Lynne Lieberman

The dorsal medial prefrontal (anterior cingulate) cortex–amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: an observational study

Summary Background In four previous studies, we have delineated the role of positive circuit coupling between the dorsal medial prefrontal (anterior cingulate) cortex and the amygdala during aversive processing in healthy people under stress. This translational circuit—the aversive amplification circuit—is thought to drive adaptive, harm-avoidant behaviour in threatening environments. We assess the role of this circuit in the pathological manifestation of anxiety disorders. Methods For this single-site study, 45 unmedicated participants (22 with generalised and/or social anxiety disorder and 23 healthy controls) were recruited via advertisements from the metropolitan area of Washington, DC (USA). People who applied to participate in the study had to pass an initial telephone screen and comprehensive screening by a clinician at the National Institutes of Health (NIH; Bethesda, MD, USA). People with a contraindicated medical disorder, past or current psychiatric disorders other than anxiety disorders, and those using psychoactive medications or illicit drugs were excluded. Eligible individuals could participate as either a healthy control or a patient, depending on diagnosis. They were asked to use a button box to complete a simple emotion identification task (fearful vs happy faces; 44 trials of each) during functional MRI at the NIH. Functional imaging analysis consisted of event-related activation analysis and psychophysiological interaction connectivity analysis of regions coupled with the amygdala during task performance. Findings A diagnosis-by-valence interaction was recorded in whole-brain amygdala connectivity within the dorsal medial prefrontal (anterior cingulate) cortex clusters identified in our previous study, driven by significantly increased circuit coupling during processing of fearful faces versus happy faces in anxious, but not healthy, participants. Importantly, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, which provides evidence of a continuous association between the circuit and subjective symptoms. Interpretation In this study and our previous work, we track the functional role of one neural circuit from its involvement in adaptive threat biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety-related circuit across its adaptive and maladaptive stages. Clinically, this study could provide a step towards a more mechanistic continuum-based approach to anxiety disorder diagnosis and might ultimately lead to more targeted treatments for patients with anxiety disorders. Funding National Institute of Mental Health, USA, and Medical Research Council

Comparing electric shock and a fearful screaming face as unconditioned stimuli for fear learning

The potency of an unconditioned stimulus (UCS) can impact the degree of fear learning. One of the most common and effective UCSs is an electric shock, which is inappropriate for certain populations (e.g., children). To address this need, a novel fear learning paradigm was recently developed that uses a fearful female face and scream as the UCS. The present study directly compared the efficacy of the screaming female UCS and a traditional shock UCS in two fear learning paradigms. Thirty-six young adults completed two fear learning tasks and a measure of trait anxiety; fear learning was indexed with fear-potentiated startle (FPS) and self-reported fear ratings. Results indicated comparable FPS across the two tasks. However, larger overall startle responses were exhibited in the shock task, and participants rated the shock UCS and overall task as more aversive than the screaming female. In addition, trait anxiety was only related to FPS in the fear learning task that employed a shock as the UCS. Taken together, results indicate that, although both UCS paradigms can be used for fear conditioning (i.e., to produce differences between CS+ and CS-), the shock UCS paradigm is more aversive and potentially more sensitive to individual differences in anxiety.

Association between problematic alcohol use and reactivity to uncertain threat in two independent samples.

BACKGROUND Recent laboratory studies have shown that acute alcohol intoxication selectively and effectively dampens aversive responding to uncertain threat. An emerging hypothesis is that individuals who exhibit heightened reactivity to uncertain threat may be especially motivated to use alcohol to dampen their distress, setting the stage for negative reinforcement processes to drive excessive alcohol use. However, no study to date has directly examined whether current problematic drinkers exhibit heightened reactivity to uncertain threat as would be expected. METHODS The present study was therefore designed to examine the association between current problematic alcohol use and reactivity to uncertain threat during sobriety in two, independent samples. In Study 1 (n=221) and Study 2 (n=74), adult participants completed the same well-validated threat-of-shock task which separately probes responses to temporally predictable and unpredictable threat. Startle potentiation was measured as an index of aversive responding. Problematic alcohol use was defined as number of binge episodes within the past 30days in Study 1 and total scores on a self-report measure of hazardous drinking in Study 2. RESULTS As hypothesized, across both studies greater levels of problematic drinking were associated with greater startle potentiation to unpredictable threat. In Study 2, hazardous drinking scores were also positively associated with startle potentiation to predictable threat. CONCLUSIONS The findings are notably consistent with the notion that heightened reactivity to uncertain threat is an important individual difference factor associated with the onset and/or maintenance of problematic drinking behaviors and may therefore be a novel prevention and intervention target.

Startle Potentiation to Uncertain Threat as a Psychophysiological Indicator of Fear-Based Psychopathology: An Examination Across Multiple Internalizing Disorders

Heightened reactivity to uncertain threat (U-threat) is an important individual difference factor that may characterize fear-based internalizing psychopathologies (IPs) and distinguish them from distress/misery IPs. To date, however, the majority of existing research examining reactivity to U-threat has been within individuals with panic disorder and major depressive disorder (MDD) and no prior study has directly tested this hypothesis across multiple IPs. The current study therefore explored whether heightened reactivity to U-threat is a psychophysiological indicator of fear-based psychopathology across 5 groups: current (a) social anxiety disorder (SAD); (b) specific phobia (SP); (c) generalized anxiety disorder (GAD); (d) MDD; and (c) individuals with no history of psychopathology (controls). All 160 adults completed a well-validated threat-of-shock task designed to probe responses to predictable (P-) and U-threat. Startle eyeblink potentiation was recorded as an index of aversive arousal. Results indicated that individuals with SAD and SP evidenced greater startle potentiation to U-threat, but not P-threat, relative to individuals with GAD, MDD, and controls (who did not differ). The current findings, along with the prior panic disorder and MDD literature, suggest that heightened reactivity to U-threat is a psychophysiological indicator of fear-based disorders and could represent a neurobiological organizing principle for internalizing psychopathology. The findings also suggest that individuals with fear disorders generally display a hypersensitivity to uncertain aversive events, which could contribute to their psychopathology.

Aversive responding to safety signals in panic disorder: The moderating role of intolerance of uncertainty

An inability to inhibit aversive responding during conditions that signal safety may be a core dysfunction associated with anxiety disorders. However, there has been inconsistent evidence as to whether individuals with panic disorder (PD) exhibit aversive responding during safety signals. It is therefore possible that only certain subgroups of PD patients, particularly those with high levels of intolerance of uncertainty (IU), evidence this type of abnormal responding. The aim of the current study was to examine whether IU moderates the association between PD and startle potentiation during (a) safety and (b) threat periods during a threat-of-shock task. Participants included 172 adults, 74 of which had current diagnoses of PD. Results indicated that at high levels of IU, PD was associated with greater startle potentiation during safety. At low levels of IU, PD was not associated with startle potentiation during safety. IU did not moderate the effect of PD on threat responding. These results suggest that PD patients with high levels of IU fail to inhibit aversive responding during safety, possibly due to a tendency to interpret distal threat as distressing.

Induced-anxiety differentially disrupts working memory in generalized anxiety disorder

BackgroundAnxiety is characterized by a bias towards threatening information, anxious apprehension, and disrupted concentration. Previous research in healthy subjects suggests that working memory (WM) is disrupted by induced anxiety, but that increased task-demand reduces anxiety and WM is preserved. However, it is unknown if patients with generalized anxiety disorder (GAD) can similarly normalize their performance on difficult WM tasks while reducing their anxiety. Increased threat-related bias and impoverished top-down control in trait anxiety suggests that patients may not reap the same cognitive and emotional benefits from demanding tasks that those low in anxiety. Here we examine this possibility using a WM task of varying difficulty.MethodsGAD patients (N = 30) and healthy controls (N = 30) performed an n-back task (no-load, 1-back, 2-back, and 3-back) while at risk for shock (threat) or safe from shock (safe). Anxiety was measured via startle reflex and self-report.ResultsAs predicted, healthy controls’ performance was impaired under threat during low-load tasks and facilitated during high-load tasks. In contrast, GAD patients’ performance was impaired under threat regardless of WM load. Anxiety was reduced as cognitive load increased in both groups.ConclusionsThe divergence of emotion regulation (reduction) and performance (persistent impairment) in the patient but not the control group, suggests that different top-down mechanisms may be operating to reduce anxiety. Continued WM disruption in patients indicates that attentional resources are allocated to emotion regulation instead of goal-directed behavior. Implications for our understanding of cognitive disruption in patients, and related therapeutic interventions are discussed.

How many blinks are necessary for a reliable startle response? A test using the NPU-threat task

Emotion-modulated startle is a frequently used method in affective science. Although there is a growing literature on the reliability of this measure, it is presently unclear how many startle responses are necessary to obtain a reliable signal. The present study therefore evaluated the reliability of startle responding as a function of number of startle responses (NoS) during a widely used threat-of-shock paradigm, the NPU-threat task, in a clinical (N=205) and non-clinical (N=92) sample. In the clinical sample, internal consistency was also examined independently for healthy controls vs. those with panic disorder and/or major depression and retest reliability was assessed as a function of NoS. Although results varied somewhat by diagnosis and for retest reliability, the overall pattern of results suggested that six startle responses per condition were necessary to obtain acceptable reliability in clinical and non-clinical samples during this threat-of-shock paradigm in the present study.

Impact of Panic on Psychophysiological and Neural Reactivity to Unpredictable Threat in Depression and Anxiety

Exaggerated anxious responding to unpredictable threat (U-threat) is a core feature of panic disorder (PD). However, it is unknown whether this abnormality is specific to the diagnosis of PD or would manifest along a continuum of panic symptomatology (PS). In addition, little is known about the neural processes underlying this abnormality among those high in PS. Finally, no studies have tested whether startle potentiation and limbic neural reactivity—commonly used indices of U-threat responsivity—are associated and therefore reflect common abnormalities. These questions were investigated in 42 adults with a range of PS. U-threat responding was measured twice during threat of shock—once with startle and once with functional magnetic resonance imaging. As hypothesized, PS positively predicted startle potentiation and dACC reactivity to U-threat. Startle potentiation and dACC activation to U-threat were positively associated. These results suggest a biobehavioral profile of aberrant responding to U-threat associated with PS.

Distinct Responses to Predictable and Unpredictable Threat in Anxiety Pathologies: Effect of Panic Attack

Background Delineating specific clinical phenotypes of anxiety disorders is a crucial step toward better classification and understanding of these conditions. The present study sought to identify differential aversive responses to predictable and unpredictable threat of shock in healthy comparisons and in non-medicated anxiety patients with and without a history of panic attacks (PAs). Method 143 adults (72 healthy controls; 71 patients with generalized anxiety disorder (GAD) or/and social anxiety disorder (SAD), 24 with and 47 without PAs) were exposed to three conditions: 1) predictable shocks signaled by a cue, 2) unpredictable shocks, and 3) no shock. Startle magnitude was used to assess aversive responses. Results Across disorders, a PA history was specifically associated with hypersensitivity to unpredictable threat. By disorder, SAD was associated with hypersensitivity to predictable threat, whereas GAD was associated with exaggerated baseline startle. Conclusions These results identified three physiological patterns. The first is hypersensitivity to unpredictable threat in individuals with PAs. The second is hypersensitivity to predictable threat, which characterizes SAD. The third is enhanced baseline startle in GAD, which may reflect propensity for self-generated anxious thoughts in the absence of imminent danger. These results inform current thinking by linking specific clinical features to particular physiology profiles.

Association between neural reactivity and startle reactivity to uncertain threat in two independent samples

Prior studies indicate that anxiety disorders are associated with heightened sensitivity to uncertain threat (U threat). Individual differences in reactivity to U threat have been measured in the laboratory with two methodologies-startle eyeblink potentiation and fMRI. While startle and fMRI are purported to relate to each other, very little research exists on whether individual differences in one measure are associated with individual differences in another and, thus, whether startle and fMRI capture shared mechanisms. Therefore, the current study was designed to investigate if and where in the brain measures of startle potentiation and fMRI BOLD signal correlate during response to U threat across two independent samples. Participants in both studies completed two threat anticipation tasks-once during collection of startle potentiation and once during fMRI. In Study 1 (n = 43), the startle and fMRI tasks both used electric shock as the threat. As an extension, in Study 2 (n = 38), the startle task used electric shock but the fMRI task used aversive images. Despite these methodological differences, greater startle potentiation to U threat was associated with greater dorsal anterior cingulate, caudate, and orbitofrontal cortex reactivity to U threat in both samples. The findings suggest that startle and fMRI measures of responding to U threat overlap, and points toward an integrated brain-behavior profile of aberrant U threat responding.