Augmentation of Positive Valence System–Focused Cognitive Behavioral Therapy by Inaudible High-Frequency Sounds for Anhedonia

Key Points Question Can inaudible high-frequency sounds augment the efficacy of cognitive behavioral therapy for anhedonia? Findings This trial protocol describes a placebo-controlled, randomized clinical pilot study testing the augmentation effect of inaudible high-frequency sounds on positive valence system–focused cognitive behavioral therapy among patients with clinically significant anhedonia and depression. The sound presentation system is designed to optimize exposure to inaudible high-frequency sounds during face-to-face cognitive behavioral therapy sessions. Meaning The preliminary results of this pilot study could contribute to the design of confirmatory randomized clinical trials that will examine the augmentation effect of inaudible high-frequency sounds on the treatment of anhedonia.


eAppendix. Biological and Theoretical Rationale and Treatment Descriptions of Positive
Valence System-Focused Cognitive Behavioral Therapy As discussed in previous literature regarding the psychological treatments developed to specifically target anhedonia or achieve a positive affect [1][2][3] , neuroscience research has been demonstrated that anhedonia is associated with various neuronal circuity or neurotransmitters related to reward processing.
In the same manner as previous novel positive affect interventions, we referred to the accumulating findings of biological, neuroscience and emotion research in our rationale for the selected treatment targets in the positive valence system-focused cognitive behavior therapy (PoCot). Since there is little evidence of specific intervention to the subprocesses or the entire process of reward processing in individuals with anhedonia, we referred to the intervention techniques that have been shown to be effective in enhancing one's positive affect or related constructs (e.g., well-being and satisfaction with life) among people in clinical and non-clinical populations. The goal, description, targeted reward processes, biological/theoretical rationale, and findings that relate to utilized intervention technique are described in eTable 1. Cited references in eTable 1 are presented in the references section of this supplemental text. In this supplemental text, we focus on the biological/neurological correlates of the positive-valence system to clarify our treatment targets in PoCot and describe the intervention technique to improve the targeted processes. Though we could not acquire the treatment protocol from the author describing positive affect training at the time we conducted this pilot clinical trial (June, 2017), our basic strategy in developing the PoCot was largely influenced by the positive affect training developed by Dr. Craske and her research team 2 .
As with positive affect training 2 , we targeted the 3 major components of reward processing: anticipation, consumption, and learning 4 5 . According to Craske et al.(2016), these components are described as follows "the anticipatory component refers to motivation for rewarding stimuli, such as planning and looking forward to a vacation, and is related to the effort expended to receive reward. It is dominated by 'wanting.' The consummatory component refers to the pleasure or hedonic impact of rewarding stimuli, such as the pleasure while on vacation, and is dominated by 'liking.' The learning component typically involves Pavlovian or instrumental associations and predictions about future rewards based on past experiences, such as the decision to take another vacation given the rewards of the last vacation (p.930)". We targeted these 3 components because biological or neuronal studies have shown that anhedonia is associated with the deficits in these subsystems of reward processing. Moreover, clear treatment technique descriptions corresponding to these components were provided in literature 2 . In the psychoeducation conducted in the first PoCot session, we presented this framework as the treatment rationale for targeting these subsystems of reward processing (i.e., wanting, liking, learning).
In terms of biological correlates of reward anticipation, it is suggested that dopaminergic signaling and specific neuronal regions such as the ventral tegmental area, amygdala, and ventral striatum are involved 6 4 . Furthermore, individuals with depression showed reduced activation in reward circuitries during reward anticipation 7 8 9 . Also, people with dysphoria may exhibit diminished positive emotions in future positive events 10 . To improve these deficits, PoCot participants were asked to schedule and conduct the activities that inspire positive emotions for them. A similar technique is used in positive affect intervention 11 , positive affect training 2 , and Engage therapy 1 .
Reward consumption is suggested to related to opioid and endocannabinoid pathways 12  Reward learning is thought to coincide with the reward anticipation and consumption. Notably, reward learning is associated with dopaminergic signaling 16 . In terms of neuronal regions, reward learning and decision making may be associated with the anterior cingulate, orbitofrontal, ventral medial prefrontal, and dorsal lateral prefrontal cortices 4 . Patients with depression showed significantly reduced reward learning signals in the ventral striatum, rostal and dorsal anterior cingulate, retrosplenial cortex, midbrain, and hippocampus 17 . Also, reduced reward learning signals correlate with depression severity 17 . Moreover, it is suggested that lower reward learning predicts higher anhedonia symptoms for the next month 18 . To improve the reward learning process, PoCot participants were asked to monitor and record their actions during the positive events. Instead of focusing on external or situational factors, they were asked to focus what they actually did to making such positive events happen and what they did when the positive experience continued. This training is expected to enhance learning and instrumental conditioning between their behavior and positive outcomes (i.e., reward learning). This technique is similar to scheduling pleasant events in positive affect training 2 . Also similar to positive affect training, we asked participants to vividly recall and savor the positive experiences during the subsequent sessions. This technique is also expected to enhance and consolidate reward learning 19 .
In addition to the above findings, we have learned from "Engage" therapy, an approach theoretically based on the framework of the positive-valence system in research domain criteria 1 . In "Engage" therapy, the subprocesses of the positive valence system such as reward valuation, effort valuation, action selection, preference-based decision making, and reward learning are targeted in the intervention. In developing PoCot, we included the treatment techniques in "Engage" therapy (e.g., reward exposure.)   Note. Full references are included in the Supplemental text