Biological Archival Report Psychiatry

Face in Social Anxiety: Visuocortical Dynamics Reveal Propensities for Hypervigilance or Avoidance

Lisa M. McTeague, Marie-Claude Laplante, Hailey W. Bulls, Joshua R. Shumen, Peter J. Lang, and Andreas Keil

ABSTRACT BACKGROUND: Theories of aberrant attentional processing in social anxiety, and anxiety disorders more broadly, have postulated an initial hypervigilance or facilitation to clinically relevant threats and consequent defensive avoidance. However, existing objective measurements utilized to explore this phenomenon lack the resolution to elucidate attentional dynamics, particularly covert influences. METHODS: We utilized a continuous measure of visuocortical engagement, the steady-state visual evoked potential in response to naturalistic angry, fearful, happy, and neutral facial expressions. Participants were treatment-seeking patients with principal diagnoses of social anxiety circumscribed to performance situations (n=21) or generalized across interaction contexts (n=42), treatment-seeking patients with panic disorder with agoraphobia (n=25), and 17 healthy participants. RESULTS: At the principal disorder level, only circumscribed social anxiety patients showed sustained visuocortical facilitation to aversive facial expressions. Control participants as well as patients with panic disorder with agoraphobia and generalized social anxiety showed no bias. More finely stratifying the sample according to clinical judgment of social anxiety severity and interference revealed a linear increase in visuocortical bias to aversive expressions for all but the most severely impaired patients. This group showed an opposing sustained attentional disengagement. CONCLUSIONS: Rather than shifts between covert vigilance and avoidance of aversive facial expressions, social anxiety appears to confer a sustained bias for one or the other. While vigilant reliably increases with social anxiety severity for the majority of patients, the most impaired patients show an opposing avoidance. These distinct patterns of attentional allocation could provide a powerful means of personalizing neuroscience-based interventions to modify attention bias and related impairment. Keywords: Agoraphobia, EEG, Panic disorder, RDoC, Social anxiety, ssVEP https://doi.org/10.1016/j.biopsych.2017.10.004

Heightened sensitivity to facial expressions, particularly those measurements utilized to explore this phenomenon (i.e., connoting threat or scrutiny, has often been observed in social functional magnetic resonance imaging [fMRI], ERP compo- anxiety disorder. This includes speeded behavioral responses nents, reaction time, eye tracking, self-report) lack the ability to to spatial cues (1), increased reflexive eye movements (2) and continuously quantify threat-related changes in visuocortical enhanced early (i.e., 100–200 ms) and later (i.e., 300–500 ms) engagement that may unfold at different latencies and for event-related potential (ERP) components (3–5). Functional different durations. Opposing attentional shifts such as initial neuroimaging findings implicate excessive recruitment of hypervigilance and reflexive avoidance, when averaged into a limbic, paralimbic, and medial prefrontal circuitry in single epoch, may contribute to inconsistent findings. conjunction with the extrastriate visual cortex (6–8). To track dynamic attention to angry, fearful, happy, and While heightened sensitivity to aversive facial expressions is neutral facial expressions, here we used scalp-recorded common in social anxiety, a corpus of work has suggested steady-state visual evoked potentials (ssVEPs) as a contin- marked inconsistency—at times revealing no bias for aversive uous measure of selective attention (i.e., the attentional spot- or even a bias for neutral faces (9,10). Aberrant light) with near-optimal time resolution (13). The ssVEP is an perceptual sensitivities in social anxiety, and anxiety disorders oscillatory electrocortical response to a stimulus modulated in more broadly, have often been interpreted in accordance luminance or in contrast (i.e., flickered). It oscillates at the with the vigilance-avoidance hypothesis—that perception of known specific frequency of the driving stimulus (14,15), threat-relevant stimuli is characterized by initial hypervigilance allowing its separation from noise and quantification in the and consequent defensive avoidance (11,12). However, the time-frequency domain (16). Generators of the ssVEP have

ª 2017 Society of Biological Psychiatry. 1 ISSN: 0006-3223 Biological Psychiatry --, 2017; -:-–- www.sobp.org/journal Biological Psychiatry Visuocortical Dynamics in Social Anxiety

been localized to extended visual cortex (14), with strong DSM-IV principal diagnoses of social anxiety disorder cir- contributions from primary visual areas (17). Importantly, cumscribed to performance situations (n=21) or generalized ssVEPs reflect repeated excitations of the visual system across interaction contexts (n=42), treatment-seeking evoked by the same “flickered” stimulus. Temporal changes in patients with principal panic disorder with agoraphobia (PDA) driven neural mass activity indexed by the ssVEP reflect initial (n=25), and 17 community control participants—all without sensory processing as well as subsequent re-entrant, top- psychosis, somatoform, substance use or eating disorders, or down modulation (18,19), likely from frontoparietal and limbic major physical disease. connections (20–22). In keeping with top-down contributions The University of Florida Institutional Review Board (IRB-01) from these regions, modulation of the ssVEP by motivation has approved the study. Participants provided informed consent, been observed as a function of instructed attention (23), fear and they completed questionnaires and the interview in the conditioning (24,25), and emotional arousal (26,27) in patterns morning and psychophysiological assessment in the afternoon. that vary with individual differences including depression (28), fearfulness (29), and anxiety (30,31). Diagnostic Classification Unlike ssVEPs provoked by emotional scenes and fear Diagnostic groups were established using the Anxiety Disor- conditioned cues, we have observed in a series of prior studies ders Interview Schedule for DSM-IV (43). For multiple Axis I that ssVEPs to facial expressions are not modulated as a disorders, diagnostic primacy was determined according to function of emotion—except in the case of social anxiety the severity rating of the Clinical Global Impressions-Severity (30–32). For example, in a study of undergraduate students (CGI-S) scale (44) (ranging from 0 [no features present] to 7 selected to be high and low on social anxiety, we observed [most severely ill patients]) reflecting both distress and inter- no modulation in the low-symptom group, and sustained ference for respective disorder presentations. The CGI-S scale enhancement to emotional (angry, fearful, happy) expressions was modified to consider functional interference and related relative to neutral that robustly increased with social fear and distress not more appropriately subsumed under another dis- avoidance severity (32). These findings prompt the hypothesis order (see the Supplement). Interviewers rated CGI-S for all that affective expressions should evoke heightened ssVEPs in disorders assessed in the Anxiety Disorders Interview those with social anxiety disorder. However, we have found that Schedule (anxiety, mood, adjustment, somatoform, substance treatment-seeking adult clinical samples are marked by sub- use, and psychotic disorders) and any Axis II disorders stantial heterogeneity in defensive reactivity. Instead of uniform assessed as warranted by Structured Clinical Interview for defensive hyperreactivity, we have observed that a substantial DSM-IV Axis II Personality Disorders screener (45) elevations. portion of patients with social anxiety as well as other anxiety Control participants denied current or lifetime diagnoses of disorders, typically those with the most severe disorder-related psychiatric illness and/or treatment and did not receive any distress and interference, show a paradoxical hyporeactivity to CGI-S scale ratings that indicated more than minimal symp- threat cues (33–35). If visuocortical dynamics mirror these toms (i.e., severity rating = 1). A doctoral-level clinical psy- findings, we hypothesize that a portion of the sample with the chologist with expertise in anxiety disorders was present in all most extreme levels of distress and impairment (36) would interviews (M-CL), and interrater reliability (via videotape) was display attentional avoidance (either sustained or subsequent calculated for 25% of patients, yielding 100% agreement for to initial hypervigilance) in response to angry faces. principal diagnosis among three master’s- or doctoral-level While the latent structure of social anxiety appears dimen- clinical psychologists. sional (37,38), a more discrete boundary between circum- Consistent with the DSM-5 performance specifier, circum- scribed (i.e., performance only) and generalized social anxiety scribed social anxiety was operationalized as disabling and subtypes has often been observed in subjective and objective disturbing anxiety about negative evaluation limited to perfor- measures (35,36). Here we also examine if ssVEP modulation mance contexts.1 Generalized social anxiety was defined as in response to facial expressions would vary by social anxiety significant disturbance in at least two of the following domains: subtype. Although facial expressions may hold particular formal performances, informal speaking and interaction, salience for individuals with social anxiety, of scrutiny are observation of behavior, and assertive interaction (46,47).2 To prominent in many disorders. Limbic and visuocortical sensi- assess the specific nature of predominant symptom pheno- tivity to emotional facial expressions has been established types on observed effects in ssVEP patterns, patients meeting across a range of disorders, particularly other anxiety disorders – fi (39 42). To assess the speci city to principal social anxiety, we 1 For example, idiographic performance fears included taking ex- included a sample of individuals with principal panic disorder aminations, musical performance, athletic participation, with agoraphobia, without comorbid social anxiety disorder. speaking in group meetings at work, giving a speech, or This clinical comparison was selected because persistent interviewing. apprehension about experiencing panic symptoms in settings 2 Circumscribed social anxiety patients endorsed fear (Anxiety Dis- fi where escape is dif cult and/or embarrassing renders cues orders Interview Schedule for the DSM-IV fear severity rating of connoting possible scrutiny especially pertinent (39). 4 and above) and/or avoidance (avoidance severity rating of 4 and above) of at least one formal, structured performance situ- METHODS AND MATERIALS ation (i.e., public speaking, participating in meetings and clas- ses, or idiographic situations). In addition, these individuals Participants exceeded the same threshold for distress and/or functional Participants were assessed at the University of Florida Fear interference regarding apprehension/avoidance of performance and Anxiety Disorders Clinic: 88 treatment-seeking adults with situations, but did not similarly rate other social contexts.

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criteria for social anxiety were exclusive of those with PDA and vice versa.3 Stimuli Experimental methods were similar to those described previ- ously (32). In brief, 96 pictures were selected from the Kar- olinska Directed Emotional Faces (48) of actors (12 women, 12 men) posing four different expressions (neutral, happy, fearful, angry) and were preprocessed to have equal overall luminance and color composition (mean luminance of 28 cd/m2; Michel- son contrast of 0.83). To gather normative affective ratings on the Self-Assessment Manikin (49), 242 unselected individuals rated the stimuli (Supplemental Table S1). Experimental Design Participants were seated in a sound-attenuated, dimly lit room and the HydroCel 129 electroencephalography (EEG) sensor net (Electrical Geodesics, Inc., Eugene, OR) was attached. Participants were instructed to view each picture for the Figure 1. (Top panel) Time domain representation of the steady-state duration of presentation, keeping their eyes comfortably visual evoked potentials, averaged across participants (n=105) when fl focused on the center of the screen. viewing neutral faces ickering at a rate of 17.5 Hz, recorded from sensor Oz. The gray box indicates the duration of the flickering faces. Insets display Faces were presented 116 cm from the participant on a the frequency spectrum of the same data (left lower panel), with a pro- 51-cm cathode ray tube monitor with a vertical refresh rate of nounced peak at the flickering frequency (17.5 Hz) and the first harmonic   70 Hz, subtending a visual angle of 5 horizontally and 6.9 frequency (35 Hz) clearly visible. The inset on the right shows a back view of vertically. Using Psychtoolbox, Version 2 (50), faces appeared the spectral amplitude topography of this response as projected to a in a random order, each flickering at a rate of 17.5 Hz (28.57 ms standard head. The location of sensor Oz is highlighted as a white circle. on and 28.57 ms off) for 3428 ms (60 cycles), with a gray Note the focal parieto-occipital distribution of the steady-state visual evoked potential signal evoked by flickering pictures. background set to the mean luminance of the faces. Faces were followed by a randomly variable 2- to 4-second intertrial  interval during which a central crosshair (1 visual angle) driving frequency of 17.5 Hz. The time-varying ssVEP appeared. Each was shown once, for 96 trials total over amplitude was extracted as the modulus of the bandpass- approximately 11 minutes. filtered ssVEP signal and the Hilbert-transformed analytic EEG Recording and Data Collection signal. EEG was continuously recorded and digitized at 250 Hz, Statistical Analysis using Cz as a recording reference. As suggested (51) for the Electrical Geodesics, Inc., high input-impedance (200 Two complementary strategies were employed to evaluate MU)amplifier, electrode impedances were kept below group differences in ssVEP amplitude: an initial step 50 kU. Data were filtered online by 0.1-Hz high-pass and assessed broad differences in time-averaged ssVEP ampli- 100-Hz low-pass elliptic filters, and offline at 30-Hz low tudes, and the subsequent step examined the ssVEP dy- pass (48 dB/octave, 18th-order Butterworth filter). An namics at each sample point. First, ssVEP amplitude was established procedure (52), as implemented in the Elec- extracted as a posterior regional mean of the viewing period. troMagnetic EncaphaloGraphy Software suite (53),was For each participant and condition, the time-varying ssVEP used to identify artifact-free epochs, extracted relative to amplitude was averaged between 800 and 3200 ms, across the onset of each picture, using 300 ms before and 4400 an occipital electrode cluster comprising electrode Oz and ms after picture onset. See the Supplement for additional its eight nearest neighbors. A linear mixed model analysis details. implemented in SPSS, Version 24 (SPSS Inc., Chicago, IL) was conducted on the average ssVEP amplitude with fixed ssVEP Analyses effects of (neutral, happy, fearful, angry), To illustrate data quality, grand mean ssVEPs recorded over sex (male, female), and diagnostic group (control, circum- central occipital sensor Oz for the neutral face condition are scribed social anxiety, PDA, generalized social anxiety), and shown in Figure 1. For ssVEP analysis, condition-based their interaction terms. Age was entered as a continuous averages were submitted to time-frequency analysis using covariate of interest, including its interaction terms with the theHilberttransform:datawerefiltered with a 10th-order categorical fixed effects. ssVEPs are sensitive to rated Butterworth bandpass filter (width 0.5 Hz) around the emotional arousal (26); thus, contents were entered in order of increasing arousal for Karolinska Directed Emotional 3 As only one participant was excluded owing to comorbid Faces stimuli (i.e., neutral, happy, fearful, and angry), generalized social anxiety and PDA, this criterion likely did not demonstrated in the present normative sample and other impact the generalizability to a naturally occurring treatment- studies (4). The subject factor was modeled as a random seeking sample. variable, nested within diagnostic group and nested within

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Table 1. Steady-State Visual Evoked Potential Amplitude by Facial Expression for Control, Social Anxiety, and Panic Disorder With Agoraphobia Groups Control Group Principal Social Anxiety: Principal Panic Disorder With Principal Social Anxiety: Facial Expression (n = 17) Circumscribed (n = 21) Agoraphobia (n = 25) Generalized (n = 42) Neutral 0.24 (0.14) 0.24 (0.21) 0.28 (0.21) 0.22 (0.14) Happy 0.23 (0.13) 0.24 (0.23) 0.28 (0.24) 0.23 (0.13) Fearful 0.24 (0.13) 0.29 (0.25)a 0.29 (0.24) 0.22 (0.13) Angry 0.25 (0.14) 0.28 (0.22) 0.27 (0.22) 0.22 (0.13) Values are mean (SD). aWithin-group comparison to neutral is significant at p , .05. No pairwise between-group comparisons were significant.

sex. Follow-up analyses to decompose omnibus effects disorder with agoraphobia (F3,75 =0.83,p=.48). Meanwhile, were conducted with a repeated-measures analysis of vari- patients with circumscribed social anxiety showed pro- ance (ANOVA), evaluating differences between facial ex- nounced sensitivity to facial expression (F3,60 =4.53,p= pressions within each group and enabling planned contrast .019). Specifically, ssVEP amplitude was enhanced when analyses of interactions between group and expression (54). patients with circumscribed social anxiety viewed fearful

The Greenhouse-Geisser correction was applied where (t20 =2.45,p=.024) and angry (t20 =2.30,p=.032), appropriate (55). Significant effects were followed up using compared with neutral expressions and fearful compared 5 paired t tests or planned contrasts. Univariate ANOVAs and with happy expressions (t20 =2.50,p=.022; Table 1). Tukey honestly significant difference tests for planned Between-group tests of emotional relative to neutral ex- comparisons determined group differences in demographic pressions (i.e., difference score) revealed a reliable difference and questionnaire data. specific to responses during fearful versus neutral expres-

A second set of analyses capitalized on the rich temporal sions (F3,101 =2.98,p=.035) with circumscribed social and spatial information contained in the dense array EEG anxiety showing greater enhancement than generalized so- recordings. In these analyses, t values (comparing specific cial anxiety. In contrast, tests of between-group differences expressions) or F contrasts comparing emotional (happy, in ssVEP amplitude by expression revealed no differences, fearful, angry) expressions with the neutral expression were underscoring that modulation rather than raw amplitude of determined for each EEG sensor, for the mean Hilbert- the ssVEP varied across groups. transformed ssVEP in the time window described above Regarding temporal dynamics contributing to these group (800 to 3200 ms after face onset), and—importantly—for effects, the time course for the occipital sensor cluster each time point individually. The latter analysis addresses employed for statistical analysis is shown in Figure 2.Hy- hypotheses regarding hypervigilance-avoidance sequences persensitivity to angry and fearful faces in circumscribed vis-à-vis temporally sustained facilitation or suppression of social anxiety patients emerged early in the viewing epoch threat cues. Thresholds for statistical significance were and persisted. The lack of enhancement to emotional ex- determined using a permutation technique (56,57).Permu- pressions in the other three groups was similarly persistent tation distributions for t and F values were generated based throughout viewing. As a follow-up to the circumscribed on randomly shuffling within each group. The maximum t or F group effects, Figure 3 displays the ssVEP time course for value for each of 5000 random permutations entered a per- each expression at sensor POz. To illustrate the finding that mutation distribution, and the top and bottom 2.5% tails of both angry and fearful expressions prompted temporally these distributions served as critical values for statistical sustained ssVEP amplification, the white line shows the time- significance. varying F value of the contrast (angry = fearful . neutral) computed for this sensor. RESULTS Topographical statistical mapping of permutation- controlled t tests was consistent with mixed model and Principal Diagnosis and ssVEP Modulation ANOVA results. Differences in ssVEP amplitude across Linear mixed model analysis of ssVEP amplitude showed an posterior locations of the scalp were solely observed for circumscribed social anxiety patients, shown for compari- interaction of facial expression and diagnosis (F9,297 =2.54, p=.008).4 No further main effects or interactions were sons between neutral versus angry and fearful faces, observed, including those of sex or age. Follow-up analyses respectively (Figure 4). Topographical analyses also to disentangle the omnibus interaction revealed no differ- demonstrated that condition differences in the circum- ences in ssVEP amplitude as a function of expression in scribed social anxiety group were strongest at parieto- occipital sensors, superior to the maximum of the ssVEP, control participants (F3,48 =0.41,p=.72), or patients with shown in Figure 1. generalized social anxiety (F3,123 =0.38,p=.76) or panic

4 Initial inspection of means and distributions indicated that age 5 The reliable ssVEP enhancement to fearful in relation to happy was not evenly distributed across diagnostic categories. When expressions among circumscribed social anxiety patients was age was added as an additional random factor nested in group, consistent with the reliably increased arousal ratings obtained the pattern of modulation of ssVEP amplitude by diagnosis for the fearful relative to happy expressions (see the remained the same. Supplement for details).

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functional impairment from control to circumscribed, PDA, and generalized social anxiety at the extreme. Anxious arousal/agoraphobia was most pronounced for PDA, fol- lowed by the generalized and circumscribed social anxiety groups and the control group. Social fear/avoidance was most extreme for the generalized social anxiety group fol- lowed by the circumscribed social anxiety, PDA, and con- trol groups. Medication usage (see the Supplement), diagnostic comorbidity, and demographics (Table 2)didnot correspond with ssVEP modulation.

Transdiagnostic Social Anxiety Severity and Impairment and ssVEP Modulation Next, we considered whether finer-grade clinical judgments of social fear and avoidance severity and interference (as opposed to diagnostic grouping) might reveal distinctions in attentional patterns. These analyses were performed transdiagnostically. Participants across principal disorders were ranked according to CGI-S scale social anxiety ratings. The mean expression-related differences in ssVEP ampli- Figure 2. Grand mean time-varying envelope of the steady-state visual tude during angry versus neutral expressions (expressed as evoked potential signal (from a posterior sensor cluster including Oz and % amplitude of neutral response) were examined according its eight nearest neighbors) evoked by the flickering faces, comparing to CGI-S scale rankings (Figure 5; Supplemental Figures S2 aversive expressions (averaged across angry and fearful expressions) and S3). The pie chart at each CGI-S scale rank reflects the with neutral expressions, for the four principal diagnostic groups: control group (CTRL) (n=17), circumscribed social anxiety group (CIRC) (n=21), proportion of each disorder contributing to a given severity generalized social anxiety (GEN) (n=42), and panic disorder with and impairment level of social anxiety. As observed in agoraphobia (PDA) (n=25). Figure 5, no differences between angry and neutral expression–evoked ssVEPs were observed for individuals not impaired by social anxiety. A linear increase across groups The pattern of ssVEP enhancement to aversive expres- was observed, starting from not impaired, and then minimally sions specific to circumscribed social anxiety was not impaired and moderately impaired, followed by individuals explained by self-reported symptoms. The results are re- markedly impaired by social anxiety showing the greatest ported in detail in Supplemental Table S2. In short, we bias to angry expressions. Patients rated as even more (i.e., observed a linear increase in broad negative affectivity and severely) impaired showed a difference relative to neutral expressions nearly on par with the markedly impaired group—in the opposite direction (i.e., neutral evoking larger ssVEP amplitudes than angry expressions). Reliability of the overall pattern was confirmed by univariate ANOVA, which demonstrated ssVEP modulation as a function of the CGI-S scale (F4,100 = 3.02, p=.021), best described by a quadratic trend (F1,100 = 4.82, p=.031). No such trend was 6 observed for fearful expressions (F4,100 = 0.95, p=.438). The opposing patterns in the marked and severe groups repre- sented sustained hyper- and hyposensitivity, respectively, to angry expressions as opposed to fluctuating attentional over- and underengagement (Figure 6). Follow-up tests of all symptom severity, prognosis, and comorbidity indices in Table 2 suggested more similarities than differences between

6 A post hoc test of the interaction of CGI-S scale rank and expression (neutral, angry) underscored the reliability of this

effect (F4,100 = 2.79, p=.03). Additional follow-up pairwise comparisons of the ssVEP amplitude difference in response to angry relative to neutral expressions across groups Figure 3. Grand mean time-varying envelope of the steady-state visual (F = 3.02, p=.02) further revealed that the markedly evoked potential signal evoked by the flickering faces with four different 4,100 expressions, for participants diagnosed with circumscribed social anxiety impaired group showed ssVEP enhancement to angry relative (n=21) recorded from parieto-occipital electrode site POz. The white line to neutral expressions that exceeded the responses of the shows the permutation-controlled F contrast comparing neutral with angry not impaired (p=.044) and severely impaired (p=.02) and fearful contents (fearful = angry . neutral). groups. All other pairwise comparisons did not differ.

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these groups.7 Follow-up tests of the Liebowitz Social Anxi- ety Scale self-report version total score, similarly separated into quintiles, showed no reliable differences, suggesting that self-reported social anxiety did not track this attentional bias as closely as clinical judgment.

DISCUSSION In the current study, continuous visuocortical responses to naturalistic emotional and neutral facial expressions were assessed in individuals with circumscribed and generalized social anxiety disorder and PDA as well as healthy control participants. At the principal disorder level, only circumscribed or performance social anxiety groups showed attentional facilitation to static aversive facial expressions. Furthermore, these group-level patterns were consistent throughout viewing. Circumscribed social anxiety patients showed a sustained pattern of hypervigilance. The other groups, despite elevated self-reported social anxiety and broad distress, showed no visuocortical sensitivity to emotional expressions. Finer-grade clinical judgments of social anxiety severity and impairment were more predictive of visuocortical anomalies to facial expressions. By stratifying—transdiagnostically—on the basis of CGI-S scale ratings of social anxiety, we observed that interpersonal apprehension and related interference predicted a linear increase in sustained perceptual sensitivity to aversive facial expressions. An exception was the most impaired group, which showed sustained attentional disengagement or avoid- ance of aversive relative to neutral facial expressions. Despite the opposing patterns of attentional bias observed in the two most extreme ranks, both were composed of principal social anxiety patients. Surprisingly, the percentage at each of these two CGI-S scale ranks belonging to circumscribed versus generalized subtypes was equivalent, despite the substantial differences in prognosis and symptomatic distress typical of these classes (36). Considering subjective symptom severity further suggested that while the severely impaired group reported more social fearfulness, anxious arousal, and

7 Consistent with the worse CGI-S scale score for social anxiety conferred to the severely impaired group relative to the markedly impaired group, the severely impaired group endorsed more social fearfulness as rated on the Liebowitz Social Anxiety Scale self-report version (total score: markedly mean = 86.96 [SD = 17.21], severely mean = 100.38 [SD = Figure 4. Mass univariate comparisons by principal disorder of mean 21.57], p=.04; fear score: markedly mean = 45.67 [SD = steady-state visual evoked potential amplitude across the viewing epoch, 8.95], severely mean = 52.92 [SD = 10.57], p=.03). evoked by fearful versus neutral and angry versus neutral faces. Red colors Repeating symptom, comorbidity, and prognosis analyses in indicate significant differences (exceeding a critical t value of 3.68). Note that Table 2 between these subgroups, however, revealed reliable steady-state visual evoked potential enhancement during aversive additional differences only in Mood and Anxiety Symptom relative to neutral face processing is observed only in participants in the Questionnaire anxious arousal (markedly mean = 26.22 [SD = principal circumscribed social anxiety group. 7.37], severely mean = 34.54 [SD = 8.81], p=.003) and fi 6 general anxiety (markedly mean = 26.41 [SD = 7.16], severely nonspeci c anxiety on select measures, these groups were mean = 31.69 [SD = 8.79], p=.049) scores. To reduce the predominantly similarly extreme in their subjective distress. array of questionnaires to underlying dimensions, we also The difference in CGI-S scale ranking was based on the extent conducted a principal components analysis using the of impairment in psychosocial functioning. That is, marked dimensional symptom measures and then compared the two impairment was characterized by significant (but not gross) groups on the resulting factors: 1) general distress/negative impairment in important areas of functioning. Severe impair- affectivity, anxious/hyperarousal, and 3) social fear and ment was characterized by at least severe impairment in anxiety (details in the Supplemental Results). The two most several domains or total impairment in one domain. Essentially, impaired groups did not differ on these broad factors. clinician judgment of psychosocial impairment was uniquely

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Table 2. Questionnaire, Interview, and Demographic Responses for Control, Social Anxiety, and Panic Disorder With Agoraphobia Groups Principal Social Principal Panic Principal Anxiety: Disorder With Social Anxiety: Control Group Circumscribed Agoraphobia Generalized Measure (n = 17) (n = 21) (n = 25) (n = 42) Group Effect Social Anxiety–Related Distress abc cd cd abd LSAS-SR total 19.53 (15.90) 53.19 (22.49) 55.96 (34.36) 92.21 (19.63) F3,101 = 33.08, p , .001 abc cd cd abd LSAS-SR fear 10.59 (7.96) 29.38 (11.43) 30.64 (15.90) 48.57 (9.81) F3,101 = 46.78, p , .001 abc cd cd abd LSAS-SR avoidance 8.94 (8.34) 23.81 (12.14) 25.32 (18.79) 43.64 (10.42) F3,101 = 33.08, p , .001 abc cd cd abd FSS social 37.35 (11.64) 63.05 (12.84) 53.40 (17.97) 78.67 (13.77) F3,101 = 38.17, p , .001 Panic-Related Distress abc bd acd bd PDSS total 0.06 (0.24) 5.71 (4.48) 14.28 (5.30) 9.10 (6.78) F3,101 = 25.19, p , .001 bc b acd bd ASI total 15.06 (9.56) 25.14 (14.72) 39.16 (10.27) 28.88 (12.04) F3,101 = 14.52, p , .001 bc b acd b MASQ anxious arousal 20.65 (3.43) 26.05 (7.73) 34.64 (9.93) 28.76 (8.35) F3,101 = 10.78, p , .001 bc b acd bd FSS agoraphobia 22.59 (5.12) 27.62 (8.24) 44.08 (11.75) 32.86 (10.98) F3,101 = 18.51, p , .001 Broad Negative Affectivity abc d d d MASQ mixed symptoms 25.35 (5.44) 36.10 (13.23) 41.40 (14.75) 43.52 (10.42) F3,101 = 10.68, p , .001 bc bc ad ad MASQ general anxiety 16.47 (4.52) 22.0 (6.47) 30.48 (5.80) 28.05 (7.85) F3,101 = 18.99, p , .001 abc bd d ad MASQ general depression 18.24 (4.49) 28.90 (11.98) 31.84 (12.08) 37.12 (10.46) F3,101 = 13.40, p , .001 abc cd d ad MASQ anhedonia 46.65 (10.91) 64.10 (16.37) 73.24 (13.87) 76.24 (14.01) F3,101 = 19.60, p , .001 abc cd d ad BDI-II total 3.18 (5.27) 11.52 (8.49) 17.76 (10.73) 18.98 (9.86) F3,101 = 13.53, p , .001 abc cd d ad STAI-trait 34.0 (7.99) 48.24 (11.85) 52.72 (10.03) 58.31 (9.34) F3,101 = 25.33, p , .001 abc cd d ad PSWQ 37.35 (8.89) 52.67 (15.33) 59.64 (11.34) 65.40 (10.33) F3,101 = 25.32, p , .001 Transdiagnostic Functional Interference abc bcd ad ad IIRS total 18.06 (9.48) 37.95 (16.19) 52.40 (15.75) 51.98 (13.92) F3,101 = 27.21, p , .001 Clinician Judgment of Distress/Impairment e ac bcd ac abd CGI-S scale: social anxiety 1.06 (0.24) 4.43 (0.68) 1.48 (0.65) 5.07 (0.75) F3,101 = 253.61, p , .001 e b b acd b CGI-S scale: panic disorder 1.0 (0) 1.05 (0.22) 4.60 (0.58) 1.10 (0.48) F3,101 = 432.32, p , .001 e b b acd b CGI-S scale: agoraphobia 1.0 (0) 1.0 (0) 4.72 (0.79) 1.02 (0.15) F3,101 = 550.38, p , .001 f bc bc ad ad CGI-S scale: total Axis I/II 29.76 (0.90) 32.23 (3.56) 39.04 (5.06) 36.83 (4.04) F3,101 = 25.34, p , .001 g c c ab Treatment prognosis 2.43 (0.81) 2.80 (1.19) 3.52 (1.21) F2,85 = 7.54, p , .01 Interview Measures h abc cd d ad Axis I disorders 0 (0) 1.29 (0.46) 1.60 (0.96) 1.83 (0.82) F3,101 = 26.37, p , .001 2 Comorbid major depressive disorder, % — 14.3 28.0 19.0 c 3 = 1.42, ns Demographics ab cd cd ab Age at assessment, years 23.94 (6.07) 34.10 (11.71) 34.52 (11.34) 25.14 (7.38) F3,101 = 9.21, p , .001 c c ab 2 Female, % 47.10 57.10 60.0 28.6 c 3 = 8.14, p , .05 abc bd d d 2 Caucasian, % 41.20 76.20 96.0 78.60 c 3 = 17.03, p , .01 c a 2 College graduate, % 41.20 66.70 44.0 28.60 c 3 = 8.41, p , .05 Values are mean (SD) unless otherwise indicated. Superscript letters indicate results of Tukey HSD or chi-square pairwise between-group comparisons. ASI, Anxiety Sensitivity Index (94); BDI-II, Beck Depression Inventory-II(95); CGI-S, Clinical Global Impressions-Severity (44);FSS,FearSurveySchedule (96); IIRS, Illness Intrusiveness Rating Scale (97); LSAS-SR, Liebowitz Social Anxiety Scale self-report version (98); MASQ, Mood and Anxiety Symptom Questionnaire (100); PDSS, Panic Disorder Severity Scale (99); PSWQ, Penn State Worry Questionnaire (101); STAI, State–Trait Anxiety Inventory (102). aComparison with circumscribed social anxiety group is significant at p , .05. bComparison with panic disorder with agoraphobia group is significant at p , .05. cComparison with generalized social anxiety group is significant at p , .05. dComparison with control group is significant at p , .05. eSeven-point scale ranging from 1 (normal/no illness or impairment) to 7 (among the most severely ill patients) (44). fSum of ratings of all Axis I disorders assessed on the Anxiety Disorder Interview Schedule (anxiety, mood, adjustment, substance use, somatoform, psychosis) as well as Axis II disorders assessed based on elevated Structured Clinical Interview for DSM-IV Axis II Personality Disorders screener scores (44). gClinician-rated estimate of treatment outcome (scale ranging from 1 [excellent] to 7 [poor]). hCount of Axis I disorders conferred during interview. related to reliable and opposing patterns of selective attention expressions. Vigilance to other aversive expressions has to aversive expressions. frequently been observed in social anxiety in both ERP com- Individuals who demonstrated heightened sensitivity to ponents and hemodynamic imaging studies (10,58), particu- angry expressions also demonstrated facilitation to fearful larly disgust expressions (59). Rather than specific

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suggestive of enhanced control (64–66). Notably, symptom amelioration is more pronounced among those patients who at pretreatment show stronger visuocortical and paralimbic reactivity to aversive cues (64,67) as well as weaker fronto- parietal activation and connectivity during simultaneous cognitive demands (67–69). Steady-state visuocortical response to social cues may be a prognostic indicator of whether a patient is primed for the sensory, cognitive, and emotional engagement optimal for cognitive behavioral ther- apy response. The finer discernment of visuocortical anomalies observed on the basis of transdiagnostic CGI-S scale ratings of social anxiety highlights the relevance of these symptoms and related attentional biases across disorders. Interpersonal apprehen- sion and avoidance are elevated in a range of psychiatric disorders including other anxiety (70,71), eating (72), person- ality (73), and substance use disorders (74), (75), uni- polar and bipolar depression (76), and psychosis (77), as well Figure 5. Differential sensitivity of the visual cortex to angry faces, as a as numerous physical health conditions (78). Relative to function of social anxiety severity as rated on the Clinical Global Impression- discrete diagnosis, the graded clinical impression weighting Severity scale for all participants. Mean difference in steady-state visual the extent of interpersonal fear, distress, and interference evoked potential (DssVEP) amplitude is shown transdiagnostically for — increasing levels of social anxiety severity, for unimpaired (n = 31), minimally yielded superior prediction of attentional dysregulation a impaired (n=9), moderately impaired (n=25), markedly impaired (n=27), potential intermediate phenotype. and severely impaired (n=13) individuals. Relative contribution of each With the rollout of the Research Domain Criteria initiative diagnostic category to the respective severity level is indicated by pie (79) to promote a science of psychopathology based around charts. PDA, panic disorder with agoraphobia. dimensions of brain-behavior relationships as opposed to subjectively based diagnostic categories, numerous clinical expressions, aversive expressions as a whole may prompt scientists have called for clearer specification of the clinical threat of scruitiny and contempt in social anxiety. targets (80). This has included calls for incorporating the Proposals that affective modulation of primary visual re- metrics of prognosis, caseness, and disability (81) while also sponses result from reentrant signals ultimately originating in attending to the need for improved reliability of experimental frontoparietal and limbic cortices (20,58) have been borne out indices, brain and behavior alike (82). The current findings in recent concurrent ssVEP-fMRI investigations (21,60). Chronic social anxiety may tune visuocortical neurons sensi- tive to facial cues via altering thresholds and gains in the networks representing expectations of interpersonal failure and its consequences. Work with ERP components may assist in identifying the extravisual processing stages that contribute to these effects (61). Limbic and paralimbic regions shown to drive reentrant modulation of the ssVEP are those consistently shown during fMRI studies to be hyperreactive to social cues in social anxiety patients (10,59). Similar to posttraumatic stress (62,63), there may be sub- types of social anxiety with different corticolimbic biases, correspondingly different patterns of reentrant modulation of visual cortex, and thus different attentional phenotypes. Our prior work with startle, autonomic, and facial expressivity measures (35) has suggested that hyper- versus hyporeactivity to social threat cues in social anxiety is related to disorder duration, with more enduring dysfunction related to response attenuation. Whether hyper- versus hyporeactivity may reflect a transition in response dispositions as a function of chronicity or is more reflective of invariant trait dispositions will await a longitudinal investigation. Regardless of the respective path- ogenesis of the attentional biases, fMRI studies of social anxiety treatment outcome hint that reactivity patterns may Figure 6. Grand mean time-varying envelope of the steady-state visual relate to prognosis: successful cognitive behavioral interven- evoked potential signal (from a posterior sensor cluster including Oz and its eight nearest neighbors) evoked by the flickering faces, comparing angry tion for social anxiety downregulates defensive activation of expressions with neutral expressions, for the two groups characterized as limbic and visuocortical regions to clinically relevant cues while most impaired by social anxiety (markedly impaired [n=27] and severely upregulating dorsolateral and medial prefrontal areas impaired [n=13] individuals).

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suggest a potential point of reconciliation—linking objective We offer special thanks to Christopher T. Sege, M.S., for his comments measures to subjective dimensional indices that account for on this manuscript. not only symptom domain severity but also broader impair- LMM reports receiving stock options in Joyable.com for consulting un- related to this work. All other authors report no biomedical financial interests ment. In the current study, follow-up analyses utilizing self- or potential conflicts of interest. reported social fear and avoidance (i.e., Liebowitz Social Anxiety Scale self-report version total score) to stratify pa- ARTICLE INFORMATION tients in a manner akin to the CGI-S scale rankings obscured From the Department of Psychiatry & Behavioral Sciences (LMM), Medical the attentional patterns revealed by clinician judgment. The University of South Carolina, Charleston, South Carolina; Women's Health present study requires replication and extension, particularly Center (M-CL), James A. Haley Veterans’ Hospital, Tampa; Department of in light of the established inconsistency of impairment ratings Health Outcomes and Behavior (HWB), Moffitt Cancer Center, Tampa; and such as the Global Assessment of Functioning, which the Center for the Study of Emotion and Attention (JRS, PJL, AK) at the contributed to its exclusion from DSM-5. Furthermore, University of Florida, Gainesville, Florida. Address correspondence to Lisa M. McTeague, Ph.D., Medical Uni- although interrater reliability for principal disorders was versity of South Carolina, Department of Psychiatry & Behavioral Sciences, 100% in the current sample, reliability was not calculated for 67 President St, Room 505B North, MSC 861, Charleston SC 29425-5712; CGI-S scale ratings. In summary, systematic efforts to E-mail: [email protected]. operationalize and clarify clinical judgment of global severity Received Apr 1, 2017; revised Sep 11, 2017; accepted Oct 2, 2017. and impairment in relation to more objective Research Supplementary material cited in this article is available online at https:// Domain Criteria–style domains could be especially produc- doi.org/10.1016/j.biopsych.2017.10.004. tive (83,84). The ssVEP is a strong candidate measure for advancing REFERENCES clinical science at the intersection of brain and behavior. With 1. Klumpp H, Amir N (2009): Examination of vigilance and disengage- selective sensitivity to visuocortical processing ssVEPs are ment of threat in social anxiety with a probe detection task. Anxiety limited in reflecting processes occurring in other brain areas. Stress Coping 22:283–296. However, their fine temporal and dynamic resolution for 2. 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