Acute orexin antagonism selectively modulates anticipatory anxiety in humans: implications for addiction and anxiety.

Research indicates that heightened anticipatory anxiety underlies several forms of psychopathology. Anticipatory anxiety can be reliably and objectively measured in the laboratory using the No-Predictable-Unpredictable (NPU) threat paradigm. The NPU paradigm is an ideal research tool for the NIH 'Fast-Fail' approach of screening promising compounds and testing human target engagement. Evidence from preclinical studies suggests that the hypocretin/orexin (ORX) hypothalamic neuropeptide system is a potential means for modulating anticipatory anxiety and disrupting stress-related alcohol use. The current study tested this question using a psychophysiological probe of the ORX system in humans. We examined whether a single dose of suvorexant (SUV; 10 mg; dual ORX receptor antagonist) can effectively and selectively target a well-validated human laboratory index of exaggerated anticipatory anxiety using a within-subjects placebo-controlled design. A total of twenty-one volunteers completed two laboratory sessions during acute administration of 10 mg SUV or placebo. Across sessions, we administered the NPU paradigm probing sustained anticipatory anxiety and fear while startle eyeblink was recorded as an index of aversive reactivity. Questionnaires assessing mood states and subjective drug effects were also collected. Results indicated SUV was well-tolerated. Compared with placebo, SUV was associated with decreased startle reactivity during anticipatory anxiety but not fear or no-threat conditions. Therefore, SUV selectively and effectively reduced objective indicators of anticipatory anxiety in humans and engaged our laboratory target of psychopathology. ORX antagonism may be a promising strategy for modulating human anxiety and potentially, stress-related alcohol use.

Association between startle reactivity to uncertain threats and structural brain volume.

Sensitivity to uncertain threat (U-threat) is a clinically important individual difference factor in multiple psychopathologies. Recent studies have implicated a specific frontolimbic circuit as a key network involved in the anticipation of aversive stimuli. In particular, the insula, thalamus, and dorsal anterior cingulate cortex (dACC) have recently been found to be robustly activated by anticipation of U-threat. However, no study to date has examined the association between U-threat reactivity and structural brain volume. In the present study, we utilized a pooled sample of 186 young adult volunteers who completed a structural MRI scan and the well-validated No-Predictable-Unpredictable (NPU) threat of electric shock task. Startle eyeblink potentiation was collected during the NPU task as an objective index of aversive reactivity. ROI-based analyses revealed that increased startle reactivity to U-threat was associated with reduced gray matter volume in the right insula and bilateral thalamus, but not the dACC. These results add to a growing literature implicating the insula and thalamus as core nodes involved in individual differences in U-threat reactivity.

Neural and Self-report Measures of Sensitivity to Uncertainty as Predictors of COVID-Related Negative Affect.

The COVID-19 pandemic has been a period of unprecedented uncertainty. Research indicates individuals differ in their response to uncertainty and these differences are mediated by anterior insula (aINS) function. Those most sensitive to uncertainty are likely vulnerable to negative affect in the context of the pandemic. The current study was designed to directly test this question using both neural and self-reported measures of sensitivity to uncertainty. Fifty-nine volunteers completed a task designed to probe neural response to anticipation of predictable (P-) and unpredictable (U-) threat-of-electric-shock during functional magnetic resonance imaging and a self-report measure of intolerance of uncertainty (IU). Approximately two years later, during the peak of the pandemic, participants reported their emotional reactions to the COVID-19 crisis. Multilevel mixed models revealed that greater aINS activation to U-threat and greater self-reported IU were independent predictors of increased COVID-related negative affect. These findings were significant when adjusting for biological sex and depression and anxiety symptom severity. The results add to a growing literature demonstrating that individual differences in response to uncertainty have a robust impact on mood and functioning. Results also highlight that individuals highly sensitive to uncertainty may be at increased risk for poor mental health during the ongoing pandemic.