[Show abstract][Hide abstract] ABSTRACT: Cognitive processing biases, such as increased attention to threat, are gaining recognition as causal factors in anxiety. Yet, little is known about the anatomical pathway by which threat biases cognition and how genetic factors might influence the integrity of this pathway, and thus, behavior. For 40 normative adults, we reconstructed the entire amygdalo-prefrontal white matter tract (uncinate fasciculus) using diffusion tensor weighted MRI and probabilistic tractography to test the hypothesis that greater fiber integrity correlates with greater nonconscious attention bias to threat as measured by a backward masked dot-probe task. We used path analysis to investigate the relationship between brain-derived nerve growth factor genotype, uncinate fasciculus integrity, and attention bias behavior. Greater structural integrity of the amygdalo-prefrontal tract correlates with facilitated attention bias to nonconscious threat. Genetic variability associated with brain-derived nerve growth factor appears to influence the microstructure of this pathway and, in turn, attention bias to nonconscious threat. These results suggest that the integrity of amygdalo-prefrontal projections underlie nonconscious attention bias to threat and mediate genetic influence on attention bias behavior. Prefrontal cognition and attentional processing in high bias individuals appear to be heavily influenced by nonconscious threat signals relayed via the uncinate fasciculus.
[Show abstract][Hide abstract] ABSTRACT: The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat-safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by ±20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.
Journal of Neuroscience 03/2014; 34(11):4043-53. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the current study, we evaluated the test-retest reliability of amygdala response using an emotional face-matching task that has been widely used to examine pathophysiology and treatment mechanisms in psychiatric populations. Activation within the fusiform face area (FFA) was also examined. Twenty-seven healthy volunteers completed a variation of the face-matching paradigm developed by Hariri et al. (2000) at two time points approximately 90 days apart. Estimates of test-retest reliability of amygdala response to fearful faces were moderate, whereas angry and happy faces showed poor reliability. Test-retest reliability of the FFA was moderate to strong, regardless of facial affect. Collectively, these findings indicate that the reliability of the BOLD MR signal in the amygdala varies substantially by facial affect. Efforts to improve measurement precision, enlarge sample sizes, or increase the number of assessment occasions seem warranted.
[Show abstract][Hide abstract] ABSTRACT: The current study, which was a reanalysis of previous data, focused on the error-related negativity (ERN)-an event-related potential (ERP) associated with error monitoring-and the feedback negativity (FN)-an ERP associated with reward processing. Two objectives motivated this study: first, to illustrate the relationship between the ERN and anxious symptoms, and the relationship between the FN and depressive symptoms; second, to explore whether the ERN and the FN relate uniquely to anxiety and depression, respectively, in children. EEG was collected from twenty-five 11- to 13-year-old participants (12 female; 23 Caucasian, 1 Asian, 1 of Caucasian and Hispanic ethnicity) during tasks designed to elicit an ERN and an FN. Participants and a parent completed questionnaires assessing the participant's anxious and depressive symptomatology. Increasing anxiety was related to a larger ERN, and increasing depression was related to a smaller FN. Further analysis demonstrated that these relationships remained significant when controlling for the contribution of other variables; that is, the ERN continued to predict anxiety when controlling for the FN and depression, and the FN continued to predict depression when controlling for the ERN and anxiety. Thus, in late childhood and early adolescence, the ERN and the FN appear to relate uniquely to anxious and depressive symptoms, respectively. Although this research is still in early stages, the ERN and the FN have the potential to inform trajectories of risk for anxiety and depression, and could be utilized in clinical settings as cost- and labor-efficient neural biomarkers.
[Show abstract][Hide abstract] ABSTRACT: The startle reflex is attenuated and potentiated when participants are viewing pleasant and unpleasant images, respectively. Research demonstrates that threatening contexts also potentiate startle, but it remains unclear how a threatening context might impact startle modulation to emotional images, especially as a function of trait anxiety. The present study measured startle reactivity while 43 participants viewed pleasant, unpleasant, and neutral images across conditions of threat-of-shock and safety (i.e., no shock). Compared to neutral images, startle was potentiated during unpleasant images and attenuated during pleasant images. Threat-of-shock potentiated startle during all picture types, suggesting that threat-of-shock broadly sensitized the defensive system but did not change affective modulation of startle. Lastly, higher levels of trait anxiety were associated with less startle potentiation during unpleasant images across both conditions-a finding in line with previous research demonstrating deficient threat mobilization in response to unpleasant stimuli among highly anxious individuals.
[Show abstract][Hide abstract] ABSTRACT: Anxiety disorders are the most frequently diagnosed form of psychopathology in children and often result in chronic impairment that persists into adulthood. Identifying neurobehavioral correlates of anxiety that appear relatively early in life would inform etiological models of development and allow intervention and prevention strategies to be implemented more effectively. The error-related negativity (ERN), a negative deflection in the event-related potential at fronto-central sites approximately 50 ms following the commission of errors, has been consistently found to be larger among anxious adults. The current study sought to extend these findings to even younger individuals: the ERN was elicited by a Go/NoGo task in 48 six year-old children with a clinical anxiety disorder assessed by diagnostic interview and 48 age-matched controls. In addition to child anxiety disorder, the ERN was examined in relation to maternal history of anxiety disorder, which was previously related to a smaller ERN. Anxious children were characterized by a larger (i.e., more negative) ERN and maternal history of anxiety disorder was associated with a smaller ERN. Thus, the relationship between an increased ERN and clinical anxiety is evident by age 6, and this effect appears independent from an opposing influence of maternal anxiety history on the ERN. These findings support the ERN as a promising neurobehavioral marker of anxiety, and implications are discussed.
Journal of Abnormal Child Psychology 05/2013; · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Post-traumatic stress disorder (PTSD) is characterized by sustained anxiety, hypervigilance for potential threat, and hyperarousal. These symptoms may enhance self-perception of one's actions, particularly the detection of errors, which may threaten safety. The error-related negativity (ERN) is an electrocortical response to the commission of errors, and previous studies have shown that other anxiety disorders associated with exaggerated anxiety and enhanced action monitoring exhibit an enhanced ERN. However, little is known about how traumatic experience and PTSD would affect the ERN. To address this gap, we measured the ERN in returning Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with combat-related PTSD (PTSD group), combat-exposed OEF/OIF veterans without PTSD [combat-exposed control (CEC) group], and non-traumatized healthy participants [healthy control (HC) group]. Event-related potential and behavioral measures were recorded while 16 PTSD patients, 18 CEC, and 16 HC participants completed an arrow version of the flanker task. No difference in the magnitude of the ERN was observed between the PTSD and HC groups; however, in comparison with the PTSD and HC groups, the CEC group displayed a blunted ERN response. These findings suggest that (1) combat trauma itself does not affect the ERN response; (2) PTSD is not associated with an abnormal ERN response; and (3) an attenuated ERN in those previously exposed to combat trauma but who have not developed PTSD may reflect resilience to the disorder, less motivation to do the task, or a decrease in the significance or meaningfulness of 'errors,' which could be related to combat experience.
Psychiatry Research Neuroimaging 05/2013; · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rewards are integral to learning associations that aid in survival. The feedback negativity (FN), an event-related potential that differentiates outcomes indicating monetary losses versus gains, has recently emerged as a possible neural measure of reward processing. If this view is correct, then the FN should correlate with measures of reward sensitivity in other domains, although few studies have investigated this question. In the current study, 46 participants completed a self-report measure of reward responsiveness, a signal detection task that generated a behavioral measure of reward sensitivity, and a gambling task that elicited an FN. Consistent with the view that the FN reflects reward-related neural activity, a larger FN correlated with increased behavioral and self-report measures of sensitivity to reward.
[Show abstract][Hide abstract] ABSTRACT: Psychotic disorders are characterized by profoundly blunted neural responses to errors, as indicated by reductions in two event-related potential (ERP) components: the error-related negativity (ERN) and error positivity (Pe). The potential utility of the ERN and Pe as biomarkers for psychotic disorders is currently limited, however, by an incomplete understanding of their psychometric properties. To address this gap in the literature, we considered the reliability and validity of these measures in both healthy individuals (n = 52) and patients with psychotic illness (n = 84) across two experimental paradigms that have been used in previous studies in schizophrenia: a flankers task and a picture/word matching task. Internal consistency reliability was higher on the flankers compared to the picture/word task overall. On the flankers task, fair internal consistency was achieved among patients with relatively few trials (ERN = five trials, Pe = 12 trials). The number of available error trials influenced reliability among patients more than among healthy individuals, and on the picture/word task more than the flankers task. Moderate convergent validity for the ERN and Pe was observed across tasks in both the patient and healthy groups. ERPs on the flankers task exhibited external validity, and were related to several clinical characteristics, including diagnosis, negative symptom severity, rehospitalization, employment, and neuroticism; associations with the picture/word task were generally weaker. These data indicate that task differences can strongly affect psychometric properties of error-related neural activity indices in healthy and patient populations. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Journal of Abnormal Psychology 05/2013; 122(2):520-531. · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Error-processing is increasingly examined using the error-related negativity (ERN) and error positivity (Pe)-event-related potentials (ERPs) that demonstrate trait-like properties and excellent reliability. The current study focuses on construct validity by applying a multitrait-multimethod approach, treating error-related ERPs (i.e., ERN, Pe and the difference between error minus correct, referred to as ΔERN and ΔPe, respectively) as traits measured across multiple tasks (i.e., Flanker, Stroop, Go/NoGo). Results suggest convergent validity of these ERPs ranging between .62 and .64 for ΔERN. Values were somewhat smaller for ERN (range .33 - .43), Pe (range .37-.49) and ΔPe (range .30-.37). Further, the correlations for ERN and Pe are higher within components across tasks than between different components suggesting discriminant validity. In conclusion, the present study revealed evidence for convergent and discriminant validity of error-related ERPs, further supporting the use of these components as psychophysiological trait markers.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Although several aspects of emotion seem to be intact in schizophrenia, there is emerging evidence that patients show an impaired ability to adaptively regulate their emotions. This event-related potential (ERP) study examined whether schizophrenia is associated with impaired neural responses to appraisal frames, that is when negative stimuli are presented in a less negative context. Method Thirty-one schizophrenia out-patients and 27 healthy controls completed a validated picture-viewing task with three conditions: (1) neutral pictures preceded by neutral descriptions ('Neutral'), (2) unpleasant pictures preceded by negative descriptions ('Preappraised negative'), and (3) unpleasant pictures preceded by more neutral descriptions ('Preappraised neutral'). Analyses focused on the late positive potential (LPP), an index of facilitated attention to emotional stimuli that is reduced following cognitive emotion regulation strategies, during four time windows from 300 to 2000 ms post-picture onset. RESULTS: Replicating prior studies, controls showed smaller LPP in Preappraised neutral and Neutral versus Preappraised negative conditions throughout the 300-2000-ms time period. By contrast, patients showed (a) larger LPP in Preappraised neutral and Preappraised negative versus Neutral conditions in the initial period (300-600 ms) and (b) an atypical pattern of larger LPP to Preappraised neutral versus Preappraised negative and Neutral conditions in the 600-1500-ms epochs. CONCLUSIONS: Modulation of neural responses by a cognitive emotion regulation strategy seems to be impaired in schizophrenia during the first 2 s after exposure to unpleasant stimuli.
Psychological Medicine 01/2013; · 5.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: There is increasing interest in error-related brain activity in anxiety disorders. The error-related negativity (ERN) is a negative deflection in the event-related potential approximately 50 ms after errors compared to correct responses. Recent studies suggest that the ERN may be a biomarker for anxiety, as it is positively associated with anxiety disorders and traits in adults and older youth. However, it is not known if the ERN in young children is related to risk for anxiety disorders. We addressed this by examining the association of six-year olds' ERNs with two established risk factors for anxiety: parental anxiety disorder and child temperamental negative emotionality (NE). Method: The ERN was assessed using a Go/No-Go task in a community sample of 413 six-year olds. In a prior assessment at age 3, child temperament was evaluated using a laboratory observational measure and parental psychopathology was assessed using semi-structured diagnostic interviews. Results: Children of mothers with anxiety disorders and children with greater temperamental NE (particularly fearfulness) exhibited significantly smaller ERNs than their peers. Paternal psychopathology, maternal mood and substance use disorders, and child positive emotionality were not associated with children's ERNs. Conclusion: Both maternal anxiety disorders and child NE (particularly fearfulness) were significantly associated with children's ERNs. However, the direction of these associations was opposite to the relations between ERNs and anxiety in older youth and adults. These results suggest that there may be a difference between risk and disorder status in the relation of error-related brain activity to anxiety between early childhood and late childhood/ early adolescence.
Journal of Child Psychology and Psychiatry 01/2013; · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reports an error in "Psychometric considerations in using error-related brain activity as a biomarker in psychotic disorders" by Dan Foti, Roman Kotov and Greg Hajcak (Journal of Abnormal Psychology, 2013[May], Vol 122, 520-531). The URL for supplemental material was missing. The URL is provided in the erratum. (The following abstract of the original article appeared in record 2013-17531-011.) Psychotic disorders are characterized by profoundly blunted neural responses to errors, as indicated by reductions in two event-related potential (ERP) components: the error-related negativity (ERN) and error positivity (Pe). The potential utility of the ERN and Pe as biomarkers for psychotic disorders is currently limited, however, by an incomplete understanding of their psychometric properties. To address this gap in the literature, we considered the reliability and validity of these measures in both healthy individuals (n = 52) and patients with psychotic illness (n = 84) across two experimental paradigms that have been used in previous studies in schizophrenia: a flankers task and a picture/word matching task. Internal consistency reliability was higher on the flankers compared to the picture/word task overall. On the flankers task, fair internal consistency was achieved among patients with relatively few trials (ERN = five trials, Pe = 12 trials). The number of available error trials influenced reliability among patients more than among healthy individuals, and on the picture/word task more than the flankers task. Moderate convergent validity for the ERN and Pe was observed across tasks in both the patient and healthy groups. ERPs on the flankers task exhibited external validity, and were related to several clinical characteristics, including diagnosis, negative symptom severity, rehospitalization, employment, and neuroticism; associations with the picture/word task were generally weaker. These data indicate that task differences can strongly affect psychometric properties of error-related neural activity indices in healthy and patient populations. (PsycINFO Database Record (c) 2013 APA, all rights reserved)
[Show abstract][Hide abstract] ABSTRACT: Recent studies on fear generalization have demonstrated that fear-potentiated startle and skin conductance responses to a conditioned stimulus (CS) generalize to similar stimuli, with the strength of the fear response linked to perceptual similarity to the CS. The aim of the present study was to extend this work by examining neural correlates of fear generalization. An initial experiment (N=8) revealed that insula reactivity tracks the conditioned fear gradient. We then replicated this effect in a larger independent sample (N=25). Activation in the insula, anterior cingulate, right supplementary motor cortex and caudate increased reactivity as generalization stimuli (GS) were more similar to the CS, consistent with participants' overall ratings of perceived shock likelihood and pupillary response to each stimulus.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of depression increases substantially during adolescence. Several predictors of major depressive disorder have been established, but their predictive power is limited. In the current study, the feedback negativity (FN), an event-related potential component elicited by feedback indicating monetary gain versus loss, was recorded in 68 never-depressed adolescent girls. Over the following 2 years, 24% of participants developed a major depressive episode (MDE); illness onset was predicted by blunted FN at initial evaluation. Lower FN amplitude predicted more depressive symptoms during the follow-up period, even after controlling for neuroticism and depressive symptoms at baseline. This is the first prospective study to demonstrate a link between a neural measure of reward sensitivity and the first onset of an MDE. The current results suggest that low reward sensitivity may be an important factor in the development of depression.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Fear generalization is thought to contribute to the development and maintenance of anxiety symptoms and accordingly has been the focus of recent research. Previously, we reported that in healthy individuals (N = 25) neural reactivity in the insula, anterior cingulate cortex (ACC), supplementary motor area (SMA), and caudate follow a generalization gradient with a peak response to a conditioned stimulus (CS) that declines with greater perceptual dissimilarity of generalization stimuli (GS) to the CS. In contrast, reactivity in the ventromedial prefrontal cortex (vmPFC), a region linked to fear inhibition, showed an opposite response pattern. The aim of the current study was to examine whether neural responses to fear generalization differ in generalized anxiety disorder (GAD). A second aim was to examine connectivity of primary regions engaged by the generalization task in the GAD group versus healthy group, using psychophysiological interaction analysis. METHODS: Thirty-two women diagnosed with GAD were scanned using the same generalization task as our healthy group. RESULTS: Individuals with GAD exhibited a less discriminant vmPFC response pattern suggestive of deficient recruitment of vmPFC during fear inhibition. Across participants, there was enhanced anterior insula (aINS) coupling with the posterior insula, ACC, SMA, and amygdala during presentation of the CS, consistent with a modulatory role for the aINS in the execution of fear responses. CONCLUSIONS: These findings suggest that deficits in fear regulation, rather than in the excitatory response itself, are more critical to the pathophysiology of GAD in the context of fear generalization.
Depression and Anxiety 01/2013; 30(3):242-250. · 4.61 Impact Factor