Context and explicit threat cue modulation of the startle reflex: Preliminary evidence of distinctions between adolescents with principal fear disorders versus distress disorders
Introduction
Anxiety and depression during adolescence are highly prevalent emotional disorders that cause significant concurrent and long-term impairment and economic burden (Bittner et al., 2007, Verduin and Kendall, 2007, Mathews et al., 2011). Furthermore, there is high comorbidity across the life span among anxiety disorders, and between anxiety and depressive disorders (e.g., Kashani and Orvaschel, 1990; for a review, see Craske and Waters, 2005). Such comorbidity has raised questions about how best to classify and define psychiatric disorders, including proposed revisions to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and the International Classification of Diseases (ICD-10). While the DSM and ICD generally emphasise self-reported or observable behaviours and emotional features as criteria for individual disorders, the aim of the recent Research Domain Criteria (RDoC) initiative of the National Institute of Health is to characterise psychiatric disorders in terms of neurobiological indicators that cut across disorders as traditionally defined (Insel and Cuthbert, 2009, Craske, 2012).
Comorbidity between anxiety and depressive disorders has been explained in various models of psychiatric disorders as reflecting a broad “internalising” factor (Kendler et al., 2003, Watson, 2005, Krueger and Markon, 2006, Lahey et al., 2008, Seeley et al., 2011) which subsumes two related sub-factors: “fear” and “distress” disorders (e.g., Clark and Watson, 2006, Prenoveau et al., 2010). Specific phobia, social phobia, separation anxiety disorder, panic disorder, and agoraphobia form the “fear” disorders, while generalised anxiety disorder (GAD), depression, post-traumatic stress disorder (PTSD), dysthymia, and possibly obsessive-compulsive disorder (OCD) form the “distress” disorders (Clark and Watson, 2006, Prenoveau et al., 2010). The major sources of evidence for the distinction between fear and distress disorders have come from self-report and genetic data (e.g., Kendler, 1996). However, more recent evidence emerging from cognitive science suggests that fear disorders may be characterised by attention biases away from threat (i.e., threat avoidance) while anxiety-related distress disorders (i.e., GAD) are characterised by attention biases towards threat (i.e., threat vigilance) (e.g., Salum et al., 2013, Waters et al., 2014b). Moreover, recent reviews of event-related negativity and eye blink startle reflex (SR) data as a function of anxiety and depressive disorders (see below) have revealed distinct neurophysiological indicators that show some consistency with structural models (e.g., Vaidyanathan et al., 2012).
The SR is a widely used psychophysiological index of human defensive responding. The SR involves the contraction of the orbicularis oculi muscle in response to a sudden, unexpected stimulus and is one of many obligatory somatic and visceral changes that comprise the human startle reaction (Graham, 1979). A variety of procedures have been used to examine SR modulation in threatening emotional states, including aversive picture-viewing and imagery experiments, as well as fear-potentiation paradigms when SR magnitudes have been assessed during explicit threat conditions (e.g., a cue signalling immediate threat of shock), when participants anticipate shocks, and during safe conditions that predict the absence of shocks. “Baseline” SR magnitudes have also been assessed either before and after fear-potentiation paradigms when threat of shock was explicitly absent or during non-cued phases throughout experiments, while context-potentiated SR refers to amplified SRs when a cue of an upcoming or unpredictable threat may be present.
Several studies have reported that individuals diagnosed with phobias (e.g., animal phobias; non-generalised social phobia), or with high levels of phobic symptoms or trait fearfulness, demonstrate greater SR magnitudes during aversive picture-viewing or imagery while showing relatively normal baseline SR magnitudes (de Jong et al., 1991, Vrana et al., 1992, Globisch et al., 1999, Cuthbert et al., 2003, Lang et al., 2007, McTeague et al., 2009, McTeague et al., 2012, Vaidyanathan et al., 2009a). Inconsistent results have been found for panic disorder (Grillon et al., 1994, Vaidyanathan et al., 2009b, McTeague et al., 2011) and generalised social phobia (McTeague et al., 2009), suggesting they may be characterised by more generalised SR activation similar to the broader and more chronic anxiety disorders discussed below. In studies utilising fear-potentiation paradigms, SR may be larger overall in some fear disorders, such as panic disorder, throughout fear-potentiation paradigms (suggestive of anticipatory apprehension) but not during baseline phases before and after fear-potentiation paradigms when threat is explicitly absent (Grillon et al., 1994). Few studies of circumscribed fears, such as specific phobias and non-generalised social phobia have utilised fear-potentiation paradigms. However, the fear conditioning literature suggests that fear disorders, such as panic disorder and social phobia, are characterised by overgeneralized defensive responding to stimuli that are safe (i.e., CS−) but are associated with danger cues (i.e., CS+) (see Lissek et al., 2009; Lissek, 2012).
In contrast, distress-related anxiety disorders such as PTSD, OCD and GAD are more consistently associated with elevated baseline SR magnitudes and amplified context-potentiated SR relative to healthy controls (Morgan et al., 1995, Grillon et al., 1996, Kumari et al., 2001, Cuthbert et al., 2003, Grillon et al., 2008, Ray et al., 2009, Pole et al., 2009). Results regarding fear-potentiated SR have been more mixed (e.g., Kumari et al., 2001, Cuthbert et al., 2003, Kaviani et al., 2004, Lang et al., 2007). PTSD and GAD have also been linked to overgeneralized defensive responding to safe stimuli (i.e., CS-) in conditioning experiments (see Lissek, 2012; Lissek et al., 2013), and SR results for PTSD in particular have been considerably mixed compared with findings for other anxiety disorders (Grillon and Baas, 2003; Pole, 2007, Vaidyanathan et al., 2009b).
Other studies have shown that depression-related distress disorders have an attenuating effect upon affective and fear-potentiated SR relative to healthy controls (Allen et al., 1999, Kaviani et al., 2004, Forbes et al., 2005, McTeague et al., 2009) and anxious samples without depression (Melzig et al., 2007). Moreover, SR modulation during emotional picture viewing in anxiety disorders is blunted by comorbid depression (Taylor-Clift et al., 2011). Depression has also been linked to diminished physiological reactivity during the anticipation of threat in conditioning experiments in offspring of mothers with a principal depressive disorder relative to offspring of mothers with a principal anxiety disorder and low risk offspring (Waters et al., 2014a). These findings could suggest that depressive disorders are associated with blunted or context insensitive emotional responding (Rottenberg et al., 2005). However, other research has found that depressive disorders are characterised by elevated SR throughout fear-potentiation experiments, contextual anxiety (i.e., placement of shock electrodes) and when shock is predictable (Grillon et al., 2013), while other findings suggest that depressive disorders have no additional effect on the elevated SR magnitudes of adults with panic disorder relative to controls during fear-potentiation experiments (Shankman et al., 2013). Differences in findings may be due to variation in methodology. Blunting in depression has been obtained during viewing of pictures and films, or emotional imagery (Allen et al., 1999, Taylor-Clift et al., 2011, McTeague et al., 2012) or in anticipation of aversive tones (Waters et al., 2014a). Thus, threat is mild, imaginary, and/or may lack personal relevance (Grillon et al., 2013). Therefore, it may be adaptive for depressed individuals to disengage from these types of threats but not from more explicit danger such as a shock in fear-potentiation paradigms (Nesse, 2000, Grillon et al., 2013, Shankman et al., 2013).
As is clear, wide variation in methodology exists across studies. Furthermore, experimental protocols that separate baseline, context and explicit threat phases might help to clarify the conditions under which neurophysiological markers cut across versus differentiate fear-related and distress-related disorders (Watson, 2005, Insel and Cuthbert, 2009, Seeley et al., 2011, Craske, 2012). Therefore, the current study utilised a SR modulation protocol involving a baseline condition when threat of an aversive muscle contraction was explicitly absent, a context condition when a cue of later threat was present (i.e., presence of muscle contraction pads over the biceps muscle), and an explicit threat cue paradigm involving phases that signalled safety from aversive stimuli (i.e., early and late stages of safe phases; early stages of danger phases) and phases that signalled immediate danger of an aversive stimulus (i.e., late stages of danger phases).
If fear disorders are characterised by overgeneralized defensive responding to safe stimuli associated with threat (e.g., Grillon et al., 1994, Lissek et al., 2009), then adolescents with a principal fear disorder (i.e., either specific phobia or non-generalised social phobia) were expected to show amplified SRs during safe phases of the explicit threat cue paradigm compared to healthy controls and adolescents with principal distress disorders. However, groups were not expected to differ in SR magnitudes in response to immediate danger of an aversive stimulus (i.e., late stages of danger phases), reflecting a biologically imperative defence response to explicit threat (Lissek et al., 2005, Craske et al., 2009). In contrast, if distress disorders are associated with elevated SRs during baseline and context conditions (i.e., placement of shock electrodes) within experiments involving fear-potentiation paradigms (Grillon et al., 1996, Pole et al., 2009, Grillon et al., 2013), i.e., the explicit threat cue paradigm in the present study, then adolescents with a principal distress disorder (i.e., either GAD, PTSD or a depressive disorder) were expected to show larger SR magnitudes during the baseline and context conditions in comparison with controls and those with a principal fear disorder.
Section snippets
Participants
Participants were high school juniors from schools in suburban Chicago, Illinois, and suburban Los Angeles, California who participated in the Northwestern University—University of California, Los Angeles (NUCLA) Youth Emotion Project (YEP) (see Craske et al., 2009, Zinbarg et al., 2010 for further details on recruitment and overall study design). Of 1269 students who completed an initial screening measure of neuroticism, 627 participants (69% female) had parental consent and gave youth assent
Group comparisons
There were no significant group differences in age, F(2, 55)=2.02, p=0.14, =0.07, ethnicity, χ2(2, n=58)=0.15, p=0.93, gender, χ2(2, n=58)=0.86, p=0.65, or number of participants recruited from each site, χ2(2, n=58)=0.41, p=0.81 There were no significant differences in the number of diagnoses, t(27)=0.25, p=0.85, or the severity of principal diagnoses between the clinical groups, t(27)=0.22, p=0.83. One-way analyses of variance (ANOVAs) of the MASQ subscales revealed significant group
Discussion
Consistent with hypotheses, adolescents with a principal fear disorder showed significantly larger SRs during safe phases and early danger phases of the explicit threat cue paradigm compared to healthy controls and adolescents with principal distress disorders. As expected, groups did not differ significantly in SR magnitudes during late danger phases when threat of the aversive contraction was immediate and all participants would be expected to show neurobiologically imperative defensive
Acknowledgements
This work was supported by Grants from the National Institutes of Health to Dr. Craske (MH065651) and Drs. Zinbarg and Mineka (MH065652) and from the Virginia Friedhofer Charitable Trust to Dr. Ornitz.
References (65)
- et al.
Affective startle modulation in clinical depression: preliminary findings
Biological Psychiatry
(1999) - et al.
Does neuroticism in adolescents moderate contextual and explicit threat cue modulation of the startle reflex?
Biological Psychiatry
(2009) - et al.
Light-enhanced and fear-potentiated startle: temporal characteristics and effects of alpha-helical corticotropin-releasing hormone
Biological Psychiatry
(2003) - et al.
Affect-modulated startle in adults with childhood-onset depression: relations to bipolar course and number of lifetime depressive episodes
Psychiatry Research
(2005) - et al.
Baseline and fear-potentiated startle in panic disorder patients
Biological Psychiatry
(1994) - et al.
A review of the modulation of the startle reflex by affective states and its application in psychiatry
Clinical Neurophysiology
(2003) - et al.
Endophenotypes: bridging genomic complexity and disorder heterogeneity
Biological Psychiatry
(2009) - et al.
Affective modulation of the startle response in depression: influence of the severity of depression, anhedonia, and anxiety
Journal of Affective Disorders
(2004) - et al.
Classical fear conditioning in the anxiety disorders: a meta-analysis
Behaviour Research and Therapy
(2005) - et al.
The strong situation: a potential impediment to studying the psychobiology and pharmacology of anxiety disorders
Biological Psychology
(2006)
Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder
Behaviour Research and Therapy
Fearful imagery in social phobia: generalization, comorbidity, and physiological reactivity
Biological Psychiatry
Aversive imagery in panic disorder: agoraphobia severity, comorbidity, and defensive physiology
Biological Psychiatry
Fear-potentiated startle in posttraumatic stress disorder
Biological Psychiatry
The use of an unpleasant sound as an unconditional stimulus in a human Pavlovian conditioning procedure
Biological Psychology
Prospective prediction of PTSD symptoms using fear-potentiated auditory startle responses
Biological Psychiatry
Testing a hierarchical model of anxiety and depression in adolescents: a tri-level model
Journal of Anxiety Disorders
Fear acquisition and extinction in offspring of anxious and depressed mothers
Developmental Cognitive Neuroscience
The Northwestern-UCLA youth emotion project: associations of cognitive vulnerabilities, neuroticism and gender with past diagnoses of emotional disorders in adolescents
Behaviour Research and Therapy
Contextual conditioning and the US pre-exposure effect in conditioned fear
Journal of Experimental Psychology: Animal Behavior Processes
What do childhood anxiety disorders predict?
Journal of Child Psychology and Psychiatry
Distress and fear disorders: an alternative empirically based taxonomy of the ‘mood’ and ‘anxiety’ disorders
British Journal of Psychiatry
The R-DOC Initiative: science and practice
Depression and Anxiety
Panic disorder, phobias, and generalised anxiety disorder
Annual Review of Clinical Psychology
Elevated responding to safety cues as a specific risk factor for anxiety versus depressive disorders: evidence from a longitudinal investigation
Journal of Abnormal Psychology
The psychophysiology of anxiety disorder: fear memory imagery
Psychophysiology
Temporal specificity of fear conditioning: effects of different conditioned stimulus-unconditioned stimulus intervals on the fear-potentiated startle effect
Journal of Experimental Psychology and Animal Behavior Processes
Eyeblink startle responses in spider phobics before and after treatment: a pilot study
Journal of Psychopathology and Behavioral Assessment
Anxiety Disorders Interview Schedule-Revised (ADIS-R)
Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition (SCID-I/NP)
Fear appears fast: temporal course of startle reflex potentiation in animal fearful subjects
Psychophysiology
Distinguishing among orienting, defense, and startle reflexes
Cited by (18)
Fear-potentiated startle predicts longitudinal change in transdiagnostic symptom dimensions of anxiety and depression
2022, Journal of Affective DisordersCitation Excerpt :These results suggest that elevated defensive reactivity to safe stimuli associated with threat is a marker of concurrent diagnosis of, and prospective risk for, anxiety disorders. Regarding fear-potentiated startle and depressive disorders, some work suggests that individuals with principal distress disorders demonstrate attenuated SR compared to individuals with fear disorders or no diagnoses (Waters et al., 2014). However, other work has pointed to elevated SR across phases among individuals with depression compared to controls (Grillon et al., 2013).
Exposure to an obesogenic diet during adolescence leads to abnormal maturation of neural and behavioral substrates underpinning fear and anxiety
2018, Brain, Behavior, and ImmunityCitation Excerpt :While these responses may involve lack of arousal or interest in the acoustic stimuli, studies indicate that individuals exhibiting high stress reactivity and anxiety may show suppressed ASR responses (Kalyan-Masih et al., 2016; López-Aumatell et al., 2009a,b; Uvnäs-Moberg et al., 1999; Yen et al., 2012). It has been proposed that blunted baseline ASR responses may reflect high trait anxiety and impaired fear extinction in rats (Russo and Parsons, 2017; Slattery and Neumann, 2010; Uvnäs-Moberg et al., 1999), and anxiety in human adolescents (Waters et al., 2014). Together, the ASR suppression may well represent an early behavioral biomarker for obesity-induced psychopathology.
Using Event-Related Potentials and Startle to Evaluate Time Course in Anxiety and Depression
2018, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingCitation Excerpt :Waters et al. (136) found that adolescents with primary fear conditions (specific phobia, social phobia) exhibited larger startle magnitude when threat was more distal compared with the startle magnitude of adolescents with distress disorders (depression, dysthymia, generalized anxiety disorder, posttraumatic stress disorder), but not when the threat was more pending. As adolescents with fear disorders also exhibited heightened startle magnitude across the safe condition, these results together suggest a pattern of hypervigilance to threat and an overgeneralization of defensive responding among individuals with fear-based conditions (136). Collectively, these studies demonstrate the effectiveness of startle eye-blink in identifying RDoC constructs and chronometric processes that distinguish fear from distress-misery disorders.
An Evaluation of the Specificity of Executive Function Impairment in Developmental Psychopathology
2017, Journal of the American Academy of Child and Adolescent PsychiatryDistress
2016, Stress: Concepts, Cognition, Emotion, and Behavior: Handbook of StressFear load: The psychophysiological over-expression of fear as an intermediate phenotype associated with trauma reactions
2015, International Journal of Psychophysiology