Impact of Cognitive-Behavioral Therapy for Social Anxiety Disorder on the Neural Dynamics of Cognitive Reappraisal of Negative Self-Beliefs

Abstract

Importance

Cognitive-Behavioral Therapy for social anxiety disorder is thought to enhance cognitive reappraisal in patients with social anxiety disorder. Such improvements should be evident in cognitive reappraisal-related prefrontal cortex responses.

Objective

To determine whether Cognitive-Behavioral Therapy for social anxiety disorder modifies cognitive reappraisal-related prefrontal cortex neural signal magnitude and timing when implementing cognitive reappraisal with negative self-beliefs.

Design

Randomized controlled trial of Cognitive-Behavioral Therapy for social anxiety disorder versus waitlist control group.

Setting

Psychology department.

Participants

Seventy-five patients with generalized social anxiety disorder randomly assigned to Cognitive-Behavioral Therapy or waitlist.

Intervention

Sixteen sessions of individual-Cognitive-Behavioral Therapy for social anxiety disorder during a study that enrolled patients from 2007 to 2010.

Main Outcome Measures

Negative emotion ratings and functional magnetic resonance blood oxygen-level dependent signal when reacting to and cognitively reappraising negative self-beliefs embedded in autobiographical social anxiety situations.

Results

During reactivity trials, compared to waitlist, Cognitive-Behavioral Therapy produced (a) greater reduction in negative emotion ratings and (b) greater blood oxygen-level dependent signal magnitude in medial prefrontal cortex. During cognitive reappraisal trials, compared to waitlist, Cognitive-Behavioral Therapy produced (c) greater reduction in negative emotion ratings, (d) greater blood oxygen-level dependent signal magnitude in dorsolateral and dorsomedial prefrontal cortex, (e) earlier temporal onset of dorsomedial prefrontal cortex activity, and (f) greater dorsomedial prefrontal cortex-amygdala inverse functional connectivity.

Conclusions and Relevance

Modulation of cognitive reappraisal-related brain responses, timing and functional connectivity may be important brain changes that contribute to the effectiveness of Cognitive-Behavioral Therapy for social anxiety.

Trial Registration

ClinicalTrials.gov identifier: NCT00380731; http://www.clinicaltrials.gov/ct2/show/NCT00380731?term=social+anxiety+cognitive+behavioral+therapy+Stanford&rank=1

INTRODUCTION

Social anxiety disorder (SAD) is characterized by high prevalence (12.1%)¹, early onset², and low rates of spontaneous remission³. SAD is linked to significant impairment in social, educational, and occupational functioning^{4, 5}, and represents a substantial problem for society^{6, 7}. Individuals with SAD experience distressing levels of social fear, humiliation and embarrassment⁸, and distorted beliefs about the social self⁹.

COGNITIVE REAPPRAISAL IN SAD

One factor thought to lead to heightened anxiety responses in SAD is a failure to successfully employ cognitive reappraisal (henceforth “reappraisal”). Reappraisal is an emotion regulation strategy that entails reframing the meaning of an emotional stimulus in order to modify its impact. In healthy controls^{10, 11}, neuroimaging studies of reappraisal show increased recruitment in brain networks implicated in cognitive control (dorsolateral (DL), dorsomedial (DM), and ventrolateral (VL) prefrontal cortex (PFC)) and attention (precuneus, superior parietal lobule, right DLPFC, dorsal anterior cingulate cortex)¹², as well as decreases in emotion processing brain regions, specifically amygdala¹³.

Neuroimaging studies have found that, compared to healthy controls, patients with SAD show lesser BOLD signal responses in cognitive control (DLPFC, DMPFC) and attention (medial precuneus, posterior cingulate, bilateral dorsal parietal cortex) brain networks during reappraisal of social threat (harsh facial expressions)¹⁴. Furthermore, when reappraising self-generated negative self-beliefs (NSBs), compared to healthy controls, patients with SAD demonstrate temporally delayed PFC activation (DMPFC, bilateral DLPFC, bilateral VLPFC) and less PFC-amygdala inverse functional connectivity¹⁵. This inability to implement reappraisal in a timely manner and less successful PFC down-regulation of amygdala responses may be related to heightened levels of anxiety that inhibit recruitment of PFC and/or to deficient reappraisal implementation in the context of anxiety inducing stimuli. What is not known is whether clinical interventions impact the magnitude, timing, and functional connectivity of reappraisal-related PFC responses.

COGNITIVE-BEHAVIORAL THERAPY FOR SAD

Individual Cognitive-Behavioral Therapy (I-CBT) for SAD, as developed by Hope and Heimberg¹⁵, has been shown to be an effective treatment for SAD^{16, 17}. One key component of CBT for SAD is cognitive restructuring, which involves reappraisal in the context of exposure to feared social situations and negative self-beliefs (NSBs)^18–20. Behaviorally, increases in reappraisal self-efficacy during I-CBT have been shown to mediate the effect of I-CBT on improvement in severity of social anxiety symptoms and to predict clinical status at one-year post-treatment¹⁷. Neurally, the first neuroimaging study of group CBT and citalopram treatment for SAD showed that regional cerebral blood flow decreases in amygdala during public speaking was associated with clinical improvement 1-year later²¹. A recent study of group CBT demonstrated that pre-treatment increases in fMRI BOLD signal in superior and inferior portions of the occipitotemporal cortex in response to angry vs. neutral face stimuli predicted improvement in social anxiety symptoms²². The current study builds on these prior studies by investigating whether I-CBT for SAD impacts BOLD signal magnitude, timing, and functional connectivity in PFC regions implicated in reappraisal of negative self-beliefs embedded in autobiographical social anxiety situations.

THE PRESENT STUDY

Our goal was to investigate the impact of I-CBT for SAD vs. Waitlist (WL) on BOLD signal magnitude and temporal dynamics in a priori regions of interest (ROIs) in the DMPFC, DLPFC, and VLPFC (implicated in reappraising NSBs¹⁵) and in the amygdala (implicated in emotion generation¹³). Additionally, we used a context-dependent functional connectivity analysis to investigate whether CBT influenced PFC-amygdala connectivity. We expected that, compared to WL, I-CBT would result in lesser negative emotion and amygdala responses to NSBs, greater and quicker responses in reappraisal-related PFC regions (DMPFC, DLPFC, VLPFC), and greater inverse functional connectivity between reappraisal-related PFC and emotion-related amygdala.

METHOD

PARTICIPANTS

Participants met DSM-IV²³ criteria for a principal diagnosis of generalized SAD based on the Anxiety Disorders Interview Schedule for the DSM-IV-Lifetime (ADIS-IV-L) version²⁴. Of 436 individuals assessed for eligibility, 110 were administered the ADIS-IV-L to determine eligibility (Figure 1). After 35 patients were excluded, the 75 patients who met DSM-IV criteria for a principal diagnosis of generalized SAD were randomly assigned to either immediate I-CBT (n=38) or a WL control group (n=37) who were subsequently offered I-CBT. After dropout from I-CBT (n=6) and WL (n=5), and incomplete neuroimaging data at post-CBT (n=1) and post-WL (n=3), the final sample for this fMRI study consisted of 31 CBT completers and 29 WL completers. Baseline data from 27 of the 60 patients with SAD examined in this study were reported in a previous paper on differential SAD vs. healthy control brain responses to negative self-beliefs¹⁵.

Figure 1.

Consolidated Standards of Reporting Trials Diagram for a Randomized Controlled Trial of Individual Cognitive-Behavioral Therapy (I-CBT) vs. Waitlist (WL) Groups.

EXCLUSION CRITERIA

Patients had to pass a MRI safety screen, be right-handed as assessed by the Edinburgh Handedness Inventory²⁵. They were excluded for current pharmacotherapy or psychotherapy, past CBT, and history of neurological disorders. Patients were also excluded if generalized SAD was not determined to be the principal clinical diagnosis. Patients were not excluded if they meet diagnostic criteria for generalized anxiety disorder, agoraphobia without panic attacks, specific phobia, major depression or dysthymia.

PROCEDURE

Patients were recruited through referrals and web listings. They had to pass a telephone screen, the ADIS-IV-L interview conducted in person, and all baseline assessments before being randomly assigned to I-CBT or WL using Efron’s biased coin randomization procedure²⁶, which promotes equal sample sizes throughout the clinical trial. All participants completed the same measures at baseline and again 19 weeks later after I-CBT or WL. This study was approved by the Institutional Review Board at Stanford University, and participants provided written informed consent.

CLINICAL ASSESSMENT

To measure social anxiety symptoms, we administered the Liebowitz Social Anxiety Scale-Self-Report (LSAS-SR^{27, 28}), which has good reliability and construct validity²⁹. Its internal consistency (Cronbach’s alpha = .91) was excellent in this study. To measure SAD-related disability in work, social, and family domains, we administered the Sheehan Disability Scale (SDS³⁰) which has good internal consistency and validty³¹ and had good internal consistency (alpha = .67) in this study.

INDIVIDUAL-COGNITIVE-BEHAVIORAL THERAPY FOR SAD

I-CBT was delivered by four Ph.D.-level clinical psychologists trained by Dr. Heimberg using Managing Social Anxiety: A Cognitive-Behavioral Therapy Approach, a manualized treatment protocol which included a therapist guide³² and a client workbook³³, and consisted of 16 individual one-hour sessions (except for the first in-session exposure session which lasted 1.5 hours) administered over 4 months. I-CBT covered: (1) psychoeducation and orientation to CBT; (2) cognitive restructuring skills; (3) graduated exposure to feared social situations, within session and as homework; (4) examination and modification of core beliefs; and (5) relapse prevention and termination^{16, 32, 33}.

All 16 sessions for each client were digitally recorded and rated using the Cognitive-Behavioral Therapy for Social Anxiety Disorder: Therapist Adherence Scale³² by research team members who had clinical training and extensive familiarity with the CBT treatment adherence. They rated each session according to various criteria, using a 5-point Likert-type scale ranging from 1 (ineffective) to 5 (extremely effective). Average adherence ratings had to be greater than 4 to be considered “in protocol.” All four study therapists achieved this standard for each therapy case (overall Mean = 4.61, SD = 0.24).

EXPERIMENTAL TASK

Patients identified four personally-salient autobiographical social situations characterized by social anxiety, humiliation, and embarrassment, and composed (a) a single paragraph to describe each situation, and (b) situation-specific NSBs that were used to probe reactivity and reappraisal.

Before scanning, patients were trained using methods developed by Gross and Ochsner^{34, 35} to either “REACT” by considering how the NSB reflected something true about themselves, or “REFRAME” by using reappraisal to “actively reframe the belief by thinking in a way that re-interprets the content of the belief and thereby make the belief less negative and toxic for you.” For example, if the NSB is “NO ONE LIKES ME,” reframing may be telling yourself “That is not always true,” “Some people like me,” or “This is only a thought, not a fact.”

During scanning, patients read their autobiographical social situations with NSBs embedded in the unfolding story. After each NSB, patients rated “How negative do you feel?” (1=not at all to 5=very much).

The task involved five situations. The first was an experimenter-composed neutral situation about cleaning a car that was used to obtain baseline emotion ratings and brain responses. The second through fifth situations were participant-generated autobiographical social anxiety situations with idiographic NSBs.

Three situations were presented in a first run lasting 9 minutes, 21 seconds, followed by two situations in a second run of 6 minutes, 24 seconds. The sequence of 5 situations was fixed (neutral, react NSB, reappraise NSB, react NSB, and reappraise NSB) for several reasons. First, we wanted to control for order effects at the pre- and post-treatment assessments. Second, we wanted to obtain an unbiased estimate of brain responses to neutral statements (prior to emotional reactivity). Third, we wanted to assess react NSB prior to reappraise in order to minimize the effect of reappraisal on reactivity. Negative emotion ratings during the first and second react NSBs blocks did not differ (p>.45).

Each situation consisted of an instruction to react or reframe (6 seconds), 16 sentences describing the situation (3 seconds each) in white font against a black background, 10 NSBs (9 seconds each) embedded in the unfolding story in uppercase letters that flashed 9 times to maximize attentional engagement with the text (850 ms on + 150 ms off), and a negative emotion rating (3 seconds) after each NSB (Figure 2). NSBs appeared in white font for react trials and green font for reframe trials as a visual reminder to react or reappraisal.

Figure 2.

Experimental Design. Components and structure of one autobiographical social situation trial. After each negative self-belief (NSB), participants provide a negative emotion rating from 1=not negative to 5=extremely negative.

The experimental task was administered during a 1.5 hours scanning session at baseline and again post-CBT/WL. After scanning, patients rated: (1) how successful they were at implementing reappraisal during reframe trials on a scale of 0% to 100% successful and (2) how often they used reappraisal during the react trials on a scale from 0 (not at all) to 50 (moderately) to 100 (always).

IMAGE ACQUISITION

We used a GE 3-T Signa magnet with a T2*-weighted gradient echo spiral-in/out pulse sequence³⁶ to acquire 630 functional volumes from 22 axial slices (repetition time=1500 milliseconds, echo time=30 milliseconds, flip angle=60°, field of view=22 cm, matrix=64×64, resolution=3.438 mm² × 4.5 mm). High-resolution anatomical scans were acquired using fast spin-echo spoiled-grass (.8594² × 1.5 mm; field of view=22 cm, frequency encoding=256).

fMRI DATA PROCESSING

We used AFNI software³⁷ to remove outliers, register, motion correct, spatially smooth (4 mm³ isotropic kernel), high-pass filter (.011 Hz), linear detrend, and convert into percent signal change each functional run. No volumes demonstrated motion in the x, y, or z directions in excess of ±0.8 mm. There was no evidence of stimulus-correlated motion (all ps>.30).

fMRI STATISTICAL ANALYSIS

We used 3dDeconvolve to conduct a multiple-regression that included removal of mean, linear, and quadratic trends, and motion-related variance in the BOLD signal. Regressors for the neutral statements, react, and reappraise were convolved with the gamma variate model³⁸ of the hemodynamic response function.

We converted brain maps into Talairach atlas space³⁹ and second-level group statistical parametric maps were produced according to a random-effects model. We investigated 10 a priori PFC ROIs in the DMPFC, dorsal anterior cingulate cortex, and bilateral medial anterior PFC, DLPFC, and VLPFC that were previously identified as more actively and rapidly recruited when reappraising NSBs in non-anxious healthy adults compared to patients with SAD¹⁵. Because of its importance in anxiety disorders and emotional reactivity, we also investigated a priori Talairach atlas defined amygdala ROIs.

We created spherical masks (radius = 7mm, volume = 1,437mm³) centered on the peak xyz Talairach coordinates within each reappraisal-related ROI and amygdala masks, extracted mean BOLD responses, and conducted a MANOVA with the Sidak correction for multiple comparisons to examine between-group differences in pre-to-post BOLD signal changes for react NSB vs. neutral and reappraise NSB vs. neutral contrasts. We removed one participant from CBT and one from WL with BOLD signal more than 3 SDs from the mean in the left amygdala. We also provide results for a supplemental whole-brain analysis of differential CBT vs. WL change for react NSB vs. neutral and reappraise NSBs vs. neutral.

We investigated neural temporal dynamics in only the a priori ROIs that showed differential pre-to-post-CBT/WL change for react NSBs versus neutral (1 ROI) and reappraise NSBs versus neutral (2 ROIs). To do this, we conducted a 2 Group (CBT, WL) × 6 time points (x 1.5 seconds = 9 seconds) repeated-measures ANOVA (Huynh-Feldt corrected for autocorrelation in time series) on BOLD signal for each trial (with a 6 seconds shift to account for the temporal delay in the hemodynamic response). A follow-up paired t-test tested for differential early (0–3 seconds) vs. late (6–9 seconds) BOLD responses.

To investigate PFC-amygdala circuitry, we implemented a context-dependent functional connectivity analysis for each group at pre and post CBT/WL for only one contrast (reappraise vs. react NSBs). To reduce false positive detection, the connectivity analysis was seeded to the single reappraisal-related a priori ROI (DMPFC) that showed both BOLD signal magnitude and timing results. We then computed pre-to-post change scores and conducted a between-group t-test to identify the interaction of group by time on PFC-amygdala connectivity. We focused the connectivity analysis within the a priori Talairach-defined amygdala search region using a t-value associated with p<.025 and cluster volume ≥160 mm³.

RESULTS

PRELIMINARY ANALYSES

Patients in I-CBT and WL groups did not differ significantly in gender, age, education, ethnicity, yearly income, marital status, current or past Axis I comorbidity, past psychotherapy or pharmacotherapy, age at symptom onset, or years since symptoms onset (Supplemental Table 1). Ethnicity was self-reported by research participants in accordance with NIH requirements.

As reported elsewhere¹⁷, an intent-to-treat analysis showed that, compared to WL, I-CBT resulted in significantly greater reduction of social anxiety symptoms, ΔI-CBT=−29.7 vs. ΔWL=−8.2; F(2,73)=20.0, p<.001, η_p²=.21, and disability, ΔI-CBT=−9.3 vs. ΔWL=−1.2; F(2,73)=5.6, p<.05, η_p²=.07. Using the Jacobson and Truax⁴⁰ method, we determined that 19 (61.3%) of 31 patients who completed I-CBT and the fMRI assessments demonstrated clinically significant reduction in social anxiety symptoms.

As a manipulation check, at post-MR scanning, we examined the self-reported success in implementing reappraisal of NSBs. A 2 Group (I-CBT, WL) × 2 Time (pre, post) repeated-measures ANOVA yielded a significant group by time interaction (F(2,55)=18.14, p<.001, η _p² =.25), no effect of group (F(1,56)=1.81, p>.18), but a significant effect of time (F(1,56)= 27.63, p<.001, η _p² =.33). Follow-up paired t-tests showed reappraisal success increased from pre-to-post-I-CBT (Mean±SD; Pre: 34.68±21.09 vs. Post: 69.52±17.62; t(30)=6.55, p<.001, η _p²=.59) and did not change from pre-to-post-WL (Pre: 44.81±19.97 vs. Post: 48.46±23.48; t(25)=0.75, p>.46). There was no significant difference between groups in reappraisal success at baseline (t(55)=1.85, p>.07).

We also examined at post-MR scanning self-reported use of reappraisal during react NSBs trials when participants were not instructed to implement reappraisal (i.e., uncued or spontaneous use of reappraisal). A 2 Group (I-CBT, WL) × 2 Time (pre, post) repeated-measures ANOVA yielded a significant group by time interaction (F(2,52)=4.34, p<.05, η _p²=.08), no effect of group (F(1,52)=0.35, p>.56), but a significant main effect of time (F(1,52)= 4.34, p<.05, η _p²=.08). Follow-up t-tests showed that spontaneous reappraisal during react NSBs increased from pre-to-post-I-CBT (Pre: 23.67±27.57 vs. Post: 37.75±30.13; t(29)=2.91, p<.01) but did not change in the WL group (Pre: 26.88±25.27 vs. Post: 26.88±21.46; t(23)=0, p>.99). There was no significant difference between groups in reappraisal during react trials at baseline (t(53)=0.57, p>.57).

RESPONSES TO NEGATIVE SELF-BELIEFS

Behavioral Responses

A 2 Group (I-CBT, WL) × 2 Time (baseline, post) repeated-measures ANOVA on negative emotion ratings resulted in a group by time interaction when reacting to NSB (F(2,58)=8.63, p=.005, η _p²=.13), a main effect of time (F(1,58)=16.24, p=.001, η _p²=.23), and no effect of group (F(1,58)=1.37, p>.24) (Figure 3). Follow-up t-tests showed CBT-related decreases in negative emotion (t(30)=5.18, p<.001, η _p²=.47) and no change in the WL group (t(27)=0.74, p>.46). There was no significant difference between groups at baseline (t(59)=0.76, p>.45).

Figure 3.

Changes in Negative Emotion Intensity Ratings for React Negative Self-Beliefs and Cognitive Reappraisal of Negative Self-Beliefs in Patients with Social Anxiety Disorder (SAD) Before and After Individual Cognitive-Behavioral Therapy (I-CBT) vs. Waitlist (WL) Groups. Negative emotion ratings after the offset of each stimulus were provided by participants in response to “How negative do you feel?” (1=not at all, 2=slightly, 3=moderately, and 4=very much, 5=extreme). * p<.001; error bars = standard error of the mean.

Brain Response Magnitude

When we examined a priori amygdala ROI responses for the contrast of react NSBs vs. neutral statements with a 2 Group (CBT, WL) × 2 Time (Baseline, Post) repeated-measures ANOVA, there were no interactions or main effects in the left (all ps>.11) or right amygdala (ps >.06).

For the 10 reappraisal-related a priori PFC ROIs, a MANOVA with the Sidak correction for multiple comparisons on pre-to-post BOLD signal change for react NSBs vs. neutral statements yielded only between-group difference in the MPFC region (F(2,58)=4.29, p<.05, η _p²=.07) consisting of CBT increases (t(30)=2.20, p<.05, η _p²=.14) but no change in WL (t(27)=1.26, p>.21).

Brain Response Temporal Dynamics

The examination of BOLD signal temporal dynamics in the MPFC across the six 1.5 second time points for react NSBs versus neutral yielded no interaction (p>.80) or main effects of group (p>.39) or time (p>.35).

COGNITIVE REAPPRAISAL OF NEGATIVE SELF-BELIEFS

Behavioral Responses

A 2 Group (I-CBT, WL) × 2 Time (baseline, post) repeated-measures ANOVA on negative emotion ratings during reappraise NSBs resulted in a group by time interaction (F(2,58)=21.59, p<.001, η _p²=.28), no effect of group (F(1,58)=1.66, p>.20), but a significant main effect of time (F(1,58)=41.29, p<.001, η _p²=.42) (Figure 3). Follow-up paired t-tests showed CBT-related decreases in negative emotion (16.1%; t(30)=8.93, p<.001, η _p²=.73) and no change in the WL group (1.7%; t(27)=1.11, p>.27). There was no difference between groups at baseline (t(59)=1.59, p>.12).

Brain Response Magnitude

For the a priori amygdala ROIs, 2 Group (CBT, WL) × 2 Time (Baseline, Post) repeated-measures ANOVA on BOLD responses for reappraise NSB vs. neutral statements yielded no main or interaction effects in the left (all ps>.15) and right amygdala (all ps>.06).

For the 10 reappraisal-related ROIs, a MANOVA with the Sidak correction for multiple comparisons on pre-to-post change for reappraise NSBs vs. neutral statements yielded overall significance between-groups (F(10,47)=3.22, p=.003, η _p²=.41). For the corrected model, there was evidence of between-group difference in only two regions: DMPFC (Δ=.10, 95% CI [.01–.19]; F(2,58)=4.70, p=.035, η _p²=.08), consisting of CBT increases (Δ=.11; t(30)=3.36, p<.002, η _p²=.27), but no change for WL (Δ=.01; t(27)=0.23, p>.82), and left DLPFC (Δ=.08, 95% CI [.01–.15]; F(2,58)=5.20, p<.026, η_p²=.09), consisting of CBT increases (Δ=.06; t(30)=2.37, p<.05, η_p²=.16) and no change for WL (Δ=−.02; t(27)=0.86, p>.39) (Figure 4). The supplemental whole-brain analysis confirmed the ROI-based observation of increased BOLD responses in DMPFC and left DLPFC (Supplemental Table 2).

Figure 4.

Changes in Brain Responses in Dorsomedial Prefrontal Cortex (DMPFC) and Left Dorsolateral Prefrontal Cortex (DLPFC) A Priori Cognitive Reappraisal-related Prefrontal Cortical Brain Regions of Interest in Patients with Social Anxiety Disorder (SAD) Before and After Individual Cognitive-Behavioral Therapy (I-CBT) vs. Waitlist (WL) Groups. The red dot represents the spherical region of interest mask used in the analysis. BOLD signal represents pre-to-post change scores in BOLD signal responses.

Brain Response Temporal Dynamics

For the DMPFC, there was a significant interaction of group by time (F(8,52)=2.42, p<.05, η_p²=.04), and no main effects of group (p>.34) or time (p>.43) (Figure 5). Follow-up pre-to-post within-group paired t-tests showed that the interaction was driven by linear changes (t=2.79, p=.007, η _p²=.12) characterized by significantly increased early (0–3s) vs. late (6–9s) responses in the I-CBT group (early: .23% vs. late: .05%; t(30)=2.22, p<.05) and decreased early vs. late responses in the WL group (early: −.15% vs. late: .01%; t(27)=2.05, p<.05). For the left DLPFC, the same analysis yielded no main or interaction effects (ps>.30).

Figure 5.

Blood Oxygen Level Dependent (BOLD) Signal Time Series in Dorsomedial Prefrontal Cortex (DMPFC) and Left Dorsolateral Prefrontal Cortex (DLPFC) During Reappraise Negative Self-Beliefs (NSBs) vs. Read Neutral Statements.

Context-Dependent Functional Connectivity

The DMPFC-seeded functional connectivity analysis for reappraise vs. react negative self-beliefs showed that, compared to WL, CBT produced greater inverse connectivity between the DMPFC and left amygdala and the right hippocampus and positive connectivity in the medial PFC and two dorsolateral PFC regions (Table 1, Figure 6).

Table 1.

Differential Between-Group Pre-to-Post Change in Dorsomedial Prefrontal Cortex-Seeded Context-Dependent Functional Connectivity of Cognitive Reappraisal vs. React Negative Self-Beliefs

Brain Regions	Pre-to-Post Change	xyz	Vol (mm3)	t-value
Positive FC
Medial PFC	CBT>WL	0 25 53	266	3.74
R DLPFC	CBT>WL	38 45 29	583	3.71
R DLPFC	CBT>WL	41 56 15	848	3.79
Inverse FC
R Posterior Hippocampus	CBT<WL	21 −44 −2	583	3.50
L Amygdala a	CBT<WL	−20 −9 −18	160	2.95

Note. xyz = Talairach coordinates, t-value ≥2.91, voxel p<.005, minimum cluster volume threshold ≥266 mm³ (5 voxels × 3.44 mm² × 4.5 mm), cluster-wise p<.01. BA=Brodmann Area, BOLD=blood oxygen dependent, FC= functional connectivity, L=left, PFC=prefrontal cortex, DLPFC=dorsolateral prefrontal cortex, R=right, Vol=volume.

^aFor this cluster within the a priori Talairach-defined amygdala search region, functional connectivity was observed at a more lenient threshold consisting of t-value≥2.30, voxel p<.025 and minimum cluster volume threshold ≥160 mm³.

Figure 6.

Differential Between-Group Pre-to-Post Change in Dorsomedial Prefrontal Cortex-Seeded Context-Dependent Functional Connectivity of Cognitive Reappraisal vs. React Negative Self-Beliefs

1=MPFC, 2=right DLPFC, 3=right MFG, 4=DMPFC seed, 5=left hippocampus, 6=left amygdala. For the whole-brain, thresholding consisted of per voxel p<.005 and cluster volume threshold ≥263 mm3. Within the amygdala search region, thresholding consisted of per voxel p<.025 and cluster volume threshold ≥160 mm3.

DISCUSSION

This study found that, compared to WL, I-CBT for SAD resulted in reduction of negative emotions when reacting and reappraising NSBs, no change in amygdala responses, and changes in BOLD signal magnitude, temporal dynamics, and functional connectivity during cognitive reappraisal of NSBs in patients with SAD.

RESPONSES TO NEGATIVE SELF-BELIEFS

When reacting to NSBs, compared to WL, I-CBT resulted in a significant reduction of self-reported negative emotion. The absence of a change in negative emotion from pre-to-post WL suggests that there was no habituation to NSBs from time 1 to time 2 assessments. Reduction in emotional reactivity to NSBs post-CBT may be associated with extensive practice in cognitive restructuring during exposures during CBT, which likely leads to greater skill in implementing reappraisal strategies. The decreases in negative emotion from pre-to-post-CBT may reflect increased spontaneous (uncued) reappraisal during react trials, an interpretation that is consistent with CBT participants’ greater reports of reappraisal during react trials.

Neurally, there were no interactions or main effects of group and time in the left or right amygdalae, suggesting that amygdala reactivity to NSBs remained consistent across time and across groups. While some studies have observed CBT-related reductions in amygdala responses using PET during public speaking²¹, the ability to detect changes in the amygdala using fMRI depends very much on task design, timing, and speed of habituation. Our baseline study showed rapid habituation of amygdala responses during both react and reappraise NSBs in both patients with SAD and healthy controls ¹⁵. There was, however, a single interaction of group by time in the medial PFC. This region is involved in reappraisal in general^{41, 42} and is specifically implicated in reappraisal of negative emotion¹⁵. Like the negative emotion ratings, this may reflect spontaneous implementation of reappraisal even when uninstructed.

COGNITIVE REAPPRAISAL OF NEGATIVE SELF-BELIEFS

Behaviorally, during reappraisal of NSBs, compared to WL, I-CBT resulted in greater reduction of self-reported negative emotion experience. The effect size (η _p²) of this reduction was larger for reappraisal (0.73) than for react NSB (0.47), which may represent the differential impact of I-CBT on cued reappraisal versus spontaneous reappraisal. These behavioral results are consistent with CBT participants’ reports of greater success at using reappraisal. The absence of change in reappraisal-related reduction of negative emotion from pre-to-post-WL highlights the stability of reappraisal deficits in patients with SAD when untreated.

Neurally, group by time interactions occurred in a priori DMPFC and left DLPFC ROIs, which were characterized by increases following I-CBT and no change following WL. These regions are implicated in the cognitive control of emotion and usually co-activate when down-regulating negative emotion⁴². A recent meta-analysis of emotion regulation processes has shown that, in contrast to fear extinction and placebo control, reappraisal uniquely involves left dorsolateral and DMPFC⁴¹.

Prior investigations of neural temporal dynamics when implementing reappraisal of NSBs¹⁵ have demonstrated differential timing in reappraisal-related PFC regions consisting of quicker recruitment in healthy controls and delayed recruitment in patients with SAD. In the present study, at post-WL, patients with SAD continued to show delayed recruitment of left dorsolateral and DMPFC. Post-CBT, however, there was a shift to the normative earlier recruitment of DMPFC, which may be related to enhanced ability to access and implement reappraisal strategies and/or due to reduced emotional reactivity to NSBs (which might interfere with implementing reappraisal effectively). Figure 5 shows a post-CBT pattern of greater earlier recruitment of DLPFC and later non-recruitment similar to DMPFC. However, the BOLD signal magnitude was too small to yield significance. This differential pattern raises the question of whether DLPFC and DMPFC serve different cognitive functions at different time points during reappraisal.

The present findings – as well of those of other studies – suggest that the DMPFC plays a key role in emotion regulation. Studies have demonstrated that greater DMPFC activity is related to greater reappraisal success in both healthy controls and patients with SAD^{14, 43}. In the present study, in addition to BOLD signal magnitude increases in DMPFC during reappraisal following I-CBT, there was evidence that CBT altered the link between DMPFC activity and amygdala response.

The DMPFC-seeded functional connectivity analysis showed a group by time DMPFC-left amygdala interaction driven by inverse DMPFC-amygdala connectivity at post-CBT only and not at baseline in either group or after WL. Interestingly, while there was no overall CBT-related BOLD signal magnitude change in amygdala responses, these results highlight that distributed rather than absolute changes in limbic-PFC patterns may be more reflective of underlying abnormalities in SAD and also in understanding one neurobiological mechanism of change during CBT. The DMPFC positive connectivity with three more PFC regions converges with prior evidence that DMPFC is important for effective top-down cognitive reappraisal of negative emotion in SAD^{14, 15, 42}. The inverse DMPFC-hippocampus connectivity may be related to lesser activation of memories associated with the autobiographical situation and NSBs.

CLINICAL IMPLICATIONS

Findings from this study highlight CBT-related enhancement of reappraisal, specifically, decreased negative emotion experience along with greater and quicker recruitment of reappraisal-related DMPFC neural responses which are related to lesser amygdala responses to NSBs. This reinforces the clinical insight that emotion regulation and clinical symptoms are modified by CBT.

Modifiable temporal dynamics of reappraisal suggests that it might be clinically valuable to have clients record how quickly they can volitionally implement reappraisal following emotional triggers in social situations. This could be experimentally controlled during therapy sessions and measured during in vivo exposures outside of therapy sessions. Bringing attention to the timing of reappraisal and what factors enhance or interfere with more rapid implementation of reappraisal strategies could itself be a specific clinical insight that can be incorporated into the cognitive restructuring and exposure components of CBT protocols for treating anxiety disorders. Specifically, research needs to determine whether different forms of attention training (e.g., that reduce self-focused attention) might impact the timing of reappraisal in SAD.

Equally intriguing is the finding indicating that CBT enhances not only cued reappraisal, but also spontaneous reappraisal. This may be due to the generalization of the skills learned during CBT and may reflect a shift from initially effortful to subsequently spontaneous or automatic implementation of reappraisal. This raises intriguing questions about the extent to which the association of cued and spontaneous reappraisal (and their neural timing) is related to (a) clinical symptoms in patients with SAD and (b) immediate and longer-term treatment outcome of CBT.

LIMITATIONS AND FUTURE DIRECTIONS

The current study is limited to inferences about reappraisal of participant-generated NSBs during autobiographical recall of personally meaningful events. Although this represents a key target of psychotherapy, it will be useful to investigate the impact of CBT on reappraisal of other-focused negative beliefs, and on reappraisal to enhance positive experiences (i.e., up-regulate positive emotions), which may also be important skill trained in CBT. Neurally, CBT for SAD yielded significant interactions in three of the 10 normative reappraisal-related a priori PFC ROIs. The functional connectivity analysis provided evidence for the co-activation in three more PFC regions implicated in cognitive reappraisal. Further research is necessary to identify which PFC regions contribute to longer-term treatment responses in SAD.

Our focus on one type of therapy for one type of disorder was dictated both by theory and by the available literature. Future research could investigate how different forms of CBT (e.g., individual vs. group) and other clinical interventions for SAD influence the temporal dynamics of brain networks involved in different emotion regulation strategies. It will be important to examine how these therapeutic effects generalize to other disorders.