Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Perceptual Decision Impairments Linked to Obsessive-Compulsive Symptoms are Substantially Driven by State-Based Effects.

Computational models of decision making have identified a relationship between obsessive-compulsive symptoms (OCS), both in the general population and in patients, and impairments in perceptual evidence accumulation. Some studies have interpreted these deficits to reflect global disease traits which give rise to clusters of OCS. Such assumptions are not uncommon, even if implicit, in computational psychiatry more broadly. However, it is well established that state- and trait-symptom scores are often correlated (e.g., state and trait anxiety), and the extent to which perceptual deficits are actually explained by state-based symptoms is unclear. State-based symptoms may give rise to information processing differences in a number of ways, including the mechanistically less interesting possibility of tying up working memory and attentional resources for off-task processing. In a general population sample (N = 150), we investigated the extent to which previously identified impairments in perceptual evidence accumulation were related to trait vs stated-based OCS. In addition, we tested whether differences in working memory capacity moderated state-based impairments, such that impairments were worse in individuals with lower working memory capacity. We replicated previous work demonstrating a negative relationship between the rate of evidence accumulation and trait-based OCS when state-based symptoms were unaccounted for. When state-based effects were included in the model, they captured a significant degree of impairment while trait-based effects were attenuated, although they did not disappear completely. We did not find evidence that working memory capacity moderated the state-based effects. Our work suggests that investigating the relationship between information processing and state-based symptoms may be important more generally in computational psychiatry beyond this specific context.

Revisiting verbal recognition memory in obsessive-compulsive disorder: A computational approach.

Deficits in primary recognition memory and confidence have previously been tested as potential contributors to excessive checking behavior in obsessive-compulsive disorder. Studies have tested both recognition for actions and, hypothesizing that recognition may be disrupted more generally across content domains, verbal recognition memory. However, studies of verbal recognition memory have yielded mixed results. We revisited this work with the benefit of hindsight, running two new experiments with larger samples, the manipulation of recognition difficulty, and a computational model-based approach to data analysis. In both datasets, we found that discriminability, defined as the difference in drift rate for old versus new stimuli in the drift-diffusion model, was reduced as a function of subclinical OCD symptoms in the general population. Paralleling work on drift rate deficits in perceptual decision making in OCD, these reductions were larger for easier recognition decisions. We also asked participants about their confidence in each recognition decision and parcellated confidence into bias, or the difference in overall confidence, and sensitivity, which represents the ability to appropriately map confidence to objective accuracy. We found no consistent evidence of a relationship between OCD symptoms and either quantity.

Acute alcohol administration dampens central extended amygdala reactivity.

Alcohol use is common, imposes a staggering burden on public health, and often resists treatment. The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce)-plays a key role in prominent neuroscientific models of alcohol drinking, but the relevance of these regions to acute alcohol consumption in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband fMRI data were acquired from 49 social drinkers while they performed a well-established emotional faces paradigm after consuming either alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from unbiased, anatomically predefined regions of interest. Analyses revealed similar levels of dampening in the BST and Ce. In short, alcohol transiently reduces reactivity to emotional faces and it does so similarly across the two major divisions of the human EAc. These observations reinforce the translational relevance of addiction models derived from preclinical work in rodents and provide new insights into the neural systems most relevant to the consumption of alcohol and to the initial development of alcohol abuse in humans.

The neurobiology of dispositional negativity and attentional biases to threat: Implications for understanding anxiety disorders in adults and youth.

When extreme, anxiety can become debilitating. Anxiety disorders, which often first emerge early in development, are common and challenging to treat, yet the neurocognitive mechanisms that confer increased risk have only recently begun to come into focus. Here we review recent work highlighting the importance of neural circuits centered on the amygdala. We begin by describing dispositional negativity, a core dimension of childhood temperament and adult personality and an important risk factor for the development of anxiety disorders and other kinds of stress-sensitive psychopathology. Converging lines of epidemiological, neurophysiological, and mechanistic evidence indicate that the amygdala supports stable individual differences in dispositional negativity across the lifespan and contributes to the etiology of anxiety disorders in adults and youth. Hyper-vigilance and attentional biases to threat are prominent features of the anxious phenotype and there is growing evidence that they contribute to the development of psychopathology. Anatomical studies show that the amygdala is a hub, poised to govern attention to threat via projections to sensory cortex and ascending neuromodulatory systems. Imaging and lesion studies demonstrate that the amygdala plays a key role in selecting and prioritizing the processing of threat-related cues. Collectively, these observations provide a neurobiologically-grounded framework for understanding the development and maintenance of anxiety disorders in adults and youth and set the stage for developing improved intervention strategies.

Dispositional negativity: An integrative psychological and neurobiological perspective.

Dispositional negativity-the propensity to experience and express more frequent, intense, or enduring negative affect-is a fundamental dimension of childhood temperament and adult personality. Elevated levels of dispositional negativity can have profound consequences for health, wealth, and happiness, drawing the attention of clinicians, researchers, and policymakers. Here, we highlight recent advances in our understanding of the psychological and neurobiological processes linking stable individual differences in dispositional negativity to momentary emotional states. Self-report data suggest that 3 key pathways-increased stressor reactivity, tonic increases in negative affect, and increased stressor exposure-explain most of the heightened negative affect that characterizes individuals with a more negative disposition. Of these 3 pathways, tonically elevated, indiscriminate negative affect appears to be most central to daily life and most relevant to the development of psychopathology. New behavioral and biological data provide insights into the neural systems underlying these 3 pathways and motivate the hypothesis that seemingly "tonic" increases in negative affect may actually reflect increased reactivity to stressors that are remote, uncertain, or diffuse. Research focused on humans, monkeys, and rodents suggests that this indiscriminate negative affect reflects trait-like variation in the activity and connectivity of several key brain regions, including the central extended amygdala and parts of the prefrontal cortex. Collectively, these observations provide an integrative psychobiological framework for understanding the dynamic cascade of processes that bind emotional traits to emotional states and, ultimately, to emotional disorders and other kinds of adverse outcomes. (PsycINFO Database Record

Estimating changing contexts in schizophrenia.

SEE STEPHAN ET AL DOI101093/AWW120 FOR A SCIENTIFIC COMMENTARY ON THIS WORK: Real world information is often abstract, dynamic and imprecise. Deciding if changes represent random fluctuations, or alterations in underlying contexts involve challenging probability estimations. Dysfunction may contribute to erroneous beliefs, such as delusions. Here we examined brain function during inferences about context change from noisy information. We examined cortical-subcortical circuitry engaging anterior and dorsolateral prefrontal cortex, and midbrain. We hypothesized that schizophrenia-related deficits in prefrontal function might overestimate context change probabilities, and that this more chaotic worldview may subsequently gain familiarity and be over-reinforced, with implications for delusions. We then examined these opposing information processing biases against less expected versus familiar information patterns in relation to genetic risk for schizophrenia in unaffected siblings. In one experiment, 17 patients with schizophrenia and 24 normal control subjects were presented in 3 T magnetic resonance imaging with numerical information varying noisily about a context integer, which occasionally shifted up or down. Subjects were to indicate when the inferred numerical context had changed. We fitted Bayesian models to estimate probabilities associated with change inferences. Dynamic causal models examined cortical-subcortical circuitry interactions at context change inference, and at subsequent reduced uncertainty. In a second experiment, genetic risk for schizophrenia associated with similar cortical-subcortical findings were explored in an independent sample of 36 normal control subjects and 35 unaffected siblings during processing of intuitive number sequences along the number line, or during the inverse, less familiar, sequence. In the first experiment, reduced Bayesian models fitting subject behaviour suggest that patients with schizophrenia overestimated context change probabilities. Here, patients engaged anterior prefrontal cortex relatively less than healthy controls, in part driven by reduced effective connectivity from dorsolateral prefrontal cortex to anterior prefrontal cortex. In processing subsequent information indicating reduced uncertainty of their predictions, patients engaged relatively increased mid-brain activation, driven in part by increased dorsolateral prefrontal cortex to midbrain connectivity. These dissociable reduced and exaggerated prefrontal and subcortical circuit functions were accentuated in patients with delusions. In the second experiment, analogous dissociable reduced anterior prefrontal cortex and exaggerated midbrain engagement occurred in unaffected siblings when processing less expected versus more familiar number sequences. In conclusion, patients overestimated ambiguous context change probabilities with relatively reduced anterior frontal engagement. Subsequent reduced uncertainty about contextual state appeared over-reinforced, potentially contributing to confirmation bias and a cascade of aberrant belief processing about a more chaotic world relevant to delusions. These opposing cortical-subcortical effects relate in part to genetic risk for schizophrenia, with analogous imbalances in neural processing of less expected versus familiar information patterns.