The statistical analysis plan for the unification of treatments and interventions for tinnitus patients randomized clinical trial (UNITI-RCT)

Background Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. Methods Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. Discussion The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. Trial registration ClinicalTrials.gov NCT04663828. The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis

Reduction of costly safety behaviors after extinction with a generalization stimulus is determined by individual differences in generalization rules

Exposure-based treatment involves repeated presentation of feared stimuli or situations in the absence of perceived threat (i.e., extinction learning). However, the stimulus or situation of fear acquisition (CS+) is highly unlikely to be replicated and presented during treatment. Thereby, stimuli that resemble the CS+ (generalization stimuli; GSs) are typically presented. Preliminary evidence suggests that depending on how one generalizes fear (i.e., different generalization rules), presenting the same GS in extinction leads to differential effectiveness of extinction learning. The current study aimed to extend this finding to safety behaviors. After differential fear and avoidance conditioning, participants exhibited discrete generalization gradients that were consistent with their reported generalization rules (Similarity vs Linear). The Linear group showed stronger safety behaviors to a selected GS compared to the Similarity group, presumably due to higher threat expectancy. After extinction learning to this GS, the Linear group exhibited stronger reduction in safety behaviors generalization compared to the Similarity group. The results show that identifying distinct generalization rules allows one to predict expectancy violation to the extinction stimulus, in addition to corroborating the idea that strongly violating threat expectancy leads to better extinction learning and its generalization. With regard to clinical implications, identifying one's generalization rule (e.g., threat beliefs) help designing exposure sessions that evoke strong expectancy violation, enhancing the reduction in the generalization of maladaptive safety behaviors.</p

Data and Analytic Code

Anonymized data and analytic code for the manuscript "Stimulus variability during extinction training does not improve the generalization of fear extinction learning

Stimulus variability during extinction training does not improve the generalization of fear extinction learning

Fear extinction procedures serve as a laboratory model for a learning process involved in exposure treatment for anxiety disorders. Clinically, exposure is typically conducted with generalization stimuli (GSs), because originally acquired fear stimuli are inaccessible. Experimental studies, however, show limited generalization of extinction when GSs are used in extinction training (i.e., GS extinction), which may represent a risk for return of fear. Stimulus variability may overcome limited extinction generalization. This study examined whether using multiple, perceptually similar GSs during fear extinction enhances GS extinction generalization. A healthy sample (N = 120) underwent a two-day fear conditioning procedure. During extinction, participants repeatedly experienced either a single GS, multiple GSs, or the original conditioned stimulus (CS+). Later, threat expectancy and skin conductance responses to novel stimuli and the CS+ were measured during three test phases. Across groups, return of fear on the second day was evident for the CS+. Contrary to our hypotheses, no group differences during test phases were apparent, suggesting comparable extinction generalization independent of extinction training stimuli. This finding was replicated in an additional web-based study. Results point to questions about the influence of (missing) awareness of perceptual differences and its interplay with higher-order cognitive processes for extinction generalization

Generalization of extinction with a generalization stimulus is determined by learnt threat beliefs

Expectancy violation refers to the mismatch between an expected and the actual outcome. Maximizing expectancy violation is crucial for exposure-based treatment. Since the original stimulus of fear acquisition (CS+) is rarely available, stimuli that resemble the CS+ (generalization stimuli; GSs) are presented during treatment. A given GS may evoke either strong or weak generalized fear depending on an individual's threat beliefs. Presenting this GS in extinction would then evoke different levels of expectancy violation, which determines the strength of the subsequent generalization of extinction to other stimuli, including the CS+. After differential fear conditioning, participants exhibited discrete generalization gradients depending on their inferred relational rules (Linear vs Similarity). Crucially, the Linear group showed strong generalized fear to the GS used in extinction. This strong expectancy violation led to enhanced extinction learning and subsequently to strong generalization of extinction as characterized by a flat generalization gradient, and reduced conditioned fear to the CS+. In contrast, the Similarity group showed weak generalized fear to the same GS in extinction, and limited generalization of extinction. These results corroborate the importance of expectancy violation in exposure-based treatment, and suggest that exposure sessions designed to evoke strong threat beliefs may lead to better treatment outcome.</p

Generalization of extinction with a generalization stimulus is determined by learnt threat beliefs

Expectancy violation refers to the mismatch between an expected and the actual outcome. Maximizing expectancy violation is crucial for exposure-based treatment. Since the original stimulus of fear acquisition (CS+) is rarely available, stimuli that resemble the CS+ (generalization stimuli; GSs) are presented during treatment. A given GS may evoke either strong or weak generalized fear depending on an individual's threat beliefs. Presenting this GS in extinction would then evoke different levels of expectancy violation, which determines the strength of the subsequent generalization of extinction to other stimuli, including the CS+. After differential fear conditioning, participants exhibited discrete generalization gradients depending on their inferred relational rules (Linear vs Similarity). Crucially, the Linear group showed strong generalized fear to the GS used in extinction. This strong expectancy violation led to enhanced extinction learning and subsequently to strong generalization of extinction as characterized by a flat generalization gradient, and reduced conditioned fear to the CS+. In contrast, the Similarity group showed weak generalized fear to the same GS in extinction, and limited generalization of extinction. These results corroborate the importance of expectancy violation in exposure-based treatment, and suggest that exposure sessions designed to evoke strong threat beliefs may lead to better treatment outcome.</p