A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity

Anxiety is one of the most common mental states of humans. Although it drives us to avoid frightening situations and to achieve our goals, it may also impose significant suffering and burden if it becomes extreme. Because we experience anxiety in a variety of forms, previous studies investigated neural substrates of anxiety in a variety of ways. These studies revealed that individuals with high state, trait, or pathological anxiety showed altered neural substrates. However, no studies have directly investigated whether the different dimensions of anxiety share a common neural substrate, despite its theoretical and practical importance. Here, we investigated a brain network of anxiety shared by different dimensions of anxiety in a unified analytical framework using functional magnetic resonance imaging (fMRI). We analyzed different datasets in a single scale, which was defined by an anxiety-related brain network derived from whole brain. We first conducted the anxiety provocation task with healthy participants who tended to feel anxiety related to obsessive-compulsive disorder (OCD) in their daily life. We found a common state anxiety brain network across participants (1585 trials obtained from 10 participants). Then, using the resting-state fMRI in combination with the participants' behavioral trait anxiety scale scores (879 participants from the Human Connectome Project), we demonstrated that trait anxiety shared the same brain network as state anxiety. Furthermore, the brain network between common to state and trait anxiety could detect patients with OCD, which is characterized by pathological anxiety-driven behaviors (174 participants from multi-site datasets). Our findings provide direct evidence that different dimensions of anxiety have a substantial biological inter-relationship. Our results also provide a biologically defined dimension of anxiety, which may promote further investigation of various human characteristics, including psychiatric disorders, from the perspective of anxiety

Sleep-amount differentially affects fear-processing neural circuitry in pediatric anxiety: A preliminary fMRI investigation.

Insufficient sleep, as well as the incidence of anxiety disorders, both peak during adolescence. While both conditions present perturbations in fear-processing-related neurocircuitry, it is unknown whether these neurofunctional alterations directly link anxiety and compromised sleep in adolescents. Fourteen anxious adolescents (AAs) and 19 healthy adolescents (HAs) were compared on a measure of sleep amount and neural responses to negatively valenced faces during fMRI. Group differences in neural response to negative faces emerged in the dorsal anterior cingulate cortex (dACC) and the hippocampus. In both regions, correlation of sleep amount with BOLD activation was positive in AAs, but negative in HAs. Follow-up psychophysiological interaction (PPI) analyses indicated positive connectivity between dACC and dorsomedial prefrontal cortex, and between hippocampus and insula. This connectivity was correlated negatively with sleep amount in AAs, but positively in HAs. In conclusion, the presence of clinical anxiety modulated the effects of sleep-amount on neural reactivity to negative faces differently among this group of adolescents, which may contribute to different clinical significance and outcomes of sleep disturbances in healthy adolescents and patients with anxiety disorders

Early affective changes and increased connectivity in preclinical Alzheimer's disease.

IntroductionAffective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a "salience network" attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown.MethodsOne hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid-PET. We hypothesized amyloid-positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes.ResultsIn participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth.ConclusionsAffective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social-emotional processing

Using Movies to Probe the Neurobiology of Anxiety

Over the past century, research has helped us build a fundamental understanding of the neurobiological underpinnings of anxiety. Specifically, anxiety engages a broad range of cortico-subcortical neural circuitry. Core to this is a ‘defensive response network’ which includes an amygdala-prefrontal circuit that is hypothesized to drive attentional amplification of threat-relevant stimuli in the environment. In order to help prepare the body for defensive behaviors to threat, anxiety also engages peripheral physiological systems. However, our theoretical frameworks of the neurobiology of anxiety are built mostly on the foundations of tightly-controlled experiments, such as task-based fMRI. Whether these findings generalize to more naturalistic settings is unknown. To address this shortcoming, movie-watching paradigms offer an effective tool at the intersection of tightly controlled and entirely naturalistic experiments. Particularly, using suspenseful movies presents a novel and effective means to induce and study anxiety. In this thesis, I demonstrate the potential of movie-watching paradigms in the study of how trait and state anxiety impact the ‘defensive response network’ in the brain, as well as peripheral physiology. The key findings reveal that trait anxiety is associated with differing amygdala-prefrontal responses to suspenseful movies; specific trait anxiety symptoms are linked to altered states of anxiety during suspenseful movies; and states of anxiety during movies impact brain-body communication. Notably, my results frequently diverged from those of conventional task-based experiments. Taken together, the insights gathered from this thesis underscore the utility of movie-watching paradigms for a more nuanced understanding of how anxiety impacts the brain and peripheral physiology. These outcomes provide compelling evidence that further integration of naturalistic methods will be beneficial in the study of the neurobiology of anxiety

The verbal nature of worry in generalized anxiety: Insights from the brain

Background: The Cognitive Avoidance Theory of Worry argues that worry is a cognitive strategy adopted to control the physiological arousal associated with anxiety. According to this theory, pathological worry, as in Generalized Anxiety Disorder (GAD), is verbal in nature, negative and abstract, rather than concrete. Neuroimaging studies link the expression of worry to characteristic modes of brain functional connectivity, especially in relation to the amygdala. However, the distinctive features of worry (verbal, abstract, negative), and their relationship to physiological arousal, have not so far been mapped to brain function. Methods: We addressed this omission by undertaking a resting-state functional magnetic resonance neuroimaging study of 19 patients with GAD and 21 controls, before and after induction of perseverative cognitions, while measuring emotional bodily arousal from heart rate (HR). Seed-based analyses quantified brain changes in whole brain functional connectivity from the amygdala. Results: In GAD, the induction increased negative thoughts and their verbal content. In line with predictions, the verbal expression of worry in GAD was associated with higher HR at baseline and attenuated HR increases after induction of perseverative cognitions. Within brain, the increased use of words during worry, and the associated dampening of HR after induction were mediated by the strength of functional connectivity between the amygdala and default mode network ‘hubs’ and the opercular cortex. The negative content of worry was further related to functional communication between amygdala and cingulo-opercular and temporal cortices. Conclusions: Findings provide a neurobiological basis for the impact of verbal worry on HR in GAD

Increased functional connectivity in gambling disorder correlates with behavioural and emotional dysregulation: Evidence of a role for the cerebellum

Gambling disorder (GD) is a psychiatric disease that has been recently classified as a behavioural addiction. So far, a very few studies have investigated the alteration of functional connectivity in GD patients, thus the concrete interplay between relevant function-dependent circuitries in such disease has not been comprehensively assessed. The aim of this research was to investigate resting-state functional connectivity in GD patients, searching for a correlation with GD symptoms severity. GD patients were assessed for gambling behaviour, impulsivity, cognitive distortions, anxiety and depression, in comparison with healthy controls (HC). Afterwards, they were assessed for resting-state functional magnetic resonance imaging; functional connectivity was assessed through a data-driven approach, by using independent component analysis. The correlation between gambling severity and the strength of specific resting-state networks was also investigated. Our results show that GD patients displayed higher emotional and behavioural impairment than HC, together with an increased resting state functional connectivity in the network including anterior cingulate cortex, the caudate nucleus and nucleus accumbens, and within the cerebellum, in comparison with the control group. Moreover, a significant correlation between behavioural parameters and the strength of the resting-state cerebellar network was found. Overall, the functional alterations in brain connectivity involving the cerebellum observed in this study underpin the emotional and behavioural impairment recorded in GD patients. This evidence suggests the employment of novel neuromodulatory therapeutic approaches involving specific and salient targets such as the cerebellum in addictive disorders

Your Resting Brain CAREs about Your Risky Behavior

Research on the neural correlates of risk-related behaviors and personality traits has provided insight into mechanisms underlying both normal and pathological decision-making. Task-based neuroimaging studies implicate a distributed network of brain regions in risky decision-making. What remains to be understood are the interactions between these regions and their relation to individual differences in personality variables associated with real-world risk-taking.We employed resting state functional magnetic resonance imaging (R-fMRI) and resting state functional connectivity (RSFC) methods to investigate differences in the brain's intrinsic functional architecture associated with beliefs about the consequences of risky behavior. We obtained an individual measure of expected benefit from engaging in risky behavior, indicating a risk seeking or risk-averse personality, for each of 21 participants from whom we also collected a series of R-fMRI scans. The expected benefit scores were entered in statistical models assessing the RSFC of brain regions consistently implicated in both the evaluation of risk and reward, and cognitive control (i.e., orbitofrontal cortex, nucleus accumbens, lateral prefrontal cortex, dorsal anterior cingulate). We specifically focused on significant brain-behavior relationships that were stable across R-fMRI scans collected one year apart. Two stable expected benefit-RSFC relationships were observed: decreased expected benefit (increased risk-aversion) was associated with 1) stronger positive functional connectivity between right inferior frontal gyrus (IFG) and right insula, and 2) weaker negative functional connectivity between left nucleus accumbens and right parieto-occipital cortex.Task-based activation in the IFG and insula has been associated with risk-aversion, while activation in the nucleus accumbens and parietal cortex has been associated with both risk seeking and risk-averse tendencies. Our results suggest that individual differences in attitudes toward risk-taking are reflected in the brain's functional architecture and may have implications for engaging in real-world risky behaviors

ELUCIDATING THE NATURE AND DEVELOPMENT OF NEURAL MECHANISMS ASSOCIATED WITH ANXIOUS APPREHENSION AND ANXIOUS AROUSAL ACROSS ADOLESCENCE

Work on adult anxiety has found that anxious apprehension, marked by chronic worry, and anxious arousal, marked by elevated sympathetic hyperarousal, are instantiated in different neurobiological systems and involve different information processing dysfunctions. However, little is known regarding how these transdiagnostic types of anxiety develop. The present dissertation seeks to apply this transdiagnostic approach to anxiety to the study of adolescent neurodevelopment. Study 1 established that anxious arousal and anxious apprehension are distinguishable via self-report, supporting that these traits are meaningfully different as early as 11 years old. Neurobiologically, anxious arousal positively correlated with dmPFC-amygdala structural connectivity, interpreted as an elevated propensity to amplify anxiety responses, whereas anxious apprehension positively correlated with right iFG structural connectivity, interpreted as reflecting elevated inhibition of immediate threat processing. Evidence was not found for neural correlates of anxiolytic dysfunction in anxious arousal, nor for neural correlates of increased internal mental rehearsal in anxious apprehension. Study 2 built on Study 1 by examining how intrinsic connectivity was related to types of anxiety both cross-sectionally and longitudinally. Study 2 found no evidence that a priori defined functional pathways mapped onto types of anxiety. In contrast, a data-driven approach revealed that functional amygdala connectivity can predict variation in anxious arousal at both waves, whereas functional iFG connectivity can predict variation in anxious apprehension in wave 2. Taken together, the present dissertation establishes that anxious arousal and anxious apprehension emerge in early adolescence, and may be marked by different kinds of information processing dysfunctions. Future work needs to more rigorously test if inferences about information processing associated with neural correlates found here are valid.Doctor of Philosoph

Trait anxiety is associated with attentional brain networks

Trait anxiety is a well-established risk factor for anxiety and depressive disorders, yet its neural correlates are not clearly understood. In this study, we investigated the neural correlates of trait anxiety in a large sample (n = 179) of individuals who completed the trait and state versions of the State-Trait Anxiety Inventory and underwent resting-state functional magnetic resonance imaging. We used independent component analysis to characterize individual resting-state networks (RSNs), and multiple regression analyses to assess the relationship between trait anxiety and intrinsic connectivity. Trait anxiety was significantly associated with intrinsic connectivity in different regions of three RSNs (dorsal attention network, default mode network, and auditory network) when controlling for state anxiety. These RSNs primarily support attentional processes. Notably, when state anxiety was not controlled for, a different pattern of results emerged, highlighting the importance of considering this factor in assessing the neural correlates of trait anxiety. Our findings suggest that trait anxiety is uniquely associated with resting-state brain connectivity in networks mainly supporting attentional processes. Moreover, controlling for state anxiety is crucial when assessing the neural correlates of trait anxiety. These insights may help refine current neurobiological models of anxiety and identify potential targets for neurobiologically-based interventions

Visual processing speed in the aging brain

Either reading a text in the office or looking for an apple in the supermarket, we are continuously flooded with visual stimuli. But how does the human brain support the efficient processing of those stimuli? And, if pathological changes occur in the brain, how do these changes lead to reductions in such efficient processing? In the present dissertation, aging is used as a model to address these two questions. First, individual differences in visual processing speed are examined in association with the coherence of the brain’s spontaneous activity and how this coherence is affected by normal aging. Second, individual differences in visual processing speed are studied in association with behavior in tasks that measure complex visual object perception in patients at risk of Alzheimer’s dementia and healthy aging adults. Based on these two approaches, evidence will be presented for an association of a slowed visual processing with (a) decreased coherent activity of a frontoinsular network in healthy aging and (b) simultaneous object perception deficits in patients at risk of Alzheimer’s dementia. This evidence provides critical insights into the particular link between visual processing speed and the coherence of the brain’s spontaneous activity and reveals perceptual deficits in patients whose clinically most apparent impairments lie in memory