Neural Markers of Treatment Mechanisms and Prediction of Treatment Outcomes in Social Anxiety

The primary aim of this study is to discover neural mechanisms (via EEG and MRI) associated with variation in response to CBT and/or combined CBT and SSRI interventions. The goal is to develop a rigorous model that predicts individual differences in response to treatments using baseline neural markers.

The investigators will recruit 190 adults with social anxiety disorder (SAD) and 50 adult controls. All adults with SAD will participate in group CBT for SAD. Non-responders will continue on with individual CBT plus the addition of sertraline for another 12 weeks. 50 controls will receive baseline EEG and MRI but will not participate in any clinical interventions. The investigators will also perform neuroimaging (task fMRI, rsfMRI, DWI, structural MRI) and collect EEG before treatment, to compare patient and control groups, and to obtain neuromarkers that predict treatment response.

MRI/EEG Tasks

Activation of Negative Valence System. The RDoC recommends "viewing aversive pictures" as a means to activate the Negative Valence System. The investigators will adapt the paradigm that accounted for 40% of CBT outcome variance in which participants viewed blocks of angry or neutral faces. The investigators chose to use a block (rather than an event-related) design because block designs have stronger measurement power for characterizing individuals. Experimental design. Stimuli will be color faces from the NimStim set with angry or neutral expressions. There will be six 15-second blocks per condition, with six faces per block; each face is presented for 1250 ms, followed by 1250 ms of fixation. The task starts and ends with a fixation block, and each pair of face blocks is separated by one fixation block. Two fixed forms are used to counterbalance condition orders. Participants perform a 1-back task by indicating, via button press, the repetition of a face.

Activation of Positive Valence System. As reviewed in Significance, there is evidence that the reward system is atypical in SAD. To investigate this further, the investigators will adapt a widely used reward processing task that was developed by Delgado and that is recommended by the RDoC for probing the initial response to reward. Experimental design. Participants play a guessing game to try to win money. Each trial begins with presentation of a "mystery card" displaying a "?" (duration: 1.5s). Participants are told that card numbers range from 1 to 9, and they indicate whether they think the mystery card number on a given trial is more or less than 5 by pressing a button. Feedback (1s) is given immediately after and consists of either (a) a reward (a green up arrow and "$1"), (b) a loss (red down arrow with "-$0.50"), or (c) a neutral outcome (the number 5 and a grey double-headed arrow). A 1 s intertrial interval (ITI) separates the trials. Participants complete two runs, each of which includes four blocks of eight trials: two blocks yield mostly rewards (6/8 trials), and two blocks yield mostly losses (6/8 trials). There are also four 15 s fixations, to facilitate deconvolution of fMRI responses.

Activation of Cognitive Control System. Based on encouraging prior findings, the investigators have included a cognitive control task in which pretreatment activation of dorsal anterior cingulate cortex (dACC) predicted response to CBT+SSRI in SAD with 83% accuracy. Experimental design. The task is known as the MSIT. It has four blocks each of two conditions (control and interference). Each block lasts 42 s and consists of 24 trials (1750 ms per trial) in pseudo-randomized order with sets of 3 digits (0, 1, 2, or 3) centrally displayed. One "target" digit differs from the other two (distractors). In the control condition, the distractors are always '0' and the target digit corresponds to its position (i.e., '1' in the leftmost position; '2' in the middle position; and '3' in the rightmost position). Thus, on control trials, the target digit and position are congruent. In the interference condition, the distractors are '1', '2', or '3' and the target digit and position are incongruent (e.g., '1' presented in the rightmost position). Participants indicate if the target digit is '1', '2', or '3' by pressing the response buttons. Ignoring the distractors and the misleading position of the target digit on interference trials requires cognitive control.

Our primary hypotheses are that: (1) The investigators will identify patterns of brain activity that distinguish adults with SAD from adults in the comparison group, and that (2) The investigators will be able to identify patterns of brain activity that predict which adults with SAD will (or will not) respond to treatment.

The primary outcome measure will be treatment response (defined elsewhere in this registration).

Inclusion criteria

for all participants:

(1) Any gender or race between 18-50 years old.

Additional inclusion criteria for healthy controls:

(1) Liebowitz Social Anxiety Scale (LSAS; Mennin et al., 2002) score <= 30, does not currently meet criteria for an Axis I psychiatric condition, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association, 2013).

Additional inclusion criteria for the social anxiety disorder (SAD) group:

• Outpatients with a primary psychiatric complaint (designated by the patient as the most important source of current distress) of social anxiety with social interaction fear as defined by an Liebowitz Social Anxiety Scale (LSAS) score >= 60.
• Overall clinical severity of at least mild as defined by Clinical Global Impressions Scale (CGI-S; Zaider et al., 2003) of at least 3.
• Medical history interview and laboratory findings without clinically significant abnormalities.
• Willingness and ability to participate in the informed consent process and comply with the requirements of the study protocol.

Exclusion criteria

• A lifetime history of bipolar disorder, schizophrenia, psychosis, delusional disorders or obsessive-compulsive disorder; an eating disorder in the past 6 months; organic brain syndrome, intellectual disability, or other cognitive dysfunction that could interfere with capacity to engage in therapy; a history of substance or alcohol abuse or dependence (other than nicotine) in the last 6 months or otherwise unable to commit to refraining from alcohol, marijuana, and stimulant use during the acute period of study participation.
• . Patients with significant suicidal ideation Montgomery-Åsberg Depression Rating Scale (10 items, self-report) or who have enacted suicidal behaviors within 6 months prior to intake will be excluded from study participation and referred for appropriate clinical intervention.
• Patients can be taking a concurrent psychotropic medication (e.g., antidepressants, anxiolytics, beta blockers, sertraline), but the dose must be stabilized for at least 2 weeks prior to initiation of randomized treatment.
• Significant personality dysfunction likely to interfere with study participation.
• Serious medical illness, associated treatment, or other instability for which hospitalization may be likely within the next year, or which may alter fMRI or EEG measurements. Participants with a history of serious medical illness or treatments that may alter fMRI measurements may enroll in the study 12 months after the condition has been remitted and ending treatment.
• Patients with a current or past history of seizures.
• Pregnant women, lactating women, and women of childbearing potential who may become pregnant.
• Any concurrent psychotherapy initiated within 3 months of baseline, or ongoing psychotherapy of any duration directed specifically toward treatment of the social anxiety is excluded. Individuals with prior CBT experience or treatments that included cognitive and behavioral skills and exposure procedures (e.g., assertiveness and social skills trainings) will be excluded. General supportive or insight-oriented therapy initiated > 3 months prior is acceptable.
• Prior non-response to adequately-delivered exposure (i.e., as defined by the patient's report of receiving specific and regular exposure assignments as part of a previous treatment).
• Patients with a history of head trauma causing loss of consciousness, seizure or ongoing cognitive impairment.
• Contraindications for MRI including metal implants, surgical clips, probability of metal fragments, braces, or claustrophobia.