پاسخ های عصبی به ارتباط چشمی و درمان پاروکستین در اختلال اضطراب اجتماعی تعمیم یافته

Abstract Generalized social anxiety disorder (GSAD) is characterized by excessive fears of scrutiny and negative evaluation, but neural circuitry related to scrutiny in GSAD has been little studied. In this study, 16 unmedicated adults with GSAD and 16 matched healthy comparison (HC) participants underwent functional magnetic resonance imaging to assess neural response to viewed images of faces simulating movement into eye contact versus away from eye contact. GSAD patients were then treated for 8 weeks with paroxetine, and 15 patients were re-imaged. At baseline, GSAD patients had elevated neural response to eye contact in parahippocampal cortex, inferior parietal lobule, supramarginal gyrus, posterior cingulate and middle occipital cortex. During paroxetine treatment, symptomatic improvement was associated with decreased neural response to eye contact in regions including inferior and middle frontal gyri, anterior cingulate, posterior cingulate, precuneus and inferior parietal lobule. Both the magnitude of GSAD symptom reduction with paroxetine treatment and the baseline comparison of GSAD vs. HCs were associated with neural processing of eye contact in distributed networks that included regions involved in self-referential processing. These findings demonstrate that eye contact in GSAD engages neurocircuitry consistent with the heightened self-conscious emotional states known to characterize GSAD patients during scrutiny.

Introduction Social anxiety disorder (SAD) has a lifetime prevalence of 5–13% (Kessler et al., 1994 and Kessler et al., 2005); the disorder is characterized by excessive fear of situations involving potential scrutiny by others, and by self-conscious emotions of embarrassment and humiliation. Generalized SAD (GSAD) is a subtype characterized by fear and avoidance of most social situations. It is associated with severity of symptoms, social and occupational impairment, depression, substance abuse and suicide (Schneier, 2006). Cognitive behavioral therapy and selective serotonin reuptake inhibitors (SSRIs) have established efficacy for SAD, but neural mechanisms of treatment response are not well understood (Schneier, 2006). Fears of making eye contact or being looked at, which evoke feelings of scrutiny and self-consciousness in persons with SAD, are associated with severity of SAD (Schneier et al., 2011). Leading explanatory models of SAD highlight the role of self-focused attention (Clark and Wells, 1995 and Schultz and Heimberg, 2008) and biased attention to threat (Bögels and Mansell, 2004), and factor analyses of the Liebowitz Social Anxiety Scale (LSAS) (Liebowitz, 1987), which includes a “fear of eye contact” item, are consistent with this fear being a core feature of SAD (Safren et al., 1999, Baker et al., 2002 and Stein et al., 2004). Eye contact functions more generally across primate species as an essential social signal, providing information on identity, status, interest, and intent (Emery, 2004). Eye contact in SAD might be expected to engage brain regions involved in processing gaze direction, self-referential processing, and fear. Functional magnetic resonance imaging (fMRI) studies in monkeys and healthy subjects have most consistently identified the superior temporal sulcus to be involved in normal processing of others' gaze direction (Nummenmaa and Calder, 2009). A meta-analysis of neuroimaging studies utilizing a variety of stimuli related to the self found that self-referential processing is mediated by cortical midline structures (Northoff et al., 2006). These include the ventromedial prefrontal cortex, dorsomedial prefrontal cortex, and posterior cingulate cortex/precuneus. Neurocircuitry associated with eye contact or scrutiny fears has been little studied in SAD or other disorders. Most fMRI studies in SAD have used harsh facial expressions as threat stimuli, and a meta-analysis has documented increased activation of fear-related circuitry including amygdala, insula, hippocampus, and anterior cingulate (Etkin and Wager, 2007). These regional activations to facial expressions are also observed in other anxiety disorders, and during fear learning in healthy subjects (HCs) (Etkin and Wager, 2007). A limitation of prior imaging studies using threat stimuli has been lack of controls for individual differences in attention paid to stimuli, a known modulator of neural responses to facial expressions in anxiety disorder patients and HCs (Pessoa et al., 2002, Pessoa et al., 2005 and Mitchell et al., 2007). Additionally, few studies have examined changes in neural activity in response to treatment of SAD, and none of these treatment studies have used fMRI, which offers advantages of high resolution, sensitivity to pharmacodynamic effects, and ability to assess neural function during performance of an ecologically valid task (Furmark et al., 2002, Kilts et al., 2006 and Evans et al., 2008). This study of GSAD patients and HCs used fMRI to contrast neural responses to viewing direct gaze from another person (i.e. involuntary eye contact, known to be feared by many GSAD patients, but inherently neutral in emotional valence) versus viewing averted gaze. Eye position of participants was monitored to assess visual attention to gaze stimuli in the scanner. Goals of this study were to compare neural response to direct vs. averted gaze stimuli in GSAD patients and HCs, and within the GSAD group to assess the relationship of changes in activations to changes in symptom severity during 8 weeks of treatment with the SSRI paroxetine.

. Results 3.1. Sample Demographic and clinical features of the analyzed sample are presented in Table 1. GSAD patients evidenced elevated levels of anxiety and avoidance related to eye contact compared to HCs, moderate to severe social anxiety, and mild, subsyndromal levels of depressive symptoms. One GSAD patient completed the first scan and was dispensed paroxetine but did not return for any subsequent appointments. Fifteen GSAD patients completed the study. Table 1. Demographic, clinical, and gaze behavior characteristics at baseline. GSAD participants (n = 16) No. (%) or Mean (S.D.) HC participants (n = 16) No. (%) or Mean (S.D.) t or X2 d.f. P Age, y 29.8 (9.0) 30.3 (9.7) 0.2 29.8 0.88 Sex F 10 (62.5%) 10 (62.5%) 0.0 1.00 M 6 (37.5%) 6 (37.5%) Race White non-Hispanic 11 (68.8%) 13 (81.3%) Asian 2 (12.5%) 1 (6.3%) 0.73a Hispanic 3 (18.8%) 2 (12.5%) Education, y 16.2 (1.9) 16.5 (2.1) 0.5 29 0.64 LSAS 81.4 (15.6) 8.2 (5.4) 17.7 18.5 < 0.001 GARS 49.8 (16.2) 6.9 (6.9) 9.8 20.3 < 0.001 HRSD-17 6.4 (3.3) 0.3 (0.7) 7.4 16.4 < 0.001 % fixations on eye region, direct stimuli 60.4 (25.0) 48.4 (22.2) − 1.4 28 0.18 % fixations on eye region, averted stimuli 60.3 (23.6) 50.1 (26.6) − 1.1 28 0.28 % fixations on eye region, direct-averted 0.1 (7.2) − 1.8 (9.0) − 0.6 28 0.54 Scanpath length (pixels), direct stimuli 3038.8 (998.3) 2578.4 (1216.4) − 1.1 28 0.27 Scanpath length (pixels), averted stimuli 2836.2 (1041.7) 2660.7 (1078.7) − 0.5 28 0.65 Scanpath length (pixels), direct-averted 202.6 (498.4) − 82.3 (430.3) − 1.7 28 0.11 LSAS = Liebowitz Social Anxiety Scale; GARS = Gaze Anxiety Rating Scale; HRSD-17 = Hamilton Rating Scale for Depression, 17-Item Version; a Fisher's Exact Test. Table options 3.2. Treatment response and behavioral response Patients evidenced statistically significant and clinically meaningful improvement in GSAD symptoms during paroxetine treatment, as evidenced by a 36-point decrease in the mean score of the LSAS, similar to change reported in randomized clinical trials of paroxetine (Stein et al., 1998). At week 8, among the 15 GSAD completers, 12 were rated responders to treatment (three were rated “very much improved” and nine were “much improved”), and three were classified as nonresponders (all rated “minimally improved”). Self-reported anxiety and avoidance related to eye contact (GARS) also improved significantly (Table 2). Mean paroxetine dosage at week 8 was 34.0 ± 8.3 mg/day (range 20–40 mg/day). Table 2. Symptom and gaze behavior measures pre- vs. post-treatment in GSAD group completers (n = 15)1. Week 0 Mean (S.D.) Week 8 Mean (S.D.) T d.f. P LSAS 82.6 (15.5) 45.9 (25.6) 5.9 14 < 0.001 GARS 51.2 (15.7) 29.6 (14.5) 5.3 14 < 0.001 HRSD-17 6.3 (3.3) 3.9 (3.5) 1.9 14 0.076 % fixations on eye region, direct stimuli 60.0 (23.4) 39.2 (27.4) 4.8 11 < 0.001 % fixations on eye region, averted stimuli 60.8 (20.9) 40.9 (25.2) 4.0 11 0.002 % fixations on eye region, direct-averted − 0.8 (7.7) − 1.6 (8.4) 0.3 11 0.76 Scanpath length (pixels), direct stimuli 3154.0 (1077.1) 4063.3 (1747.1) 1.3 11 0.22 Scanpath length (pixels), averted stimuli 2842.2 (1167.8) 4191.1 (2050.0) 1.7 11 0.11 Scanpath length (pixels), direct-averted 311.8 (491.1) − 127.9 (945.2) 1.5 11 0.17 LSAS = Liebowitz Social Anxiety Scale; GARS = Gaze Aversion Rating Scale; HRSD-17 = Hamilton Rating Scale for Depression, 17-Item Version. 1Eye gaze data for 3 patients were excluded from analysis due to technical problems with acquisition. Table options At baseline, there were no significant between-group differences in visual attention to stimuli (Table 1). From pre- to post-treatment (week 0 to week 8), GSAD patients evidenced no changes in the difference in percent of fixations on the eye region in response to direct vs. averted gaze (direct-averted, Table 2). However, percent of fixations on the eye region in response to direct gaze and percent of fixation on the eye region in response to averted gaze stimuli each decreased significantly pre- to post-treatment. These decreases were not significantly associated with improvement in GSAD symptoms (Rs = − 0.02 for direct gaze and Rs = − 0.04 for averted gaze). 3.3. Imaging results To address the question of what neural regions are activated during the processing of direct gaze in persons with symptoms of GSAD, we report directional findings at week 0 for GSAD > HC, direct > averted gaze; and at weeks 0 and 8, within GSAD patients, for direct > averted gaze, week 0 > week 8. 3.3.1. Baseline analyses Group differences in baseline blood-oxygen-level-dependent (BOLD) response at baseline (see Table 3 and Fig. 1) were present in regions associated with emotion and place perception (parahippocampal cortex), self-referential processing (inferior parietal lobule, supramarginal gyrus, and posterior cingulate), and high level visual processing (middle occipital cortex) (Russ et al., 2003, Sugiura et al., 2005, Platek et al., 2006 and Uddin et al., 2006). The 2 × 2 ANOVA for group vs. gaze direction was consistent with a differential response to gaze direction (P < 0.01) for ROIs including inferior parietal lobule and posterior cingulate. Table 3. Group differences at baseline: areas of significant activation for group (GSAD > HC) by stimuli (direct > averted gaze) at week 0. Region Voxels x y z T R parahippocampal gyrus 21 22 − 40 2 2.97 R inferior parietal lobule 11 40 − 30 28 2.95 R inferior parietal lobule, supramarginal gyrus 160 52 − 58 44 3.22 R posterior cingulate gyrus 32 28 − 30 38 3.44 R middle occipital gyrus 13 36 − 72 − 2 3.15 All activations are effects observed in whole-brain analyses and are significant at P < 0.01 Table options Group differences at baseline. Legend: Participants with generalized social ... Fig. 1. Group differences at baseline. Legend: Participants with generalized social anxiety disorder had significantly greater blood-oxygen-level-dependent responses than healthy comparison participants for direct vs. averted gaze in posterior cingulate cortex (PCC) and inferior parietal lobule (LPi). Numbers below each image refer to z-coordinates. Figure options Secondary within-group analyses (direct > averted) for the HC group demonstrated BOLD responses to eye contact (P < 0.01) bilaterally in superior temporal sulci, the region most associated with response to gaze direction ( Hooker et al., 2003, Pelphrey et al., 2004 and Materna et al., 2008) (L temporal cortex, 400 voxels, x = − 38, y = 0, z = − 12, t = 4.44; and right temporal cortex, 578 voxels, x = 36, y = 6, z = − 16, t = 4.09). These areas were not significantly activated within the GSAD group, which instead demonstrated significant BOLD responses in left globus pallidus, 23 voxels, x = − 24, y = − 16, z = 0, t = 4.02; L insula, 38 voxels, x = − 36, y = − 18, z = 14, t = 4.43; bilateral cingulate gyrus, 58 voxels, x = − 2, y = − 10, z = 28, t = 3.17 and 21 voxels, x = 8, y = − 12, z = 40, t = 3.26; and right inferior parietal lobule, x = 54, y = − 54, z = 48, t = 3.63. Secondary within-group contrasts of fixation cross vs. direct and averted gaze stimuli conditions were used to evaluate response polarity in selected ROIs, identified with MarsBaR (Brett et al., 2002). These included regions previously shown to be activated by social threat in SAD (Stein et al., 2002) (amygdala and insula, defined anatomically) and regions activated by direct vs. averted gaze at baseline in this study (inferior parietal lobule and posterior cingulate cortex, defined functionally). BOLD signal in amygdala, insula, and inferior parietal lobule was significantly greater for both direct and averted gaze stimuli (relative to fixation cross) in both SAD and HCs, but for posterior cingulate cortex there were no significant differences. 3.3.2. Pre- vs. post-treatment Within the GSAD group, regions showing a stimulus gaze direction by time interaction (week 0 > week 8, direct > averted, see Table 4 and Fig. 2) included regions associated with interoception and emotion (insula), high level visual processing (middle temporal gyrus, occipital cortex) and self-referential processing (posterior cingulate cortex and precuneus)(Vogt and Laureys, 2005 and Paulus and Stein, 2006). The 2 × 2 ANOVA for stimulus gaze direction vs. time (pre-treatment and post-treatment) is consistent with a post-treatment reduction in the effect of direct eye gaze relative to averted gaze (P < 0.01) for ROIs including occipital cortex and middle temporal gyrus. Table 4. Pre- vs. post-treatment: areas of significant activation for treatment (Wk 0 > Wk 8) by stimuli (direct > averted gaze), within GSAD group. Region Voxels x y z T L insula 48 − 34 − 12 14 3.61 R middle temporal gyrus 18 40 − 52 − 2 3.46 R precentral gyrus 29 50 − 4 18 3.54 R posterior cingulate gyrus, precuneus 88 6 − 40 48 4.28 L superior occipital gyrus 29 − 26 − 72 28 3.90 All activations are effects observed in whole-brain analyses and are significant at P < 0.01. Table options Among participants with generalized social anxiety disorder, magnitude of ... Fig. 2. Among participants with generalized social anxiety disorder, magnitude of symptomatic improvement during paroxetine treatment was associated with decreases in blood-oxygen-level-dependent responses for direct vs. averted gaze. GFm and GFi indicate middle and inferior frontal gyri, ACC and PCC anterior and posterior cingulate cortices, PCL paracentral lobule. Numbers below each image refer to z-coordinates. Figure options 3.3.3. Correlates of symptomatic improvement Within the GSAD group, regions in which changes in activations (direct > averted gaze) covaried with reductions in social anxiety during treatment (see Table 5 and Fig. 1) included areas with functions that include emotion regulation and self-referential processing (subgenual anterior cingulate, ventromedial prefrontal cortex, inferior frontal gyrus, posterior cingulate cortex, precuneus, and inferior parietal lobule) (Buccino et al., 2001, Castelli et al., 2002, Vogt et al., 2006 and Morita et al., 2008). Table 5. Correlates of symptomatic improvement: areas of change in activation significantly associated with change in LSAS during treatment, within GSAD Group. Region Voxels x y z T L inferior frontal gyrus 261 − 20 20 − 2 4.69 L subgenual anterior cingulate 100 − 14 54 6 4.62 R middle frontal gyrus 77 24 36 − 14 4.35 L caudate 53 − 2 2 0 3.26 R anterior cingulate 52 20 24 − 6 3.98 R dorsal cingulate gyrus 49 4 − 4 34 2.97 L lentiform nucleus 47 − 22 − 12 − 8 4.73 R lentiform nucleus 20 16 − 2 2 3.06 R thalamus 40 28 − 22 4 4.14 R thalamus 29 14 − 8 8 3.23 R&L posterior cingulate 493 − 6 − 38 12 5.87 R paracentral lobule 43 4 − 38 54 3.91 R&L precuneus 89 4 − 54 50 3.48 L inferior parietal lobule 97 − 30 − 52 62 3.89 All activations are effects observed in whole-brain analyses and are significant at P < 0.01.