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Background: Functional neuroimaging may elucidate the pathophysiologic features of anxiety disorders and the site of action of anxiolytic drugs. A large body of evidence suggests that the amygdala and associated limbic structures play a critical role in the expression of anxiety and may be treatment targets for anxiolytic drugs., Objective: To determine whether lorazepam dose-dependently attenuates blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) activation in the amygdala and associated limbic structures during an emotion face assessment task., Participants and Design: Fifteen healthy volunteers participated in a double-blind, placebo-controlled, randomized dose-response study. Subjects underwent imaging 3 times (at least a week apart) and were given either a single-dose placebo or 0.25 mg or 1.0 mg of lorazepam 1 hour prior to an MRI session. During fMRI, subjects completed an emotion face assessment task, which has been shown to elicit amygdala activation., Main Outcome Measures: The BOLD-fMRI activation in amygdala, insula, and medial prefrontal cortex during the emotion face assessment task., Results: Lorazepam significantly attenuated the BOLD-fMRI signal in a dose-dependent manner in bilateral amygdala and insula but not in the medial prefrontal cortex. Lorazepam did not affect the BOLD-fMRI signal in the primary visual cortex., Conclusions: The current finding provides the first neuroimaging evidence of a dose-dependent change induced by an established therapeutic agent in brain regions known to be critical for the mediation of anxiety. This investigation may help to support the use of BOLD-fMRI with pharmacological probes to investigate the neural circuits underlying anxiety and the use of fMRI as a tool in the development of new anxiolytic agents.

The process of accurately predicting which actions are associated with advantageous versus disadvantageous outcomes is an important function of daily life. An integral part of this process is being able to detect when the association between an action and an outcome changes. This investigation examined the hypothesis that the inferior prefrontal cortex is critical for the detection of trends and that a trend process derived from the temporal difference model accomplishes this detection. Nineteen normal right-handed volunteers completed 120 4-s trials of a Rock Paper Scissors (RPS) task during functional magnetic resonance imaging. Subjects acquired the selection of advantageous actions during the RPS task. Activations in the medial frontal gyrus (BA 10), left ventrolateral frontal gyrus (BA 11/47), and left pallidum were significantly higher during trials in which subjects acquired the advantageous action. The time course of individually derived trend detection functions was found to be time-locked to the hemodynamic changes in the inferior frontal gyrus. These findings are consistent with the hypothesis that the inferior prefrontal cortex computes a trend from previously experienced action-outcome sequences based on a value function derived from the temporal difference model.

Decision making and risk taking are interrelated processes that are important for daily functioning. The somatic marker hypothesis has provided a conceptual basis for processes involved in risk-taking decision making and has been used to link discrete neural substrates to risk-related behaviors. This investigation examined the hypothesis that the degree of risk-taking is related to the degree of activation in the insular cortex. Seventeen healthy, right-handed subjects performed a risk-taking decision-making task during functional magnetic resonance imaging (fMRI) using a fast event-related design. This investigation yielded three main findings. First, right insula (BA 13) activation was significantly stronger when subjects selected a "risky" response versus selecting a "safe" response. Second, the degree of insula activation was related to the probability of selecting a "safe" response following a punished response. Third, the degree of insula activation was related to the subjects' degree of harm avoidance and neuroticism as measured by the TCI and NEO personality questionnaires, respectively. These results are consistent with the hypothesis that insula activation serves as a critical neural substrate to instantiate aversive somatic markers that guide risk-taking decision-making behavior.

A.V. is a young herpes simplex encephalitis (HSE) survivor who suffered extensive bilateral damage to the medial temporal lobe (MTL) leading to a severe and pervasive form of anterograde amnesia. Structural Magnetic Resonance Imaging (MRI) revealed lesions that encompass the hippocampus and amygdala in both hemispheres and that extend more laterally in the right temporal lobe. At the same time, detailed neuropsychological testing showed that the disparity between A.V.'s preserved intellectual functioning (Full Scale IQ: 115) and severe memory deficit (Delayed Memory Index: 42) is one of the largest on record. Despite this deficit, A.V. has regained a higher level of functioning and autonomy compared to previously documented amnesic cases with major bilateral MTL lesions. As a millennial, one advantage which A.V. has over prior amnesic cases is fluency with digital technology - particularly the smartphone. The analysis of his phone and specific app usage showed a pattern that is consistent with the strategy to offload cognitive tasks that would normally be supported by the MTL. A.V.'s behavior is significant in terms of rehabilitation and may have broader implications at the societal level and for public health given the ubiquity of smartphone technology and its potential to become integrated with neural mnemonic functions. [ABSTRACT FROM AUTHOR]

Importance: β-Adrenergic stimulation elicits heart palpitations and dyspnea, key features of acute anxiety and sympathetic arousal, yet no neuroimaging studies have examined how the pharmacologic modulation of interoceptive signals is associated with fear-related neurocircuitry in individuals with generalized anxiety disorder (GAD).Objective: To examine the neural circuitry underlying autonomic arousal induced via isoproterenol, a rapidly acting, peripheral β-adrenergic agonist akin to adrenaline.Design, Setting, and Participants: This crossover randomized clinical trial of 58 women with artifact-free data was conducted from January 1, 2017, to November 31, 2019, at the Laureate Institute for Brain Research in Tulsa, Oklahoma.Exposures: Functional magnetic resonance imaging was used to assess neural responses during randomized intravenous bolus infusions of isoproterenol (0.5 and 2.0 μg) and saline, each administered twice in a double-blind fashion.Main Outcomes and Measures: Blood oxygen level-dependent responses across the whole brain during isoproterenol administration in patients with GAD vs healthy comparators. Cardiac and respiratory responses, as well as interoceptive awareness and anxiety, were also measured during the infusion protocol.Results: Of the 58 female study participants, 29 had GAD (mean [SD] age, 26.9 [6.8] years) and 29 were matched healthy comparators (mean [SD] age, 24.4 [5.0] years). During the 0.5-μg dose of isoproterenol, the GAD group exhibited higher heart rate responses (b = 5.34; 95% CI, 2.06-8.61; P = .002), higher intensity ratings of cardiorespiratory sensations (b = 8.38; 95% CI, 2.05-14.71; P = .01), higher levels of self-reported anxiety (b = 1.04; 95% CI, 0.33-1.76; P = .005), and significant hypoactivation in the ventromedial prefrontal cortex (vmPFC) that was evident throughout peak response (Cohen d = 1.55; P < .001) and early recovery (Cohen d = 1.52; P < .001) periods. Correlational analysis of physiological and subjective indexes and percentage of signal change extracted during the 0.5-μg dose revealed that vmPFC hypoactivation was inversely correlated with heart rate (r56 = -0.51, adjusted P = .001) and retrospective intensity of both heartbeat (r56 = -0.50, adjusted P = .002) and breathing (r56 = -0.44, adjusted P = .01) sensations. Ventromedial prefrontal cortex hypoactivation correlated inversely with continuous dial ratings at a trend level (r56 = -0.38, adjusted P = .051), whereas anxiety (r56 = -0.28, adjusted P = .27) and chronotropic dose 25 (r56 = -0.14, adjusted P = .72) showed no such association.Conclusions and Relevance: In this crossover randomized clinical trial, women with GAD exhibited autonomic hypersensitivity during low levels of adrenergic stimulation characterized by elevated heart rate, heightened interoceptive awareness, increased anxiety, and a blunted neural response localized to the vmPFC. These findings support the notion that autonomic hyperarousal may be associated with regulatory dysfunctions in the vmPFC, which could serve as a treatment target to help patients with GAD more appropriately appraise and regulate signals of sympathetic arousal.Trial Registration: ClinicalTrials.gov Identifier: NCT02615119. [ABSTRACT FROM AUTHOR]

Several studies have examined the role of different neurotransmitter systems in modulating risk-taking behavior. This investigation was aimed to determine whether the benzodiazepine lorazepam dose-dependently alters risk-taking behavior and underlying neural substrates. Fifteen healthy, nonsmoking, individuals (six women, nine men), aged 18–39 years (mean 27.6 ± 1.4 years) with 12–18 years of education (mean 15.6 ± 0.3 years) underwent functional magnetic resonance imaging while performing a risk-taking decision-making task. Our results show that lorazepam did not affect risky behavior at 0.25 and 1 mg, but dose-dependently attenuated activation in (a) the amygdala and medial prefrontal cortex during the response selection phase, and in (b) the bilateral insular cortex and amygdala during the outcome (i.e., rewarded or punished) phase. Furthermore, a lorazepam-induced increase in insular cortex activation was associated with less risky responses. Taken together, our findings support the idea that GABAergic modulation in limbic and paralimbic structures is important during both the response selection and outcome phase of risk-taking decision-making. [ABSTRACT FROM AUTHOR]

Neuroticism is a core personality trait that profoundly affects how individuals interpret and interact with their environment. Understanding neuroticism at a neurobiological level will be an important step toward identifying novel vulnerability factors for psychiatric illnesses such as depression and anxiety. Along these lines, recent work has identified neural activation patterns within the right anterior insula that correlates with an individual's degree of neuroticism. The present study aims to further characterize the circumstances under which neuroticism modulates insular activity. Sixteen healthy participants underwent functional magnetic resonance imaging while playing a card game with varying degrees of outcome uncertainty. Activation within the bilateral anterior insula was found during all decisions, irrespective of uncertainty. However, a significant positive correlation between neuroticism and anterior insula activity was found only during 'certain decisions' (i.e. situations where the most probable outcome was clearly evident). Moreover, an increase in the right anterior insula activity during certain decisions was related to a behavioral mirroring effect such that the response latency for certain decisions approached the response latency for uncertain decisions. These findings suggest that increasing levels of neuroticism modulate neural activation in such a way that the brain interprets certainty as uncertain. [ABSTRACT FROM AUTHOR]

Abstract: Decision-making is a complex process that comprises the assessment of a situation, the selection of an action, and the evaluation of an outcome. Distinct neural systems may contribute differentially during various stages within a decision-making situation. This study investigated whether neural activation during assessment or action selection is critically dependent on previous outcomes or actions. Twelve healthy, right-handed subjects (6 females) played a Rock Paper Scissors (RPS) computer game during functional magnetic resonance imaging. Bilateral insula and medial prefrontal cortex (including the anterior cingulate) were specifically engaged during the assessment and action selection stages of decision-making, whereas bilateral superior frontal gyrus and right inferior parietal lobule activated more during the outcome. Two regions of activation within the bilateral superior temporal gyrus activated only when the previous outcome was a win. Moreover, right insula and superior temporal gyrus were active more when the subject switched responses relative to staying with the same choice made on the previous trial. These findings support the hypothesis that distinct neural systems underlie different stages of the decision-making process. Furthermore, the superior temporal gyrus may play an important role in integrating previous actions and successful outcomes into one''s decision-making strategy. [Copyright &y& Elsevier]

Background: Individuals with high trait anxiety (HTA) can be studied to examine the effect of elevated levels of anxiety on the processing of stimuli and the selection of actions. The anterior cingulate cortex has been implicated in the detection and processing of errors. This investigation examined the hypothesis that HTA subjects are more sensitive to errors than nonanxious comparison subjects during a simple decision-making task and show increased activation in the anterior cingulate, particularly at low error rates.Methods: Thirteen HTA subjects were compared with 13 normal trait anxiety (NTA: 40th–60th percentile) subjects during functional magnetic resonance imaging while performing a two-choice prediction task at three different error rates.Results: Both HTA and NTA subjects performed similarly during a simple two-choice prediction task; however, during the low-error-rate condition, activation in the anterior cingulate and medial prefrontal cortex was significantly higher in HTA subjects and was correlated with trait but not state anxiety.Conclusions: These results support the idea that HTA subjects devote more processing resources to decision making than do NTA subjects during times in which there is little chance of incorrect responding (i.e., the low-error-rate condition). The extent to which this altered activation within the anterior cingulate contributes to anxiety-proneness remains to be determined. [Copyright &y& Elsevier]

Abstract: Background: Young adults who use stimulants (e.g., cocaine, amphetamines) are at particular risk of transitioning to dependence. Previously, we demonstrated increased risk-taking in young adults who had used stimulants (Leland, D.S., Paulus, M.P., 2005. Increased risk-taking decision-making but not altered response to punishment in stimulant-using young adults. Drug. Alcohol Depend. 78, 83-90). Since outcome uncertainty is a critical element of risk, we investigated whether such individuals have different neural responses to uncertainty than their stimulant-naive peers. Method: Eleven young adults (age 18–25) who had used stimulants were compared with 11 age- and education-matched stimulant-naive controls using functional magnetic resonance imaging and a card prediction task with relatively certain/uncertain outcome conditions. Results: The caudate, an area involved in processing salient events, was among those regions more active in users than controls in response to uncertainty. Personality measures revealed that users were more impulsive than controls, and that neural response to uncertainty in a number of areas, including the thalamus/caudate, was positively correlated with impulsivity. Conclusions: These results are consistent with the idea that young adults who have used stimulants find uncertainty particularly salient, due in part to preexisting differences in impulsivity, and may be subject to more “action pressure” when making decisions under uncertainty. This neural and personality profile may constitute a marker for increased risk of stimulant use. [Copyright &y& Elsevier]

Abstract: Semantic organization, an aspect of semantic processing, requires a pre-existing network of semantic knowledge that relies on a widely distributed neural network. The inferior prefrontal cortex (IPFC) has been identified as a vital structure for processing competing semantic information when making a decision about the meaning of a stimulus. However, the precise role of the IPFC in maintaining or creating a consistent semantic organizational structure is unclear. In this study, a semantic triadic decision-making task (Tallent, K.A., Weinberger, D.R., and Goldberg, T.E. 2001. Associating semantic space abnormalities with formal thought disorder in schizophrenia: use of triadic comparisons. J. Clin. Exp. Neuropsychol. 285–296) was used during functional magnetic resonance imaging to test the hypothesis that the degree of activation in the IPFC correlates with the consistency of semantic organization in healthy subjects. In this sample, subjects who had greater activation in the IPFC also demonstrated smaller stress coefficients in a two-dimensional “semantic space”, indicating a greater organization of words along semantic dimensions. This finding is consistent with the role of the IPFC in establishing self-generated semantic relationships between stimuli. [Copyright &y& Elsevier]

Background: Electroencephalography (EEG) studies suggest that major depressive disorder (MDD) is associated with lower left than right frontal brain activity (asymmetry), a pattern appearing stronger in women than men, and when elicited during emotionally-relevant paradigms versus an uncontrolled resting state. However, it is unclear whether this asymmetry pattern generalizes to the common presentation of MDD with co-occurring anxiety. Moreover, asymmetry may differ for anxiety subtypes, wherein anxious apprehension (AnxApp: worry characteristic of generalized anxiety disorder) appears left-lateralized, but anxious arousal (AnxAro: panic characteristic of social anxiety, posttraumatic stress, and panic disorders) may be right-lateralized.Methods: This analysis attempted to replicate frontal EEG asymmetry patterns using functional magnetic resonance imaging (fMRI). Participants completed clinical interviews and a monetary incentive delay (MID) task during fMRI recording. We compared five groups of right-handed women from the Tulsa 1000 study, MDD (n=40), MDD-AnxApp (n=26), MDD-AnxAro (n=34), MDD-Both (with AnxApp and AnxAro; n=26), and healthy controls (CTL; n=24), as a function of MID anticipation condition (no win/loss, win, loss) and hemisphere on frontal blood oxygen-level-dependent (BOLD) signal.Results: CTL exhibited higher bilateral superior, middle, and inferior middle frontal gyrus BOLD signal than the four MDD groups for high arousal (win and loss) conditions. However, frontal attenuations were unrelated to current depression/anxiety symptoms, suggestive of a trait as opposed to a state marker.Limitations: This was a cross-sectional analysis restricted to women.Conclusions: Reduced prefrontal cortex recruitment during processing of both positively and negatively valenced stimuli is consistent with the emotion context insensitivity theory of MDD. [ABSTRACT FROM AUTHOR]