Mobile Virtual Positive Experiences for Anhedonia

Anhedonia is a symptoms dimension that characterizes many individuals suffering from
depression, as well as some types of anxiety, psychosis, and substance use. Anhedonia refers
to deficits in positive affect as observed through 1) loss of enjoyment in pleasurable
activities and/or 2) loss of desire to engage in pleasurable activities. Within depression,
anhedonia is more strongly associated with the core disturbance of depressions (e.g.
lassitude) than with the nonspecific symptoms that are shared without emotion disorders (e.g.
insomnia). Approximately one¬-third of depressed individuals have clinically significant
anhedonia symptoms, as defined by cutoffs on scales that measure enjoyment of social and
physical pleasure. Anhedonia extends beyond major depression to social anxiety disorder and
generalized anxiety disorder, although with a smaller magnitude of effect than depression.
Anhedonia is also relevant to schizophrenia and substance use disorder. Thus, anhedonia
represents a dimension of psychopathology that crosses diagnostic boundaries.

Anhedonia is associated with several indices of psychopathology. First, self¬-reported
anhedonia (lower levels of positive emotion) is a robust predictor of poorer longitudinal
course of symptoms of major depression across a number of prospective studies. Relatedly, the
trait variance component of low positive affect prospectively predicts the onset of not only
major depression, but also social anxiety disorder and generalized anxiety disorder, albeit
through correlates with neuroticism. Second, anhedonia within major depression is a major
predictor of suicide, and the predictive effects upon suicidal ideation persist even when
controlling for other cognitive and affective symptoms of depression. Third, anhedonia is a
predictor of poorer response to pharmacological treatments for depression. Some preliminary
data from our laboratory replicate this relationship in terms of psychological treatments, at
least for social anxiety disorder: in a sample of 75, the investigators found that low
positive affect again significantly predicted poorer outcomes (b = ¬-.70, B = -¬.25, p <
.05).

Approach Motivation: Dopaminergic signaling is related to the motivation for reward. In
humans, neural regions most strongly linked to the approach motivation for reward include the
ventral tegmental area, amygdala, and striatum, all of which are innervated by or project to
dopaminergic nuclei. Phasic bursts in dopaminergic neurons in the ventral tegmental area have
been shown to co¬-occur in response to violations in reward expectancy. Dopamine signaling in
the nucleus accumbens (which has dense dopaminergic projections from the ventral tegmental
area) is also associated with reward motivation in rodents. Increased mPFC activation may
function to reduce striatal response and behavioral drive for rewarding dopaminergic
stimulation. Approach motivation is also tied to reward learning, which involves Pavlovian or
instrumental associations and predictions about future rewards based on past experiences. As
with the approach motivation for reward, learning of reward is associated with dopaminergic
signaling. Various areas of the prefrontal cortex have been implicated in decision making and
reward learning, and animal research highlights areas such as the ACC, orbitofrontal cortex,
vmPFC and dlPFC. Not only do depressed individuals show reduced activation in reward
circuitries in anticipation of reward but reduced ventral striatum responsivity to incentive
stimuli is particularly related to anhedonic symptoms. Further evidence is derived from
behavioral indices in which trait anhedonia among healthy individuals correlates with
choosing easy tasks for a small reward over harder tasks for larger rewards, indicative of
less motivation (i.e., expenditure of effort) to gain reward. Also, depressed individuals
make fewer higher reward/high effort choices than healthy controls, and importantly, the
motivational effort they expend to obtain rewards correlates negatively with anhedonia. In
self-¬report measures, dysphoric individuals expect to feel less positive emotion in future
positive events and report less positive emotion in anticipation of a monetary reward
compared to healthy controls, although the evidence is not entirely robust.

Responsiveness to Reward Attainment: Responsiveness to reward attainment (or hedonic
capacity) is more strongly related to opioid and endocannabinoid pathways. Neural regions
most strongly linked with liking of reward include the ventral striatum (representing overlap
with the approach motivation component) and orbitofrontal cortex. Depressed individuals show
ventral striatum hypo-activity to positive stimuli, and the hypo-activity is particularly
strongly associated with symptoms of anhedonia. Furthermore, Wacker et al. (2009) established
that the effects were specific to anhedonia above and beyond negative symptoms of anxiety and
depression. Further evidence for deficits in initial responsiveness to attainment derives
from cognitive measures, with depressed individuals showing less attention to positive
stimuli than controls as measured by response latency times in dot probe tasks and eye
tracking. Moreover, attention to positive information is associated with positive affect. The
evidence for deficits in self-¬rated liking of reward in depressed individuals is mixed.
Importantly, lower levels of self¬-reported positive emotions to positive stimuli (e.g. sweet
taste test) are more strong related to anhedonia than depression.

Targeted Treatment for Anhedonia: In light of the evidence summarized above, a treatment that
specifically targets reward approach motivation and learning, and responsiveness to reward
attainment may be particularly potent for anhedonia. As noted, existing psychological
treatments mostly target negative affect, and while behavioral activation is designed to
increase engagement in pleasant activities, little attention has been given to date to how to
optimize positive emotions during the planning and conduct of such activities. Drawing from
affective neuroscience and experimental psychopathology, the investigators have developed a
treatment that specifically targets these components of the reward system. The treatment is
comprised of therapeutic techniques that directly target one or more of these subdomains. The
first phase of treatment (sessions 1-7) involves modified behavioral activation (called
behavioral training), which combines planning for engagement in pleasurable activities
(reward approach and motivation) and reinforcement via positive mood inducing effects (reward
learning) with 'in¬-the-¬moment' recounting designed to savor pleasurable moments and enhance
hedonic impact (responsiveness). The second phase of treatment (sessions 8¬-13) adds two
additional components to ongoing behavioral training: cognitive training designed to shift
attention towards positive stimuli in the environment (reward approach motivation), reinforce
associations between responses and positive outcomes (reward learning) and train motivation
for positive events and emotions through imagery (reward approach motivation); and compassion
training that focuses on motivating toward (reward approach motivation) and savoring positive
experiences (responsiveness). The investigators found that this treatment is effective in
both reducing negative affect (depression and anxiety) and improving positive affect,
especially for individuals who are most anhedonic at baseline. Specifically, patients who
meet entry criteria of elevated levels of depression, anxiety (somatic), or stress (worry) on
the Depression, Anxiety and Stress Scale (DASS-21), and who are at least moderately impaired
according to the Sheehan Disability Scale (SDS), are randomly assigned to receive treatments
aimed at increasing reward sensitivity (Positive Affect Treatment, PAT) or at reducing threat
sensitivity (Negative Affect Treatment, NAT). Here the investigators present data from the
first 61 enrolled patients (N=20 PAT and N=41 NAT) who began the 15 ¬treatment session
protocol. Self-¬reported symptoms of depression (DASS-¬D) and stress (DASS-¬S) decreased from
a severe range at pre-¬treatment to a normal range at post-¬treatment in PAT and NAT
(DASS¬-D: Cohen's d=1.89 and 1.41, respectively; DASS¬-S: d=1.35 and d=1.65, respectively).
Self¬-reported anxiety (DASS¬-A) decreased from extremely severe to normal for PAT and from
moderate to mild for NAT (d=1.02 and 1.47). The investigators found significant improvements
for our anhedonia outcome measure, Positive and Negative Affect Schedule Positive Scale
(PANAS-¬P). Positive affect improved linearly in both treatment, but significantly greater
changes occurred with PAT (d=1.40) versus NAT (d=.59) (Group x Time; p=.001). Only PAT
significantly and satisfactorily normalized deficits in positive affect (changes from 20th to
46th percentile on the scale developed by Crawford Henry, 2004. In NAT treatment, levels of
PANAS-¬P remained lower than the population average (change from 18th to 32nd percentile).

Virtual Reality-Reward Training: While our "reward training" treatment has a strong
preliminary efficacy signal, it is dependent on delivery by highly trained clinicians, which
reduces its scalability and accessibility to large section of the population. Furthermore,
evaluation of mechanisms is somewhat impeded by variability both within the between
individuals in terms of rate of exposure to rewarding stimuli. Finally, chronically anhedonic
individuals, especially those with limited social contact and therefore lack of social
reinforcement, may be faced with difficulties when asked to repeatedly engage in rewarding
experiences. Repeated imagining of positive outcomes from multiple scenarios has already been
shown to be an effective means for raising positive affect. However, imagery alone provides
limited control over the content of images and is dependent upon an individual's ability to
imagine vividly. Virtual reality provides a vehicle for repeated programmatic immersion in
rewarding experiences that can include training to identify positive stimuli, sustain
attention upon positive stimuli, receive reinforcement for such attention, and notice mood
enhancing effects, with training extending from primary reward (e.g. physical and social) to
acts of generosity/loving kindness. This type of automated training offers the potential to
eventually become a self-¬guided treatment which would increase implementation on a large
scale. Furthermore, it offers a mechanistic dose-¬response evaluation since the dosage of
rewarding experiences within virtual reality can be fully controlled. Virtual reality with
relaxing scenes has been shown to increase ratings of happiness. Virtual reality has already
been tested and shown to be an effective tool for raising positive affect in patients with
chronic or terminal medical conditions.

Potential participants will complete a brief online screener to verify eligibility. Eligible
participants will be randomized to VR-RT or a delayed waitlist control condition. All
participants will complete a Baseline assessment at Week 0 through Qualtrics that measures
symptoms of anhedonia, depression, and anxiety. Participants randomized to VR-RT will be
provided with VR viewers to allow them to use their smartphone devices to view virtual
reality scenes. At an initial orientation, they will be instructed how to access the VR
scenes online and view them using the virtual reality viewer, as well as how to use Qualtrics
to guide their recall of the VR scenes and autobiographical memories. They will complete
VR-RT sessions twice weekly for 8 weeks (13 sessions total, one of which occurs at the
Baseline assessment), and they will be contacted by the method of their choice, reminding
them to complete these treatment sessions twice per week and to troubleshoot technical
difficulties. All independent mobile VR sessions are expected to take no more than one hour.
Online measures of anhedonia, depression, and anxiety will be repeated at Week 4
(Mid-treatment) and Week 8 (Post-treatment). Participants randomized to the delayed wait-list
control will complete the same measures at Week 0, 4, and 8, but they will not complete any
training. After completion of the Week 8 assessment, they will be offered the VR-RT, although
their response will not be assessed. Those who score in the cutoffs listed below for the BAS
will be sent a recruitment email with further information about participation.

Participants will view several VR scenes and complete the I-PANAS-SF at the beginning and end
of each session.

After providing online consent, participants will provide contact information (which will
include phone verification and email verification steps), age and sex, and preferred mode of
contact through a secured registration system. Once this information is collected,
participants will receive a notification that they will be contacted within three business
days to complete the final screening step by phone. If participants are not eligible after
completing the online screening or decline to provide consent, they will be sent a
notification of their ineligibility and a list of resources. If the participants are found
eligible, they will be randomized to the treatment or waitlist control group and scheduled
for all of the VR-¬RT sessions and assessments. Participants will complete in-person
assessments at Baseline, Mid-treatment (before session 8), and Post-treatment (24 hours after
session 13). Qualtrics links to self-¬report measures of demographics (Screening only) and
positive and negative affect (I-PANAS-SF, the International Positive and Negative Affect
Schedule Short Form) will be emailed to participants to complete before and after each of the
VR-RT sessions.

At each assessment, the participant will complete the PANAS-SF (at beginning and end),
MASQ-AD 14 item, DASS-21, Ruminative Responses Scale, SDS, EEfRT task, and Pizzagalli task.
Each of these sessions is expected to take approximately one hour.

Description of Virtual Reality Reward Training (VR-RT): VR-RT will consist of 13 sessions,
twice weekly (total 8 weeks), each lasting roughly 45 minutes. These sessions will occur at a
comfortable, private location (e.g. at home) with a sufficiently strong Wi-Fi connection
chosen at the participant's discretion. The investigators have determined that UCLA's campus
has sufficiently strong Wi-Fi connection to complete the VR-RT viewings and tasks.
Participants will therefore be offered the option to complete their sessions on campus in the
laboratory of Dr. Craske in the Life Sciences Building.

The first session will consist of an overview of the treatment, instruction in the use of the
virtual reality equipment, and Session 1 of VR-RT. Each session will involve unique virtual
reality scenes. All virtual reality scenes will contain physical (e.g. walking through a
beautiful forest) and/or social (e.g. being welcomed as entering a social gathering)
reward-related sub-scenes in which higher-intensity rewarding stimuli are embedded and are to
be discovered through searching (e.g. sun filtering through the forest in one of several
hiking trials; being invited to join a group within a larger social gathering); negative
sub-scenes may also be embedded (e.g. clouds looming overhead; a group who ignore the
participant) in order to emphasize focus on the positive aspects of the scenes. Some of the
social reward scenes will involve acts of generosity and loving kindness.

Each session will be comprised of three components: 1) Preparation. Participants will be
given a description of the virtual scene to which they will be exposed. They will be informed
that their task is to become as fully immersed in the scene as possible, to notice their
emotions, physical reactions and thoughts as they participate, and to move away from embedded
negative stimuli and discover embedded higher intensity rewarding stimuli through searching
behavior and to move away from embedded negative scenes; this represents training in goal
setting and approach motivation. Participants will rate their mood using the International
Positive and Negative Affective Schedule Short Form (I-PANAS-SF) to assess positive affect
and negative affect, anchored to current mood states. They will then connect their smartphone
to the virtual reality equipment, queuing up the VR video for that session. 2) Experience.
Each session will consist of two to six videos and average approximately 15 minutes. 3)
Evaluate and Recount. Participants will complete a Post- VR I-PANAS-SF. Participants will
type into Qualtrics their recollection of the VR scene(s). They will then listen to a guided
mindfulness summary of the scene(s) they just watched. Participants will then type into
Qualtrics their recollection of an autobiographical memory; the autobiographical memory they
recall will be prompted by the program, differing by session. Participants will then listen
to a guided mindfulness recording that prompts them to recall their own, prompted
autobiographical memory. In doing so, the training targets savoring or attainment of reward
and reward learning (i.e., my mood is changed by this activity). Participants will then rate
their mood again according to the I-PANAS-SF.

Inclusion Criteria:

- fluent in English

- below the population mean on either the Behavioral Activation Scale (BAS) Reward Drive
subscale (score of ≤ 11), or BAS Responsiveness subscale (score of ≤16)

- score in mild-moderate range on DASS-21 following established score cutoffs:
Depression (10-27); at least a score of Anxiety (8-14); and a score of at least Stress
(15-25)

- Sheehan Disability Scale (SDS) overall score must be ≥ 6

- agree to refrain from initiating other psychosocial treatments throughout the duration
of the study

Exclusion Criteria:

- Lifetime history of bipolar disorder, psychosis, intellectual disabilities, or organic
brain damage

- substance use disorder in the past 6 months

- current use of psychotropic medications

- currently pregnant or planning to become pregnant

- self-reported frequent motion sickness, self-reported seizures within the last year
and/or a diagnosis of epilepsy