As a regulatory capacity, EF is central to a range of normal and abnormal behavior particularly relevant for psychiatric illness, and has been suggested to impact psychiatric functioning through involvement in, and overlap with, emotional regulation ER processes. Indeed, both EF and ER deficits are pervasive throughout psychiatric disorders, to varying degrees of severity and specificity, and hence may be of significant transdiagnostic importance.
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There is evidence that the neural circuitry that supports EF and ER is largely overlapping. In this review we will focus specifically on the contribution of circuit abnormalities relevant to EF and ER to psychiatric disorders. We restrict our focus to patients aged 60 and below to insure that the relationship of cognitive deficits to psychiatric disorders is not primarily due to age-related changes in cognition.
We will begin with an overview of the neural systems underlying EF and ER, followed by a description of how deficits in these systems, or their behavioral output, subserve a range of psychiatric disorders. Finally, we will examine the relationship between EF and ER capacities and current treatments, as well as avenues for novel treatments through a neurobiological understanding of EF and ER. Cognitive regulation of behavior and emotions is supported by several circuits in the PFC. While the PFC is typically not necessary for the learning or performance of simple tasks, when task demands change, the PFC is required for proper adjustments in behavior to maintain accuracy and goal-directed behavior.
This capacity of the PFC is conserved across mammalian species. In order to accomplish this, the PFC must be able to maintain a representation of goals in the face of distraction, update these representations as new information is received through multiple sensory modalities, and provide a feedback signal that can select the neural pathways appropriate for the current task context. Within this broad capacity for EF, several more specific subgroupings of functions are possible, commonly considered to be inhibition, working memory, and cognitive flexibility. Nonetheless, any individual task paradigm aimed at one of these domains will, to some degree, involve one or both of the others.
Working memory in particular is a function common to most tests of EF. Figure 1A 7 , 8 In addition to these common cognitive control networks, a set of regions including the inferior frontal gyrus, supplementary motor area, and subthalamic nucleus have been implicated in response inhibition specifically. This network is comprised of medial prefrontal, medial, and lateral parietal, and medial temporal regions. Concomitant with engagement of the frontoparietal and cingulo-opercular network, the default mode network deactivates Figure 1A.
Deactivation is associated with a negative blood oxygen level-dependent response on functional magnetic resonance imaging fMRI scans, and suppression of gamma band activity on intracranial recordings. Evidence indicates that the above described EF circuitry is also crucially implicated in the regulation of emotions. Emotions themselves are complex, coordinated phenomena that involve behavioral, cognitive, and physiological changes, activate action tendencies, and create subjective feelings. Implicit ER, on the other hand, has only recently begun to be understood at the neurobiological level.
We have reported on a task wherein subjects spontaneously regulate emotional conflict, a salient emotional stimulus, adaptively from trial to trial. In this task, the ventral anterior cingulate cortex vACC regulates emotional conflict on a trial-by-trial basis by dampening amygdala activity, but without involvement of activation in EF-related cognitive control networks Figure 1C. While psychosis is a hallmark symptom of schizophrenia and dominates its acute clinical presentation, cognitive dysfunction both predates onset of psychosis and is present in the absence of psychotic symptoms.
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Cognitive dysfunction is more chronic, predicts poor outcome including impairments in functional capacity , and is not substantially helped by available pharmacotherapies. Moreover, deficits in many of these cognitive domains are seen in unaffected first-order relatives of patients with schizophrenia, consistent with a strong genetic contribution to the risk of schizophrenia. Recent work has also implicated a similar range of cognitive deficits in other disorders that include psychosis. Even when euthymic, patients with bipolar disorder show cognitive impairments relative to healthy controls with medium to large effect sizes, especially within EF.
Consistent with the neuropsychological literature, imaging studies of schizophrenia have used a variety of tasks that probe elements of EF with fMRI or positron emission tomography PET imaging. A meta-analysis that included all of these studies found that across all of the EF domains tested, patients consistently hypoactivated a set of largely lateral and medial prefrontal regions. This is consistent with the failure to engage normal cognitive control circuitry in the prefrontal cortex.
Interestingly, greater activation was found in patients in a more posterior region of the dACC, along with a portion of the VLPFC, which may reflect network inefficiency or efforts to compensate for impaired activation of prefrontal cognitive control regions. In part, however, whether hypoactivation or hyperactivation is observed reflects the difficulty of the task. DLPFC activity in healthy subjects, for example, decreases from its peak as working memory is stressed beyond its maximal capacity. The network formulation of EF circuitry outlined above argues that cognitive impairments may arise because of failure to activate prefrontal cognitive control networks, failure to deactivate the default mode network, or abnormalities in the interaction between prefrontal cognitive control networks and the default mode network.
In line with this prediction, patients with schizophrenia also display a failure to suppress activity in the default mode network with cognitively engaging tasks. Blockade of the NMDA receptor in healthy subjects using ketamine results in decreased cognitive control network activation, blunted default mode network activation, reductions in the reciprocal connectivity relationship between these regions, and impairment in working memory task performance. Of the affective disorders, MDD has been best studied with respect to neuropsychological measures of cognition. Deficits in a range of EFs have been found in MDD with small to large effect sizes, depending on the test or component of EF under investigation.
In a recent large meta-analysis of these studies, the authors failed to find an effect of current symptoms ie, symptomatic versus remitted patients on many aspects of EF task performance, 45 suggesting that many of these impairments persist beyond the current mood episode, much as noted in bipolar disorder. Popular models of PTSD center around impairments in the learning and extinction of fear-based memories. Available evidence, however, demonstrates a similarly broad EF deficit in PTSD to that in MDD, including inhibition, sustained attention, working memory, and task shifting.
In one meta-analysis, presence of comorbid depression significantly moderated the magnitude of PTSD deficits in sustained attention, working memory, and attentional shifting.
Outside of PTSD, limited neuropsychological assessment data are available on social anxiety disorder, in which the subtle deficits that have been observed in cognition appear to be at least partially related to elevated situational anxiety. For generalized anxiety disorder and panic disorder, studies are limited and findings mixed.
However, some investigations indicate that individuals with anxiety comorbid with another psychiatric disorder are more likely to have executive function deficits than those without comorbid anxiety. Much as with schizophrenia, individual studies have reported both hypoactivation and hyperactivation of prefrontal cognitive control regions in depression, compared with healthy controls.
Though few direct comparisons have been made between patients with depression and those with schizophrenia, DLPFC inefficiency may be greater in schizophrenia than depression. Depressed patients also fail to deactivate the default mode network, 56 which is also related to local glutamate concentrations.
Nonetheless, preliminary evidence implicates abnormalities in cognitive control network activation during working memory in PTSD. Cognitive dysfunction, and in particular impairments in EF, can be found across a wide range of psychiatric disorders. The greatest severity of impairment appears to be in chronic psychosis, but can nonetheless be seen in nonpsychotic mood and anxiety disorders.
Moreover, these impairments largely persist into periods with reduced or absent expression of disorder-related symptoms, and are also largely not normalized by current antidepressant, mood-stabilizing, or antipsychotic medications. The imaging findings from studies of EF across psychotic and affective disorders mirror the neuropsychological findings, wherein broadly similar abnormalities were observed across symptomatically disparate disorders.
Specifically, deficits were observed in activation of cognitive control networks, deactivation of the default mode network, and in the reciprocal interaction between these two brain systems, all of which may contribute to cognitive dysfunction. In psychosis, where these impairments appear to be greatest, and where there is less evidence for biased emotional processing, they may be expressed primarily as severe cognitive deficits.
In affective disorders, in which biased emotional processing has been well-documented especially in terms of biases towards negative stimuli , 62 these network impairments may contribute to both cognitive dysfunction and perseverative emotion-related cognition such as rumination. Overall, dysfunction in EF and the neurocircuits subserving these cognitive control processes, may represent a potential core endophenotype of severe mental illnesses across traditional diagnostic categories. In light of the relationship between cognitive dysfunction and worse functional capacity in various disorders, the severity of trans-diagnostic real-world functional impairment may be the primary symptomatic expression of the severity of the disturbance in cognition.
Given the close relationship between circuitry important for EF and ER, the expectation is that in those patients in whom there is a deficit in EF, there will also be a deficit in ER. Moreover, even for those patients in whom the EF deficit is more subtle, the combination of a mild EF deficit with robust emotional capture of attention could result in an ER deficit due to heightened reactivity. However, unlike for EF, there are no well-validated neuropsychological assessments of ER, and hence the literature developed on ER focuses on neuroimaging.
Though the emotion regulation literature has focused primarily on affective disorders, one study of patients with schizophrenia found that they failed to activate a VLPFC region implicated in explicit ER during efforts to downregulate negative emotion, and failed to show the expected reciprocal amygdala-prefrontal relationship. The authors interpreted this as suggesting a deficit in engagement of cognitive control over emotion in schizophrenia, and inefficiency of this circuitry, once engaged, in bipolar disorder.
One additional factor that may account for different ER abnormalities in schizophrenia and bipolar disorder is that bipolar patients generally overengage emotional systems in response to facial expression stimuli, while schizophrenics underengage these systems. Studies in affective disorders have also shown relativelysimilar deficits in explicit ER across disorders.
A neurobiological approach to the cognitive deficits of psychiatric disorders
Depressed patients generally activated cognitive control circuitry the same as, or more than, controls during explicit downregulation of negative emotion, but either did not show amygdala decreases, 67 , 68 did not show the expected reciprocal amygdala-prefrontal relationship during regulation, 69 or were unable to sustain those decreases.
Implicit ER has only very recently been investigated with neuroimaging, and its parameters are only now being fleshed out. Despite a bias in the study of ER towards affective disorders and the relatively early stage of this literature, the available neuroimaging evidence suggests abnormalities. It may be, however, that the cause of these abnormalities differ across disorder, with a primary deficit in EF and disruption of normal pathways for emotion processing accounting for ER abnormalities in schizophrenia, and more subtle EF deficits together with heightened emotional capture in affective disorders accounting for ER abnormalities in those conditions.
Available evidence suggests that EF and ER abnormalities persist during euthymic states, are seen during periods of lower expression of psychotic symptoms, and are not normalized, even when symptoms have remitted with treatment. As such, EF and ER represent a broad domain of dysfunction in psychiatric illness that is unaddressed by current treatments. What is notable about MATRICS is that it was conceived as a process that would also involve changing expectations at the FDA to allow as a primary indication the improvement in cognition, even in the absence of effects on other symptoms of the disorder.
Potential compounds emerging from this and related work target glutamatergic transmission, nicotinic acetylcholine receptors, and selective dopaminergic agents. Another emerging trend involves brain training approaches.
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Having already identified the neural circuits important for EF and ER, as well as demonstrated abnormalities in these circuits across multiple psychiatric disorders, it may be possible to strengthen the functioning of these neural circuits by repeatedly doing adaptive versions of the tasks that normally engage them. In other words, deficits in working memory may be ameliorated through a challenging course of working memory training. There is a growing body of evidence suggesting that this once-controversial proposition may be possible, at least in certain contexts.
Moreover, adult brains, even those dysfunctional because of mental illness, still retain a surprising degree of plasticity. Brain training has been most extensively investigated in schizophrenia, where it derives from a tradition of cognitive remediation research and psychosocial rehabilitation. In schizophrenia, evidence shows that brain training alone, aimed at EF and basic sensory discrimination and gating, can yield beneficial effects on tests of EF and in terms of daily functioning. There is already evidence in anxiety disorders that training subjects to avert their attention from threat stimuli may modify their attentional bias and diminish symptoms.
More generally, computer-based brain training interventions have the advantage that they can be readily standardized and well controlled in randomized trials, do not require involvement of a therapist or even particular treatment expertise in the provider, and can be readily disseminated. Much more work, however, will be needed to optimize this training approach eg, dose, duration, type of stimuli, ideal target populations from where it currently is.
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Finally, and in line with the concepts driving brain training, it may be possible to selectively target EF- and ERrelated circuitry using brain stimulation. Transcranial magnetic stimulation TMS , for example, can be used to activate local superficial cortical sites, and their interconnected network partners, and when applied repetitively rTMS produces plastic circuit changes. One recent resting-state fMRI study examined connectivity patterns of sites within the DLPFC that are in clinical studies associated with better or worse clinical outcome.
We found that targeting a region in the posterior DLPFC, typically associated with the fronto-parietal network, causally inhibits in particular the mPFC component of the default mode network. The importance of abnormalities in EF and ER is clear across a broad range of psychiatric disorders, suggesting that they represent core and related endophenotypes of severe mental illnesses. The findings reviewed here demonstrate that a clearer neurobiological understanding of these disruptions in both EF and ER is beginning to emerge, and that this understanding has already led to promising avenues for remediation of these deficits.
National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v. The overarching goal of the course is to provide a neurobiological perspective on how information is encoded, consolidated and later retrieved and the significance of dysfunction in these processes associated with neurologic disease.
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