Cognitive Flexibility: A Default Mode Perspective

The intra/extradimensional set-shifting task (IED) provides a reliable assessment of cognitive flexibility, the shifting of attention to select behaviorally relevant stimuli in a given context. Impairments in this domain were previously reported in patients with altered neurotransmitter systems such as schizophrenia and Parkinson's disease. Consequently, corticostriatal connections were implicated in the mediation of this function. In addition, parts of the default mode network (DMN), namely the medial prefrontal and posterior cingulate/precuneus cortices, are also being progressively described in association with set-shifting paradigms. Nevertheless, a definitive link between cognitive flexibility and DMN connectivity remains to be established. To this end, we related resting state functional magnetic resonance imaging (fMRI)-based functional connectivity of DMN with IED task performance in a healthy population, measured outside the scanner. The results demonstrated that greater posterior cingulate cortex/precuneus (DMN) connectivity with the ventromedial striatopallidum at rest correlated with fewer total adjusted errors on the IED task. This finding points to a relationship between DMN and basal ganglia connectivity for cognitive flexibility, further highlighting this network's potential role in adaptive human cognition.The Evelyn Trust (RUAG/018) supported this research. Additionally, DV received funding from the Yousef Jameel Academic Program; DKM is funded by the NIHR Cambridge Biomedical Centre (RCZB/004), and an NIHR Senior Investigator Award (RCZB/014), and EAS is supported by the Stephen Erskine Fellowship Queens’ College, Cambridge. We would also like to thank Dr. Guy Williams and Victoria Lupson and the rest of the staff in the Wolfson Brain Imaging Centre (WBIC) at Addenbrooke’s Hospital for their assistance in scanning. Finally, we thank all the participants for their contribution to this studyThis is the author accepted manuscript. The final version is available from Mary Ann Liebert via http://dx.doi.org/10.1089/brain.2015.038

Differential effects of dopaminergic therapies on dorsal and ventral striatum in Parkinson\u27s disease: implications for cognitive function.

Cognitive abnormalities are a feature of Parkinson\u27s disease (PD). Unlike motor symptoms that are clearly improved by dopaminergic therapy, the effect of dopamine replacement on cognition seems paradoxical. Some cognitive functions are improved whereas others are unaltered or even hindered. Our aim was to understand the effect of dopamine replacement therapy on various aspects of cognition. Whereas dorsal striatum receives dopamine input from the substantia nigra (SN), ventral striatum is innervated by dopamine-producing cells in the ventral tegmental area (VTA). In PD, degeneration of SN is substantially greater than cell loss in VTA and hence dopamine-deficiency is significantly greater in dorsal compared to ventral striatum. We suggest that dopamine supplementation improves functions mediated by dorsal striatum and impairs, or heightens to a pathological degree, operations ascribed to ventral striatum. We consider the extant literature in light of this principle. We also survey the effect of dopamine replacement on functional neuroimaging in PD relating the findings to this framework. This paper highlights the fact that currently, titration of therapy in PD is geared to optimizing dorsal striatum-mediated motor symptoms, at the expense of ventral striatum operations. Increased awareness of contrasting effects of dopamine replacement on dorsal versus ventral striatum functions will lead clinicians to survey a broader range of symptoms in determining optimal therapy, taking into account both those aspects of cognition that will be helped versus those that will be hindered by dopaminergic treatment

Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior

The Role of the Nucleus Accumbens and Rostral Anterior Cingulate Cortex in Anhedonia: Integration of Resting EEG, fMRI, and Volumetric Techniques

Anhedonia, the reduced propensity to experience pleasure, is a promising endo-- phenotype and vulnerability factor for several psychiatric disorders, including depression and schizophrenia. In the present study, we used resting electroencephalography, functional magnetic resonance imaging, and volumetric analyses to probe putative associations between anhedonia and individual differences in key nodes of the brain's reward system in a non-clinical sample. We found that anhedonia, but not other symptoms of depression or anxiety, was correlated with reduced nucleus accumbens (NAcc) responses to rewards (gains in a monetary incentive delay task), reduced NAcc volume, and increased resting delta current density (i.e., decreased resting activity) in the rostral anterior cingulate cortex (rACC), an area previously implicated in positive subjective experience. In addition, NAcc reward responses were inversely associated with rACC resting delta activity, supporting the hypothesis that delta might be lawfully related to activity within the brain's reward circuit. Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression.Psycholog

Neurobiological Foundations Of Stability And Flexibility

In order to adapt to changing and uncertain environments, humans and other organisms must balance stability and flexibility in learning and behavior. Stability is necessary to learn environmental regularities and support ongoing behavior, while flexibility is necessary when beliefs need to be revised or behavioral strategies need to be changed. Adjusting the balance between stability and flexibility must often be based on endogenously generated decisions that are informed by information from the environment but not dictated explicitly. This dissertation examines the neurobiological bases of such endogenous flexibility, focusing in particular on the role of prefrontally-mediated cognitive control processes and the neuromodulatory actions of dopaminergic and noradrenergic systems. In the first study (Chapter 2), we examined the role of frontostriatal circuits in instructed reinforcement learning. In this paradigm, inaccurate instructions are given prior to trial-and-error learning, leading to bias in learning and choice. Abandoning the instructions thus necessitates flexibility. We utilized transcranial direct current stimulation over dorsolateral prefrontal cortex to try to establish a causal role for this area in this bias. We also assayed two genes, the COMT Val158Met genetic polymorphism and the DAT1/SLC6A3 variable number tandem repeat, which affect prefrontal and striatal dopamine, respectively. The results support the role of prefrontal cortex in biasing learning, and provide further evidence that individual differences in the balance between prefrontal and striatal dopamine may be particularly important in the tradeoff between stability and flexibility. In the second study (Chapter 3), we assess the neurobiological mechanisms of stability and flexibility in the context of exploration, utilizing fMRI to examine dynamic changes in functional brain networks associated with exploratory choices. We then relate those changes to changes in norepinephrine activity, as measured indirectly via pupil diameter. We find tentative support for the hypothesis that increased norepinephrine activity around exploration facilitates the reorganization of functional brain networks, potentially providing a substrate for flexible exploratory states. Together, this work provides further support for the framework that stability and flexibility entail both costs and benefits, and that optimizing the balance between the two involves interactions of learning and cognitive control systems under the influence of catecholamines

The Link Between Creativity, Cognition, and Creative Drives and Underlying Neural Mechanisms

Having a creative mind is one of the gateways for achieving fabulous success and remarkable progress in professional, personal and social life. Therefore, a better understanding of the neural correlates and the underlying neural mechanisms related to creative ideation is crucial and valuable. However, the current literature on neural systems and circuits underlying creative cognition, and on how creative drives such as motivation, mood states, and reward could shape our creative mind through the associated neuromodulatory systems [i.e., the dopaminergic (DA), the noradrenergic (NE) and the serotonergic (5-HT) system] seems to be insufficient to explain the creative ideation and production process. One reason might be that the mentioned systems and processes are usually investigated in isolation and independent of each other. Through this review, we aim at advancing the current state of knowledge by providing an integrative view on the interactions between neural systems underlying the creative cognition and the creative drive and associated neuromodulatory systems (see Figure 1)

Examinations of pathomechanisms in schizophrenic and bipolar disorders – results from two functional magnetic resonance imaging studies

Psychiatric disorders, in particular schizophrenia and bipolar disorder, affect the patients’ lives deeply on many levels and place a heavy burden on the healthcare system. The treatment of these diseases is often complicated and marked by many setbacks. Symptoms that have the strongest consequences for coping with everyday life are the impairments of cognitive performance, for example memory or attention deficits. Therefore, it is of great interest to better understand the underlying pathomechanisms to eventually improve treatment options for those patients. In this thesis two different fMRI studies were used to investigate the functional correlates of patients suffering from schizophrenia or bipolar disorder while performing a combined oddball-incongruence task and a reward associated task. Study A conducted a categorical comparison between bipolar and schizophrenia patients of the brain activation during an oddball and incongruence task. The results showed pathophysiological differences in the activation intensities between bipolar and schizophrenia patients as well as between the patient groups and healthy individuals. Overall it seems as if the brain activation severely depended on the task difficulty leading to compensatory hyperactivations in frontal brain areas of bipolar patients during the oddball task. Schizophrenia patients demonstrated low threshold hyperactivations in the intraparietal cortex compared to healthy controls. In the cognitively more demanding incongruence condition these compensatory mechanisms seemed to fail leading to hypoactivations in various brain regions such as the middle frontal gyrus or ventral pathway. Pilot study B searched retrospectively for functional markers which enable support vector machine algorithms predicting specific treatment response to typical and atypical antipsychotics as well as aripiprazole in a transnosological sample consisting of bipolar and schizophrenia patients. Consequently, (de-)activation differences between responders and non-responders in their respective treatment arm resulting from the desire-reason-dilemma paradigm were applied to support vector machine algorithms. The implementation of parameter estimates from deactivations of aripiprazole non-responders in brain regions partially associated with the default mode network, led to a successful treatment response prediction of patients receiving aripiprazole. Even though in future studies the sample sizes should be increased and monotherapeutical treatment ensured, this thesis already provides important insights on the pathomechanisms of bipolar disorder and schizophrenia patients or more specifically within the spectrum of both diseases. Prospectively, further studies can help to specify potential functional biomarkers which also might be able to predict treatment response and consequently approach personalized precision treatment in psychiatric disorders

The social transmission of metacontrol policies: mechanisms underlying the interpersonal transfer of persistence and flexibility

Humans often face binary cognitive-control dilemmas, with the choice between persistence and flexibility being a crucial one. Tackling these dilemmas requires metacontrol, i.e., the control of the current cognitive-control policy. As predicted from functional, psychometric, neuroscientific, and modeling approaches, interindividual variability in metacontrol biases towards persistence or flexibility could be demonstrated in metacontrol-sensitive tasks. These biases covary systematically with genetic predispositions regarding mesofrontal and nigrostriatal dopaminergic functioning and the individualistic or collectivistic nature of the cultural background. However, there is also evidence for mood- and meditation-induced intraindividual variability (with negative mood and focused-attention meditation being associated with a bias towards persistence, and positive mood and open-monitoring meditation being associated with a bias towards flexibility), suggesting that genetic and cultural factors do not determine metacontrol settings entirely. We suggest a theoretical framework that explains how genetic predisposition and cultural learning can lead to the implementation of metacontrol defaults, which however can be shifted towards persistence or flexibility by situational factors.Action Contro

Neural and cognitive biomarkers of binge and heavy drinking

BACKGROUND: Theories suggest two motivations that drive people to consume alcohol at pathological levels: (1) seeking of short-term pleasurable effects and (2) alleviation of unpleasant states. The former is associated with binge drinking (BD; i.e. high intake during fewer occasions) and the latter with heavy drinking (HD; substantial intake during more occasions). Although direct comparisons have not been made, BD has been associated with impairments in top-down executive control (related to frontal-parietal regions) and HD has been linked to bottom-up changes in internal mentation (related to the default mode network anatomical structure and function). This dissertation compares the two drinking patterns with the goal of testing for differential neurocognitive and neuroanatomical characteristics that would be indicative of two disorder subtypes. METHODS: The sample consisted of adult participants with a history of adolescent onset: BD (N = 16), HD (N = 15), and Healthy Controls (HC; N = 21). All groups were equated on age, education, amount of lifetime alcohol consumed (BD and HD groups), as well as other factors. The study compared group performance on an affective go/no go task and group differences in brain volume and cortical thickness based on structural MRI. RESULTS: Behavioral results showed a higher number of errors for the HD group, in comparison to other groups. Volumetric results indicated a smaller bilateral ventral diencephalon in both BD and HD, in comparison to the HC, and smaller bilateral globus pallidus in BD only. Cortical thickness analyses revealed a thinner left superior parietal region (overlapping with the dorsal attention and fronto-parietal networks) in BD, whereas a left medial occipito-parietal region was thicker in HD (overlapping mainly with the visual network). CONCLUSION: These data, interpreted in the context of prior studies, suggest that BD findings might be indicative of an executive control dysregulation that could contribute to continued BD. HD findings might be indicative of tissue damage due to frequent drinking. Prior research has found the occipital region to have the highest concentration γ-Aminobutyric acid receptors that are affected by alcohol, which might explain the thicker occipital region findings in the HD group