Heightened sensitivity to threat and reduced sensitivity to reward are potential mechanisms of dysfunction in anxiety and depressive disorders, respectively. However, few studies have simultaneously examined whether these mechanisms are unique or common to these disorders. In this study, sensitivity to predictable and unpredictable threat (measured by startle response during threat anticipation) and sensitivity to reward (measured by frontal electroencephalographic [EEG] asymmetry during reward anticipation) were assessed in 4 groups (N = 191): those with (1) panic disorder (PD) without a lifetime history of depression, (2) major depression (MDD) without a lifetime history of an anxiety disorder, (3) comorbid PD and MDD, and (4) controls. General distress/negative temperament (NT) was also assessed via self-report. Results indicated that PD (with or without comorbid MDD) was uniquely associated with heightened startle to predictable and unpredictable threat, and MDD (with or without comorbid PD) was uniquely associated with reduced frontal EEG asymmetry. Both psychophysiological measures of threat and reward sensitivity were stable on retest approximately 9 days later in a subsample of participants. Whereas the comorbid group did not respond differently on the tasks relative to the PD-only and MDD-only groups, they did report greater NT than these 2 groups (which did not differ from each other). Results suggest that heightened sensitivity to threat and reduced sensitivity to reward may be specific components of PD and MDD, respectively. In addition, relative to noncomorbid depression and PD, comorbid MDD and PD may be characterized by heightened NT, but not abnormal levels of these “specific” components.

BackgroundWhite matter (WM) integrity may represent a shared biomarker for emotional disorders (ED). Aims: To identify transdiagnostic biomarkers of reduced WM by meta-analysis of findings across multiple EDs.MethodWeb of Science was searched systematically for studies of whole brain analysis of fractional anisotropy (FA) in adults with major depressive disorder, bipolar disorder, social anxiety disorder, obsessive-compulsive disorder or posttraumatic stress disorder compared with a healthy control (HC) group. Peak MNI coordinates were extracted from 37 studies of voxel-based analysis (892 HC and 962 with ED) and meta-analyzed using seed-based d Mapping (SDM) Version 4.31. Separate meta-analyses were also conducted for each disorder.ResultsIn the transdiagnostic meta-analysis, reduced FA was identified in ED studies compared to HCs in the left inferior fronto-occipital fasciculus, forceps minor, uncinate fasciculus, anterior thalamic radiation, superior corona radiata, bilateral superior longitudinal fasciculi, and cerebellum. Disorder-specific meta-analyses revealed the OCD group had the most similarities in reduced FA to other EDs, with every cluster of reduced FA overlapping with at least one other diagnosis. The PTSD group was the most distinct, with no clusters of reduced FA overlapping with any other diagnosis. The BD group were the only disorder to show increased FA in any region, and showed a more bilateral pattern of WM changes, compared to the other groups which tended to demonstrate a left lateralized pattern of FA reductions.ConclusionsDistinct diagnostic categories of ED show commonalities in WM tracts with reduced FA when compared to HC, which links brain networks involved in cognitive and affective processing. This meta-analysis facilitates an increased understanding of the biological markers that are shared by these ED.

Two emotional/motivational constructs that have been posited to underlie anxiety and depressive disorders are heightened sensitivity to threat and reduced sensitivity to reward, respectively. It is unclear, though, whether these constructs are only epiphenomena or also connote risk for these disorders (and relatedly, whether they connote risk for separate disorders). Using family history of psychopathology as an indicator of risk, the present study examined whether biomarkers of sensitivity to threat (startle potentiation) and reward (frontal EEG asymmetry) were associated with similar or different familial liabilities. In addition, the present study examined whether these biomarkers were associated with risk independent of proband DSM-IV diagnosis. One hundred seventy-three individuals diagnosed with panic disorder (PD), early-onset major depressive disorder (MDD), both (comorbids), or controls completed two laboratory paradigms assessing sensitivity to predictable/unpredictable threat (measured via startle response) and reward (measured via frontal EEG asymmetry during a gambling task). Results indicated that across all participants: 1) startle potentiation to unpredictable threat was associated with family history of PD (but not MDD) and 2) frontal EEG asymmetry while anticipating reward was associated with family history of MDD (but not PD). Additionally, both measures continued to be associated with family history of psychopathology after controlling for proband DSM-IV diagnosis. Results suggest that the proposed biomarkers of sensitivity to unpredictable threat and reward exhibit discriminant validity and may add to the predictive validity of the DSM-IV defined constructs of PD and MDD, respectively.

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An important characteristic of aversive stimuli that determines emotional responses is whether the stimuli are predictable. Human laboratory studies in this area have typically operationalized predictability as being able to predict the occurrence of aversive events, but animal studies suggest that being able to predict other characteristics of the stimuli may also play a role in aversive responding. To examine this, the present study examined two characteristics: the timing and intensity of aversive stimuli. Specifically, participants were randomly assigned to receive shocks that were either predictable or unpredictable in terms of when they would occur (timing) and/or their intensity. Indicators of aversive emotional responses were EMG startle responses and subjective anxiety ratings. Results revealed that aversive responding was elevated for unpredictable timing and intensity suggesting that the predictability of both characteristics play a role in aversive responding (though the effects for timing were stronger). In sum, the anxiogenic effects of unpredictability may generalize to situations beyond unpredictable timing.

Individuals with anxiety disorders have previously demonstrated abnormal habituation to aversiveness over time. As anxiety sensitivity (AS), or an individuals’ propensity to fear anxiety-related sensations, has been shown to be a risk factor for anxiety disorders (particularly panic disorder), the present study examined whether AS was also associated with abnormal habituation. This association was examined in two independent samples of undergraduates (total N=178). Habituation was operationalized as the reduction in startle response to multiple startle probes presented over 2.5 minutes and three definitions of this reduction were employed. Results indicated that individuals with higher levels of AS evidenced deficits in startle habituation, but the strength of this relationship was somewhat dependent on the definition of startle habituation, with the most robust definition being an analysis of participants’ individual slopes across all nine blinks. The present findings suggest that startle habituation is key mechanism underlying AS, and may help elucidate the role this risk factor plays in the pathogenesis of anxiety disorders.

Research suggests that lower respiratory sinus arrhythmia (RSA) is associated with greater aversive responding. One physiological indicator of aversive responding is startle potentiation. While a few studies have demonstrated an inverse association between RSA and startle potentiation, no study to date has distinguished whether this relation is similar for predictable versus unpredictable aversive stimuli. This is an important distinction, given that degree of predictability has been shown to be an important determinant of aversive responding. The present study examined whether resting RSA was associated with startle eye blink responding during predictable and unpredictable threat of electric shock. Resting RSA was collected during a 6-minute seated baseline phase at the beginning of the experimental session. Participants then completed a computerized startle task in which predictable and unpredictable shocks were administered. Results indicated that lower resting RSA was associated with greater startle potentiation during unpredictable threat, but not during predictable threat. These findings are consistent with a growing body of literature suggesting that individual differences in RSA are associated with aversive responding, and extend previous work by suggesting that RSA may be more robustly associated with a heightened sensitivity to unpredictable threat. This pattern of results may have implications for the understanding of pathological anxiety given that individuals with anxiety disorders typically exhibit low RSA and heightened responding during unpredictable threat.

The approach-withdrawal model posits that depression and anxiety are associated with a relative right asymmetry in frontal brain activity. Most studies have tested this model using measures of cortical brain activity such as electroencephalography. However, neuropsychological tasks that differentially employ left vs. right frontal cortical regions can also be used to test hypotheses from the model. In two independent samples (Study 1 and 2), the present study investigated the performance of currently depressed individuals with or without a comorbid anxiety disorder and healthy controls on neuropsychological tasks tapping primarily left (verbal fluency) or right (design fluency) frontal brain regions. Across both samples, results indicated that comorbid participants performed more poorly than depressed only and control participants on design fluency, while all groups showed equivalent performance on verbal fluency. Moreover, comorbid participants showed “asymmetrical” performance on these two tasks (i.e., poorer design [right frontal] relative to verbal [left frontal] fluency), while depressed only and control participants showed approximately symmetrical profiles of performance. Results from these two samples suggest an abnormal frontal asymmetry in neurocognitive performance driven primarily by right frontal dysfunction among anxious-depressed individuals and highlight the importance of considering comorbid anxiety when examining frontal brain functioning in depression.