structures] plays a central role in the detection of behaviorally relevant stimuli and the coordination of neural resources “^​1​ ” he process of salience detection is the first step toward attention allocation and subsequent implementation of flexible responses. While the posterior and mid-insula act to integrate and transmit interoceptive signals, the AI plays a critical role in orchestrating dynam- ic interactions between large-scale brain networks for externally oriented and internally oriented attention in neurotypical adults and children “^​1​

Attention

” The dorsal attention network (DAN), composed of the intraparietal sulcus (IPS) and frontal eye fields (FEFs), is thought to underlie top-down processing and the ven- tral attention network (VAN), composed of the right temporoparietal junction (TPJ) and ventrolateral pre- frontal cortex (vlPFC), supports bottom-up attention [17]. Laboratory tasks of cognitive flexibility may involve both of these attentional systems. For example, unexpect- ed stimuli that cue a switch phase direct attention via the VAN. In other tasks, experimenters may provide cues that indicate what rule should be implemented and thus the participant exerts top-down control to orient to the relevant features of the stimulus. These attentional sys- tems may also work synergistically to filter incoming sensory information that is relevant to the goal. Regard- less of the extent to which these attentional systems are recruited, the DAN and VAN are critically involved in successful cognitive flexibility “^​1​

Task Switching

” In general, task switch-ing paradigms, which are inherently more complex than set shifting tasks, tend to impose greater working memory demands. fMRI studies implementing working memory paradigms generally demonstrate activation of the dorso-lateral PFC, vlPFC, and premotor and parietal cortices [18], constituting the ECN. If working memory load is not properly controlled for in task designs, potential confounds can arise when attempting to identify neural correlates of cognitive flexibility. “^​1​

” The IFJ may be particularly necessary for the updating of task rule representations during task switching [1]. The IFJ is consistently activated across various paradigms eliciting cognitive flexibility such as set shifting and task switching [26]. Further, inhibitory control tasks, in addi- tion to cognitive flexibility tasks, tend to activate the IFJ [28]. The right IFJ is strongly activated for context moni- toring during inhibition [29]. The results of these studies suggest a fundamental role of the IFJ in cognitive flexibili- ty, but it is unclear precisely what cognitive operation is implemented by the IFJ. A survey of the tasks engaging the IFJ suggests that this brain region is either the site of response-set updating of task rules or the site of inhibition f the previous response set. The fact that inhibition is inherently involved in cognitive flexibility may explain why the IFJ is consistently activated across paradigms requiring participants to flexibly switch their response set or task rule representation “^​1​

Neurotransmitters

” Results indicate that (1) stress impaired perform- ance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. Therefore, psychological stress, such as public speaking, negatively impacts performance on tasks requiring cognitive flexibility in normal individuals, and this effect is reversed by beta-adrenergic antagonism. This may provide support for the hypothesis that stress-related impair- ments in cognitive flexibility are related to the noradrenergic system “^​2​

Norepinephrine

” Stress-induced activation of the locus ceruleus–norepinephrine (LC–NE) system produces significant cognitive and behavioral effects, including enhanced arousal and attention. Improvements in discrimination task performance and memory have been attributed to this stress response. In contrast, for other cognitive functions that require cognitive flexibility, increased activity of the LC–NE system may produce deleterious effects.”^​2​‘

” Many studies examining cognitive flexibility have examined the effect of the serotonergic (…) and do- paminergic (…) systems. However, stressors impact the locus ceruleus–noradrenergic system (LC–NE) to stimulate the release of norepinephrine (NE) (…). In general, behavioral studies suggest that increased noradrenergic activity enhances processing of salient stimuli concomi- tant with suppression of irrelevant stimuli; in effect, NE acts to narrow attentional focus (…). Furthermore, increased distractibility can result from decreased NE activity (…). These may occur as a result of the effect of NE on the signal-to-noise ratio within cortical neurons “^​2​

“However, flexibility of access to the lexical–semantic and associative network may not be affected in the same manner. Stress has been shown to impair other aspects of prefrontal cortical function (Arnsten, 2000), a region throughout which NE stimula- tion from the LC is received (Lewis & Morrison, 1989), and which is, in general, important for performance on a wide variety of aspects of cognitive flexibility (Stemme, Deco, Busch, & Schneider, 2005; Dalley, Cardinal, & Robbins, 2004). Furthermore, some of these aspects of prefrontal cortical function are impaired by stress- induced beta-1 adrenergic activity (Ramos et al., 2005) and alpha-1 adrenergic activity”^​2​

Serotonin

” We have previously demonstrated that different forms of cognitive flexibility, dependent upon distinct regions of the prefrontal cortex (PFC), are differentiallymodulated by serotonin (5-hydrox- ytryptamine [5-HT]) “^​3​ ” hus, 5-HT depletion impairs the ability to switch responding between one of the two visual stimuli on a serial discrimination reversal (SDR) task, an ability previously shown to depend upon the orbitofrontal cortex (OFC) in humans “^​3​ ” Further examination of the nature of the behavioral deficit (Experiment 2) revealed that the failure of 5-HT-lesioned monkeys to cease responding to the previously correct stimulus was due to an inability to disengage from that stimulus and was not due to a failure to reengage with the stimulus previously learned to be incorrect (learned avoidance) or to an attenuation of proactive interference. “^​3​ ” in conclusion, these studies suggest that the discrimination reversal deficits induced by ventral prefrontal 5-HT depletion are due specifically to a failure to cease responding to the previously rewarded stimulus “^​3​

Dopamine

” Stimulating D2Rs improves performance of subjects in a WCST [130], and increases functional imaging signals in frontal cortex during rule switching [131]. These findings lead to the conclusion that the contribution of dopamine to cognitive flexibility is mainly mediated by D2Rs [18], or by cooperative actions of D1Rs and D2Rs with complex dose–response functions “^​4​ ” An even stronger influence was reported by blocking prefrontal D2Rs, which leads to an impaired performance by increasing perseverative errors, in other words rats maintain the same response strategy and need more trials to shift their strategy “^​4​ ” In humans, D1R availability in PFC is positively correlated with flexibly shifting between rules during a Wisconsin card-sorting test (WCST), a task probing the ability of a subject to flexibly shift between strategies [127,128]. Blocking D2Rs impairs shifting between response strategies in a variation of the WCST in which subjects were required to learn new visual discriminations based on different stimulus dimensions “^​4​

“Dopamine (DA) D2 receptor antagonists have been shown to produce similar impair- ments to those seen in Parkinson’s disease. These include working memory and set-shifting deficits”^​5​ “Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. “^​5​ ” These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory “^​5​ ” However, switch- ing cognitive behaviour (i.e. reorienting sensory/internal resources to behaviourally relevant targets), at the stimu- lus, attentional, or task level has been postulated to involve DA neurotransmission “^​5​ ” The specific lengthening of switch-costs on the task set- switching paradigm following sulpiride (and the similar trend seen for the attentional set-shifting test) is in keeping with earlier suggestions that DA activity is important for the flexibility of behaviour utilising available sensory information “^​5​

” Importantly, patients with Parkinson’s disease are impaired in switching between two tasks (Cools et al. 2001b), and dopaminergic medication remediates this impairment “^​5​

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