Distinct neurofunctional alterations during motivational and hedonic processing of natural and monetary rewards in depression - a neuroimaging meta-analysis.

Reward processing dysfunctions are considered a candidate mechanism underlying anhedonia and apathy in depression. Neuroimaging studies have documented that neurofunctional alterations in mesocorticolimbic circuits may neurally mediate these dysfunctions. However, common and distinct neurofunctional alterations during motivational and hedonic evaluation of monetary and natural rewards in depression have not been systematically examined. Here, we capitalized on pre-registered neuroimaging meta-analyses to (1) establish general reward-related neural alterations in depression, (2) determine common and distinct alterations during the receipt and anticipation of monetary v. natural rewards, and, (3) characterize the differences on the behavioral, network, and molecular level. The pre-registered meta-analysis (https://osf.io/ay3r9) included 633 depressed patients and 644 healthy controls and revealed generally decreased subgenual anterior cingulate cortex and striatal reactivity toward rewards in depression. Subsequent comparative analyses indicated that monetary rewards led to decreased hedonic reactivity in the right ventral caudate while natural rewards led to decreased reactivity in the bilateral putamen in depressed individuals. These regions exhibited distinguishable profiles on the behavioral, network, and molecular level. Further analyses demonstrated that the right thalamus and left putamen showed decreased activation during the anticipation of monetary reward. The present results indicate that distinguishable neurofunctional alterations may neurally mediate reward-processing alterations in depression, in particular, with respect to monetary and natural rewards. Given that natural rewards prevail in everyday life, our findings suggest that reward-type specific interventions are warranted and challenge the generalizability of experimental tasks employing monetary incentives to capture reward dysregulations in everyday life.

Diverse functional interaction driven by control-default network hubs supports creative thinking.

Complex cognitive processes, like creative thinking, rely on interactions among multiple neurocognitive processes to generate effective and innovative behaviors on demand, for which the brain's connector hubs play a crucial role. However, the unique contribution of specific hub sets to creative thinking is unknown. Employing three functional magnetic resonance imaging datasets (total N = 1,911), we demonstrate that connector hub sets are organized in a hierarchical manner based on diversity, with "control-default hubs"-which combine regions from the frontoparietal control and default mode networks-positioned at the apex. Specifically, control-default hubs exhibit the most diverse resting-state connectivity profiles and play the most substantial role in facilitating interactions between regions with dissimilar neurocognitive functions, a phenomenon we refer to as "diverse functional interaction". Critically, we found that the involvement of control-default hubs in facilitating diverse functional interaction robustly relates to creativity, explaining both task-induced functional connectivity changes and individual creative performance. Our findings suggest that control-default hubs drive diverse functional interaction in the brain, enabling complex cognition, including creative thinking. We thus uncover a biologically plausible explanation that further elucidates the widely reported contributions of certain frontoparietal control and default mode network regions in creativity studies.

Ongoing Brain Activity and Its Role in Cognition: Dual versus Baseline Models.

What is the role of the brain's ongoing activity for cognition? The predominant perspectives associate ongoing brain activity with resting state, the default-mode network (DMN), and internally oriented mentation. This triad is often contrasted with task states, non-DMN brain networks, and externally oriented mentation, together comprising a "dual model" of brain and cognition. In opposition to this duality, however, we propose that ongoing brain activity serves as a neuronal baseline; this builds upon Raichle's original search for the default mode of brain function that extended beyond the canonical default-mode brain regions. That entails what we refer to as the "baseline model." Akin to an internal biological clock for the rest of the organism, the ongoing brain activity may serve as an internal point of reference or standard by providing a shared neural code for the brain's rest as well as task states, including their associated cognition. Such shared neural code is manifest in the spatiotemporal organization of the brain's ongoing activity, including its global signal topography and dynamics like intrinsic neural timescales. We conclude that recent empirical evidence supports a baseline model over the dual model; the ongoing activity provides a global shared neural code that allows integrating the brain's rest and task states, its DMN and non-DMN, and internally and externally oriented cognition.

The right inferior frontal gyrus as pivotal node and effective regulator of the basal ganglia-thalamocortical response inhibition circuit.

Background: The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in animal models. However, the pivotal nodes and directed causal regulation within this inhibitory circuit in humans remains controversial. Objective: The main aim of the present study was to determine the causal information flow and critical nodes in the basal ganglia-thalamocortical inhibitory circuits and also to examine whether these are modulated by biological factors (i.e. sex) and behavioral performance. Methods: Here, we capitalize on the recent progress in robust and biologically plausible directed causal modeling (DCM-PEB) and a large response inhibition dataset (n = 250) acquired with concomitant functional magnetic resonance imaging to determine key nodes, their causal regulation and modulation via biological variables (sex) and inhibitory performance in the inhibitory circuit encompassing the right inferior frontal gyrus (rIFG), caudate nucleus (rCau), globus pallidum (rGP), and thalamus (rThal). Results: The entire neural circuit exhibited high intrinsic connectivity and response inhibition critically increased causal projections from the rIFG to both rCau and rThal. Direct comparison further demonstrated that response inhibition induced an increasing rIFG inflow and increased the causal regulation of this region over the rCau and rThal. In addition, sex and performance influenced the functional architecture of the regulatory circuits such that women displayed increased rThal self-inhibition and decreased rThal to GP modulation, while better inhibitory performance was associated with stronger rThal to rIFG communication. Furthermore, control analyses did not reveal a similar key communication in a left lateralized model. Conclusions: Together, these findings indicate a pivotal role of the rIFG as input and causal regulator of subcortical response inhibition nodes.

Dynamic changes in brain lateralization correlate with human cognitive performance.

Hemispheric lateralization constitutes a core architectural principle of human brain organization underlying cognition, often argued to represent a stable, trait-like feature. However, emerging evidence underlines the inherently dynamic nature of brain networks, in which time-resolved alterations in functional lateralization remain uncharted. Integrating dynamic network approaches with the concept of hemispheric laterality, we map the spatiotemporal architecture of whole-brain lateralization in a large sample of high-quality resting-state fMRI data (N = 991, Human Connectome Project). We reveal distinct laterality dynamics across lower-order sensorimotor systems and higher-order associative networks. Specifically, we expose 2 aspects of the laterality dynamics: laterality fluctuations (LF), defined as the standard deviation of laterality time series, and laterality reversal (LR), referring to the number of zero crossings in laterality time series. These 2 measures are associated with moderate and extreme changes in laterality over time, respectively. While LF depict positive association with language function and cognitive flexibility, LR shows a negative association with the same cognitive abilities. These opposing interactions indicate a dynamic balance between intra and interhemispheric communication, i.e., segregation and integration of information across hemispheres. Furthermore, in their time-resolved laterality index, the default mode and language networks correlate negatively with visual/sensorimotor and attention networks, which are linked to better cognitive abilities. Finally, the laterality dynamics are associated with functional connectivity changes of higher-order brain networks and correlate with regional metabolism and structural connectivity. Our results provide insights into the adaptive nature of the lateralized brain and new perspectives for future studies of human cognition, genetics, and brain disorders.

Association between parental age, brain structure, and behavioral and cognitive problems in children.

OBJECTIVE: To investigate the relation between parental age, and behavioral, cognitive and brain differences in the children. METHOD: Data with children aged 9-11 of 8709 mothers with parental age 15-45 years were analyzed from the Adolescent Brain Cognitive Development (ABCD) study. A general linear model was used to test the associations of the parental age with brain structure, and behavioral and cognitive problems scores. RESULTS: Behavioral and cognitive problems were greater in the children of the younger mothers, and were associated with lower volumes of cortical regions in the children. There was a linear correlation between the behavioral and cognitive problems scores, and the lower brain volumes (r > 0.6), which was evident when parental age was included as a stratification factor. The regions with lower volume included the anterior cingulate cortex, medial and lateral orbitofrontal cortex and amygdala, parahippocampal gyrus and hippocampus, and temporal lobe (FDR corrected p < 0.01). The lower cortical volumes and areas in the children significantly mediated the association between the parental age and the behavioral and cognitive problems in the children (all p < 10-4). The effects were large, such as the 71.4% higher depressive problems score, and 27.5% higher rule-breaking score, in the children of mothers aged 15-19 than the mothers aged 34-35. CONCLUSIONS: Lower parental age is associated with behavioral problems and reduced cognitive performance in the children, and these differences are related to lower volumes and areas of some cortical regions which mediate the effects in the children. The findings are relevant to psychiatric understanding and assessment.

Segregating domain-general from emotional context-specific inhibitory control systems - ventral striatum and orbitofrontal cortex serve as emotion-cognition integration hubs.

Inhibitory control hierarchically regulates cognitive and emotional systems in the service of adaptive goal-directed behavior across changing task demands and environments. While previous studies convergently determined the contribution of prefrontal-striatal systems to general inhibitory control, findings on the specific circuits that mediate emotional context-specific impact on inhibitory control remained inconclusive. Against this background we combined an evaluated emotional Go/No Go task with fMRI in a large cohort of subjects (N=250) to segregate brain systems and circuits that mediate domain-general from emotion-specific inhibitory control. Particularly during a positive emotional context, behavioral results showed a lower accuracy for No Go trials and a faster response time for Go trials. While the dorsal striatum and lateral frontal regions were involved in inhibitory control irrespective of emotional context, activity in the ventral striatum (VS) and medial orbitofrontal cortex (mOFC) varied as a function of emotional context. On the voxel-wise whole-brain network level, limbic and striatal systems generally exhibited highest changes in global brain connectivity during inhibitory control, while global brain connectivity of the left mOFC was less decreased during emotional contexts. Functional connectivity analyses moreover revealed that negative coupling between the VS with inferior frontal gyrus (IFG)/insula and mOFC varied as a function of emotional context. Together these findings indicate separable domain- general as well as emotional context-specific inhibitory brain systems which specifically encompass the VS and its connections with frontal regions.

Mindfulness practice for protecting mental health during the COVID-19 pandemic.

Emerging evidence shows that the coronavirus disease 2019 (COVID-19) pandemic is negatively affecting mental health around the globe. Interventions to alleviate the psychological impact of the pandemic are urgently needed. Whether mindfulness practice may protect against the harmful emotional effects of a pandemic crisis remains hitherto unknown. We investigated the influence of mindfulness training on mental health during the COVID-19 outbreak in China. We hypothesized that mindfulness practitioners might manifest less pandemic-related distress, depression, anxiety, and stress than non-practitioners and that more frequent practice would be associated with an improvement in mental health during the pandemic. Therefore, we assessed pandemic-related distress and symptoms of depression, anxiety, and stress, as well as the frequency of meditation practice at the peak of new infections (Feb 4-5; N = 673) and three weeks later (Feb 29-30; N = 521) in mindfulness practitioners via online questionnaires. Self-reported symptoms were also collected from non-practitioners at peak time only (N = 1550). We found lower scores of pandemic-related distress in mindfulness practitioners compared to non-practitioners. In general, older participants showed fewer symptoms of depression and anxiety. In younger practitioners, pandemic-related distress decreased from peak to follow-up. Importantly, increased mindfulness training during the preceding two weeks was associated with lower scores of depression and anxiety at both assessments. Likewise, practice frequency predicted individual improvement in scores of depression, anxiety, and stress at follow-up. Our results indicate that mindfulness meditation might be a viable low-cost intervention to mitigate the psychological impact of the COVID-19 crisis and future pandemics.

Varying demands for cognitive control reveals shared neural processes supporting semantic and episodic memory retrieval.

The categorisation of long-term memory into semantic and episodic systems has been an influential catalyst for research on human memory organisation. However, the impact of variable cognitive control demands on this classical distinction remains to be elucidated. Across two independent experiments, here we directly compare neural processes for the controlled versus automatic retrieval of semantic and episodic memory. In a multi-session functional magnetic resonance imaging experiment, we first identify a common cluster of cortical activity centred on the left inferior frontal gyrus and anterior insular cortex for the retrieval of both weakly-associated semantic and weakly-encoded episodic memory traces. In an independent large-scale individual difference study, we further reveal a common neural circuitry in which reduced functional interaction between the identified cluster and ventromedial prefrontal cortex, a default mode network hub, is linked to better performance across both memory types. Our results provide evidence for shared neural processes supporting the controlled retrieval of information from functionally distinct long-term memory systems.

The neural correlates of ongoing conscious thought.

A core goal in cognitive neuroscience is identifying the physical substrates of the patterns of thought that occupy our daily lives. Contemporary views suggest that the landscape of ongoing experience is heterogeneous and can be influenced by features of both the person and the context. This perspective piece considers recent work that explicitly accounts for both the heterogeneity of the experience and context dependence of patterns of ongoing thought. These studies reveal that systems linked to attention and control are important for organizing experience in response to changing environmental demands. These studies also establish a role of the default mode network beyond task-negative or purely episodic content, for example, implicating it in the level of vivid detail in experience in both task contexts and in spontaneous self-generated experiential states. Together, this work demonstrates that the landscape of ongoing thought is reflected in the activity of multiple neural systems, and it is important to distinguish between processes contributing to how the experience unfolds from those linked to how these experiences are regulated.

Connectome-based evidence for creative thinking as an emergent property of ordinary cognitive operations.

Creative thinking is a hallmark of human cognition, which enables us to generate novel and useful ideas. Nevertheless, its emergence within the macro-scale neurocognitive circuitry remains largely unknown. Using resting-state fMRI data from two large population samples (SWU: n = 931; HCP: n = 1001) and a novel "travelling pattern prediction analysis", here we identified the modularized functional connectivity patterns linked to creative thinking ability, which concurrently explained individual variability across ordinary cognitive abilities such as episodic memory, working memory and relational processing. Further interrogation of this neural pattern with graph theoretical tools revealed both hub-like brain structures and globally-efficient information transfer paths that together may facilitate higher creative thinking ability through the convergence of distinct cognitive operations. Collectively, our results provide reliable evidence for the hypothesized emergence of creative thinking from core cognitive components through neural integration, and thus allude to a significant theoretical advancement in the study of creativity.

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture.

BACKGROUND: Despite the marked interindividual variability in the clinical presentation of schizophrenia, the extent to which individual dimensions of psychopathology relate to the functional variability in brain networks among patients remains unclear. Here, we address this question using network-based predictive modeling of individual psychopathology along 4 data-driven symptom dimensions. Follow-up analyses assess the molecular underpinnings of predictive networks by relating them to neurotransmitter-receptor distribution patterns. METHODS: We investigated resting-state functional magnetic resonance imaging data from 147 patients with schizophrenia recruited at 7 sites. Individual expression along negative, positive, affective, and cognitive symptom dimensions was predicted using a relevance vector machine based on functional connectivity within 17 meta-analytic task networks following repeated 10-fold cross-validation and leave-one-site-out analyses. Results were validated in an independent sample. Networks robustly predicting individual symptom dimensions were spatially correlated with density maps of 9 receptors/transporters from prior molecular imaging in healthy populations. RESULTS: Tenfold and leave-one-site-out analyses revealed 5 predictive network-symptom associations. Connectivity within theory of mind, cognitive reappraisal, and mirror neuron networks predicted negative, positive, and affective symptom dimensions, respectively. Cognitive dimension was predicted by theory of mind and socioaffective default networks. Importantly, these predictions generalized to the independent sample. Intriguingly, these two networks were positively associated with D1 receptor and serotonin reuptake transporter densities as well as dopamine synthesis capacity. CONCLUSIONS: We revealed a robust association between intrinsic functional connectivity within networks for socioaffective processes and the cognitive dimension of psychopathology. By investigating the molecular architecture, this work links dopaminergic and serotonergic systems with the functional topography of brain networks underlying cognitive symptoms in schizophrenia.

Shared alterations in resting-state brain connectivity in adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a developmental condition that often persists into adulthood with extensive negative consequences on quality of life. Despite emerging evidence indicating the genetic basis of ADHD, investigations into the familial expression of latent neurocognitive traits remain limited. METHODS: In a group of adult ADHD probands (n = 20), their unaffected first-degree relatives (n = 20) and typically developing control participants (n = 20), we assessed endophenotypic alterations in the default mode network (DMN) connectivity during resting-state functional magnetic resonance imaging in relation to cognitive performance and clinical symptoms. In an external validation step, we also examined the dimensional nature of this neurocognitive trait in a sample of unrelated healthy young adults (n = 100) from the Human Connectome Project (HCP). RESULTS: The results illustrated reduced anti-correlations between the posterior cingulate cortex/precuneus and right middle frontal gyrus that was shared between adult ADHD probands and their first-degree relatives, but not with healthy controls. The observed connectivity alterations were linked to higher ADHD symptoms that was mediated by performance in a sustained attention task. Moreover, this brain-based neurocognitive trait dimensionally explained ADHD symptom variability in the HCP sample. CONCLUSIONS: Alterations in the default mode connectivity may represent a dimensional endophenotype of ADHD, hence a significant aspect of the neuropathophysiology of this disorder. As such, brain network organisation can potentially be employed as an important neurocognitive trait to enhance statistical power of genetic studies in ADHD and as a surrogate efficacy endpoint in the development of novel pharmaceuticals.

Intrinsic connectivity of the prefrontal cortex and striato-limbic system respectively differentiate major depressive from generalized anxiety disorder.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent and debilitating disorders. The high overlap on the symptomatic and neurobiological level led to ongoing debates about their diagnostic and neurobiological uniqueness. The present study aims to identify common and disorder-specific neuropathological mechanisms and treatment targets in MDD and GAD. To this end we combined categorical and dimensional disorder models with a fully data-driven intrinsic network-level analysis (intrinsic connectivity contrast, ICC) to resting-state fMRI data acquired in 108 individuals (n = 35 and n = 38 unmedicated patients with first-episode GAD, MDD, respectively, and n = 35 healthy controls). Convergent evidence from categorical and dimensional analyses revealed MDD-specific decreased whole-brain connectivity profiles of the medial prefrontal and dorsolateral prefrontal cortex while GAD was specifically characterized by decreased whole-brain connectivity profiles of the putamen and decreased communication of this region with the amygdala. Together, findings from the present data-driven analysis suggest that intrinsic communication of frontal regions engaged in executive functions and emotion regulation represent depression-specific neurofunctional markers and treatment targets whereas dysregulated intrinsic communication of the striato-amygdala system engaged in reinforcement-based and emotional learning processes represent GAD-specific markers.

The psychological correlates of distinct neural states occurring during wakeful rest.

When unoccupied by an explicit external task, humans engage in a wide range of different types of self-generated thinking. These are often unrelated to the immediate environment and have unique psychological features. Although contemporary perspectives on ongoing thought recognise the heterogeneity of these self-generated states, we lack both a clear understanding of how to classify the specific states, and how they can be mapped empirically. In the current study, we capitalise on advances in machine learning that allow continuous neural data to be divided into a set of distinct temporally re-occurring patterns, or states. We applied this technique to a large set of resting state data in which we also acquired retrospective descriptions of the participants' experiences during the scan. We found that two of the identified states were predictive of patterns of thinking at rest. One state highlighted a pattern of neural activity commonly seen during demanding tasks, and the time individuals spent in this state was associated with descriptions of experience focused on problem solving in the future. A second state was associated with patterns of activity that are commonly seen under less demanding conditions, and the time spent in it was linked to reports of intrusive thoughts about the past. Finally, we found that these two neural states tended to fall at either end of a neural hierarchy that is thought to reflect the brain's response to cognitive demands. Together, these results demonstrate that approaches which take advantage of time-varying changes in neural function can play an important role in understanding the repertoire of self-generated states. Moreover, they establish that important features of self-generated ongoing experience are related to variation along a similar vein to those seen when the brain responds to cognitive task demands.

Distinct patterns of thought mediate the link between brain functional connectomes and well-being.

Ongoing thought patterns constitute important aspects of both healthy and abnormal human cognition. However, the neural mechanisms behind these daily experiences and their contribution to well-being remain a matter of debate. Here, using resting-state fMRI and retrospective thought sampling in a large neurotypical cohort (n = 211), we identified two distinct patterns of thought, broadly describing the participants' current concerns and future plans, that significantly explained variability in the individual functional connectomes. Consistent with the view that ongoing thoughts are an emergent property of multiple neural systems, network-based analysis highlighted the central importance of both unimodal and transmodal cortices in the generation of these experiences. Importantly, while state-dependent current concerns predicted better psychological health, mediating the effect of functional connectomes, trait-level future plans were related to better social health, yet with no mediatory influence. Collectively, we show that ongoing thoughts can influence the link between brain physiology and well-being.

The role of default mode network in semantic cue integration.

Recent accounts of large-scale cortical organisation suggest that the default mode network (DMN) is positioned at the top of a principal gradient, reflecting the separation between heteromodal and unimodal sensory-motor regions in patterns of connectivity and in geodesic distance along the cortical surface (Margulies et al., 2016). This isolation of DMN from external inputs might allow the integration of disparate sources of information that can constrain subsequent cognition. We tested this hypothesis by manipulating the degree to which semantic decisions for ambiguous words (e.g. jam) were constrained by preceding visual cues depicting relevant spatial contexts (e.g. supermarket or road) and/or facial emotions (e.g. happy vs. frustrated). We contrasted (i) the effects of a single preceding cue with a no-cue condition employing scrambled images, and (ii) convergent spatial and emotion cues with single cues. Single cues elicited stronger activation in the multiple demand network relative to no cues, consistent with the requirement to maintain information in working memory. The availability of two convergent cues elicited stronger activation within DMN regions (bilateral angular gyrus, middle temporal gyrus, medial prefrontal cortex, and posterior cingulate), even though behavioural performance was unchanged by cueing - consequently task difficulty is unlikely to account for the observed differences in brain activation. A regions-of-interest analysis along the unimodal-to-heteromodal principal gradient revealed maximal activation for the convergent cue condition at the heteromodal end, corresponding to the DMN. Our findings are consistent with the view that regions of DMN support states of information integration that constrain ongoing cognition and provide a framework for understanding the location of these effects at the heteromodal end of the principal gradient.

Rapid Rule-Based Reward Reversal and the Lateral Orbitofrontal Cortex.

Humans and other primates can reverse their choice of stimuli in one trial when the rewards delivered by the stimuli change or reverse. Rapidly changing our behavior when the rewards change is important for many types of behavior, including emotional and social behavior. It is shown in a one-trial rule-based Go-NoGo deterministic visual discrimination reversal task to obtain points, that the human right lateral orbitofrontal cortex and adjoining inferior frontal gyrus is activated on reversal trials, when an expected reward is not obtained, and the non-reward allows the human to switch choices based on a rule. This reward reversal goes beyond model-free reinforcement learning. This functionality of the right lateral orbitofrontal cortex shown here in very rapid, one-trial, rule-based changes in human behavior when a reward is not received is related to the emotional and social changes that follow orbitofrontal cortex damage, and to depression in which this non-reward system is oversensitive and over-connected.

Atomoxetine and citalopram alter brain network organization in Parkinson's disease.

Parkinson's disease has multiple detrimental effects on motor and cognitive systems in the brain. In contrast to motor deficits, cognitive impairments in Parkinson's disease are usually not ameliorated, and can even be worsened, by dopaminergic treatments. Recent evidence has shown potential benefits from restoring other neurotransmitter deficits, including noradrenergic and serotonergic transmission. Here, we study global and regional brain network organization using task-free imaging (also known as resting-state), which minimizes performance confounds and the bias towards predetermined networks. Thirty-three patients with idiopathic Parkinson's disease were studied three times in a double-blinded, placebo-controlled counter-balanced crossover design, following placebo, 40 mg oral atomoxetine (selective noradrenaline reuptake inhibitor) or 30 mg oral citalopram (selective serotonin reuptake inhibitor). Neuropsychological assessments were performed outside the scanner. Seventy-six controls were scanned without medication to provide normative data for comparison to the patient cohort. Graph theoretical analysis of task-free brain connectivity, with a random 500-node parcellation, was used to measure the effect of disease in placebo-treated state (versus unmedicated controls) and pharmacological intervention (drug versus placebo). Relative to controls, patients on placebo had executive impairments (reduced fluency and inhibitory control), which was reflected in dysfunctional network dynamics in terms of reduced clustering coefficient, hub degree and hub centrality. In patients, atomoxetine improved fluency in proportion to plasma concentration (P = 0.006, r 2 = 0.24), and improved response inhibition in proportion to increased hub Eigen centrality (P = 0.044, r 2 = 0.14). Citalopram did not improve fluency or inhibitory control, but its influence on network integration and efficiency depended on disease severity: clustering (P = 0.01, r 2 = 0.22), modularity (P = 0.043, r 2 = 0.14) and path length (P = 0.006, r 2 = 0.25) increased in patients with milder forms of Parkinson's disease, but decreased in patients with more advanced disease (Unified Parkinson's Disease Rating Scale motor subscale part III > 30). This study supports the use of task-free imaging of brain networks in translational pharmacology of neurodegenerative disorders. We propose that hub connectivity contributes to cognitive performance in Parkinson's disease, and that noradrenergic treatment strategies can partially restore the neural systems supporting executive function.