Fear Conditioning for Anxiety and Post-Traumatic Stress Disorder

Recruiting at 1 trial location

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Texas at Austin

Must not be taking: Benzodiazepines, Psychotropics

Disqualifiers: Major illness, Neurological disorder, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1 month

240 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how the brain links neutral and negative experiences to better understand anxiety and PTSD (Post-Traumatic Stress Disorder). Researchers use fear conditioning (a type of behavioral therapy) and MRI scans to uncover how the brain manages fear and anxiety. The trial includes two groups: one with healthy individuals and another with those diagnosed with PTSD. This study may suit individuals diagnosed with PTSD or those with no psychiatric history who do not have metal implants or severe claustrophobia. As an unphased trial, it offers participants the chance to contribute to foundational research that could lead to new insights into anxiety and PTSD.

Will I have to stop taking my current medications?

The trial requires that participants with PTSD must be stable on their current medications, so you may not need to stop taking them. However, the protocol does not specify for other participants, so it's best to discuss your specific situation with the study team.

What prior data suggests that fear conditioning is safe for use in this study?

Research has shown that fear conditioning, a method used to understand how the brain links neutral and negative experiences, is generally safe. Studies have found that this technique plays a crucial role in exposure therapy, commonly used to treat anxiety and stress-related conditions like PTSD (Post-Traumatic Stress Disorder).

In these studies, participants encounter certain situations in a controlled environment. This approach is usually well-tolerated, with few reports of serious side effects. Most individuals experience only temporary increases in anxiety, a normal part of the process as the therapy helps them learn to manage their fears.

Overall, fear conditioning has been safely used in many research settings. The technology employed in these studies, such as MRI (a type of brain scan), is also safe for most people, although participants are screened for any conditions that might make MRI unsafe for them. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the trial for fear conditioning as a treatment for anxiety and PTSD because it offers a fresh approach that differs from traditional therapies like medication and talk therapy. Unlike typical treatments that aim to manage symptoms, fear conditioning focuses on retraining the brain's response to fear-inducing stimuli. This method could potentially lead to more lasting changes in how patients experience and react to fear, offering hope for more effective management of anxiety and PTSD symptoms. By directly targeting the brain’s fear response mechanisms, this approach could provide a new pathway for relief, especially for those who haven’t found success with existing treatments.

What evidence suggests that fear conditioning might be an effective treatment for anxiety and PTSD?

This trial will compare the effects of fear conditioning, a type of exposure therapy, across different participant groups. Research has shown that fear conditioning can reduce PTSD symptoms. Studies indicate that exposure therapies work by gradually helping patients face their fears in a safe setting, which can lessen PTSD symptoms. One study found significant improvement in symptoms during treatment. Another study showed that exposure therapy also improved depression symptoms in children and teens with PTSD. While results can vary, evidence consistently supports the effectiveness of exposure-based therapies for treating PTSD. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with PTSD and those without any psychiatric disorders. Participants should not have major medical or neurological issues, significant head trauma, a history of substance abuse, or be at immediate suicide risk. Pregnant women and people with certain metal implants that affect MRI safety are also excluded.

Inclusion Criteria

I have PTSD and may also have a mood or anxiety disorder, but not bipolar disorder.

I do not have metal implants or conditions that prevent me from undergoing an MRI.

I have PTSD diagnosed by specific symptom severity and criteria.

Exclusion Criteria

Individuals considered an immediate suicide risk based on the Columbia Suicide Severity Scale (C-SSRS) or who would likely require hospitalization during the course of the study

Volunteers meeting DSM-5 criteria for history of or current psychotic or bipolar affective disorders, a current eating disorder (bulimia, anorexia nervosa), or dissociative identity disorder

Volunteers meeting DSM-5 criteria for another substance use disorder, with the exception of caffeine or nicotine, within the past 12 months

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Baseline and Assessment

Participants undergo baseline assessments and are scheduled for MRI visits

2 weeks

1 visit (in-person)

Treatment

Participants undergo a learning paradigm inside the MRI scanner over 3 days, with the first two days consecutive and the third visit 1 month later

1 month

3 visits (in-person)

Follow-up

Participants are monitored for changes in physiological arousal and MRI data

1 month

What Are the Treatments Tested in This Trial?

Interventions

• Fear conditioning

Trial Overview The study uses fMRI to explore how the human brain forms memories associated with fear and safety. It aims to understand the neural mechanisms involved in emotional response regulation when encountering fearful stimuli.

How Is the Trial Designed?

Group I: PTSD group Experimental Treatment 1 Intervention

Participants will be screened and diagnosed using typical screening procedures and diagnostic criteria (e.g., the clinically administered PTSD scale). Participants also screened for contraindications for MRI. The learning paradigm inside the MRI scanner occurs over 3 days. The first two days are consecutive (back-to-back) and the third MRI visit is 1 month later. Participants are asked to look at a screen and listen to simple tones over headphones, while the experimenter measures brain activity and physiological measures of arousal (e.g., sweating from sensors on the hand). These visits will be scheduled within two weeks from the baseline and assessment visit.

Group II: Healthy control group Experimental Treatment 1 Intervention

Participants will be healthy adults without a history of psychiatric illness. Participants also screened for contraindications for MRI. The learning paradigm inside the MRI scanner occurs over 3 days. The first two days are consecutive (back-to-back) and the third MRI visit is 1 month later. Participants are asked to look at a screen and listen to simple tones over headphones, while the experimenter measures brain activity and physiological measures of arousal (e.g., sweating from sensors on the hand). These visits will be scheduled within two weeks from the baseline and assessment visit.

Fear conditioning is already approved in United States, European Union for the following indications:

Approved in United States as Exposure Therapy for:

• Anxiety Disorders
• Post-Traumatic Stress Disorder (PTSD)
• Obsessive-Compulsive Disorder (OCD)

Approved in European Union as Exposure Therapy for:

• Anxiety Disorders
• Post-Traumatic Stress Disorder (PTSD)
• Obsessive-Compulsive Disorder (OCD)

Who Is Running the Clinical Trial?

University of Texas at Austin

Lead Sponsor

Trials

387

Recruited

86,100+

Published Research Related to This Trial

An intensive outpatient program combining Prolonged Exposure therapy and complementary interventions showed a high retention rate of 96.3% among 80 veterans with chronic PTSD, leading to significant reductions in PTSD, depression, and neurological symptoms after just two weeks.

77% of participants experienced clinically significant improvements in PTSD symptoms, indicating that this integrated care model is effective for diverse patient demographics and symptom presentations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction to Rauch et al. (2021). [2023]

Posttraumatic Stress Disorder (PTSD) is now recognized as a serious psychiatric disorder resulting from extreme psychological trauma, with exposure therapy identified as the most effective treatment based on controlled studies.

Despite the effectiveness of exposure therapy, PTSD's complexity, especially in chronic or combat-related cases, means that no single treatment has been successful in alleviating all symptoms, particularly the psychophysiological overarousal associated with traumatic memories.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Posttraumatic stress disorder: conceptualization and treatment. Boudewyns, PA.[2007]

In a study of four PTSD cases, different behavioral treatments showed varying effectiveness; in-vivo exposure was particularly effective for reducing phobic anxiety.

Imaginal exposure, especially when using audio-taped sessions, helped improve feelings of dysphoria and some phobic symptoms, suggesting its importance in PTSD treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure therapy for post-traumatic stress disorder. Four case studies. Richards, DA., Rose, JS.[2019]

A study involving 84 firefighters found that deficits in extinction learning, measured before trauma exposure, can predict the severity of posttraumatic stress symptoms after experiencing trauma.

Specifically, reduced ability to extinguish a conditioned emotional response was linked to 31% of the variance in posttraumatic stress severity, suggesting that this impairment may be a risk factor for developing PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extinction learning before trauma and subsequent posttraumatic stress. Guthrie, RM., Bryant, RA.[2022]

The review highlights various classical conditioning paradigms, such as extinction learning and fear generalization, which are crucial for understanding the development and treatment of PTSD, supported by case examples from patients with severe symptoms.

It discusses the neurobiological mechanisms involved in conditioning and extinction across different populations, suggesting that biological, behavioral, and cognitive factors play significant roles in how PTSD symptoms are learned and treated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical applications and practical relevance of human conditioning paradigms for posttraumatic stress disorder. Zuj, DV., Norrholm, SD.[2019]

Current models of exposure therapy for phobias and anxiety disorders may not accurately predict therapeutic outcomes based on fear levels during exposure trials, as neither the reduction in fear nor the final fear level correlates with success.

Enhancing inhibitory learning—rather than focusing solely on fear reduction—could improve the effectiveness of exposure therapy, suggesting that context and timing play crucial roles in how well patients retain what they learn during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing inhibitory learning during exposure therapy. Craske, MG., Kircanski, K., Zelikowsky, M., et al.[2022]

The M-Maze task is a new method for studying fear extinction in rodents, allowing for automated and simultaneous testing of multiple animals, which can lead to more efficient long-term experiments.

The protracted aversive conditioning (PAC) model induces persistent extinction impairments and heightened anxiety in rats, providing a more severe model of fear that may better mimic PTSD symptoms and help in developing new therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The M-Maze task: An automated method for studying fear memory in rats exposed to protracted aversive conditioning. Souza, RR., Robertson, NM., Pruitt, DT., et al.[2019]

Despite 92.3% of surveyed clinicians understanding or being trained in exposure-based therapies for PTSD, only 55.5% actually use prolonged exposure (PE) therapy, indicating a gap between knowledge and practice.

Clinicians with a cognitive behavioral therapy (CBT) orientation and training in PE are more likely to utilize exposure therapies and hold less negative beliefs about them, suggesting that enhancing training and addressing misconceptions could improve the use of effective PTSD treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure Therapy Beliefs and Utilization for Treatment of PTSD: A Survey of Licensed Mental Health Providers. Kline, AC., Klein, AB., Bowling, AR., et al.[2021]

Exposure therapy is an effective cognitive intervention for anxiety disorders, as it specifically alters patients' expectations of harm, which is crucial for reducing fear responses.

The review highlights the importance of understanding fear conditioning and extinction processes in animals, as these models can inform and improve therapeutic approaches for anxiety disorders in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Hofmann, SG.[2018]

The COPE treatment, which integrates prolonged exposure therapy with usual care, significantly reduced PTSD symptoms in patients with both PTSD and substance dependence, showing a mean difference of -16.09 points compared to usual treatment alone.

Importantly, the COPE treatment did not lead to an increase in substance dependence severity, indicating that it is a safe and effective option for treating individuals with co-occurring PTSD and substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated exposure-based therapy for co-occurring posttraumatic stress disorder and substance dependence: a randomized controlled trial. Mills, KL., Teesson, M., Back, SE., et al.[2022]

PTSD patients exhibit excessive fear responses during both fear acquisition and extinction learning compared to trauma-exposed individuals without PTSD, indicating a significant impairment in fear extinction mechanisms.

After undergoing prolonged exposure (PE) therapy, patients who responded well to treatment (≥50% symptom reduction) were able to maintain fear extinction learning, while those with lower responses (<50% reduction) experienced a significant return of fear, highlighting the importance of treatment response in the effectiveness of PE therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquisition, extinction, and return of fear in veterans in intensive outpatient prolonged exposure therapy: A fear-potentiated startle study. Maples-Keller, J., Watkins, LE., Nylocks, KM., et al.[2023]

Exposure therapy is a safe and effective treatment for Posttraumatic Stress Disorder (PTSD), supported by strong evidence from well-controlled studies across various trauma populations.

Despite its effectiveness, misconceptions about exposure therapy may hinder its broader acceptance, highlighting the importance of proper application by experienced therapists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure therapy for posttraumatic stress disorder. Rothbaum, BO., Schwartz, AC.[2018]

In a study of 231 Veterans undergoing an 8-week modified prolonged exposure therapy for PTSD, most participants (n = 190) did not respond positively to the treatment, indicating that this modified approach may not be effective for many individuals.

The only significant predictor of treatment success was baseline anxiety levels, with nonresponders showing higher anxiety symptoms and lower social support compared to responders, suggesting that those with higher anxiety may need different treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors and Outcomes of Growth Mixture Modeled Trajectories Across an Exposure-Based PTSD Intervention With Veterans. Allan, NP., Gros, DF., Myers, US., et al.[2019]

Fear conditioning experiments reveal the complex neurobiological mechanisms behind PTSD, highlighting different fear-related dimensions such as fear extinction and generalization, which can inform targeted treatment strategies.

These paradigms not only enhance our understanding of PTSD but also serve as a platform for developing new pharmacological and non-pharmacological interventions, emphasizing the need for further research to optimize their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors. Briscione, MA., Jovanovic, T., Norrholm, SD.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7139336/

Exposure Therapy for Post-Traumatic Stress Disorder Recent research indicates that there is mixed success in using exposure therapies on patients with post-traumatic stress disorder (PTSD).

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9006570/

The efficacy and acceptability of exposure therapy for ... ET showed superiority in efficacy at post-treatment/follow-up and depressive symptoms improvement in children and adolescents with PTSD.

3. ptsd.va.gov ptsd.va.gov/professional/articles/article-pdf/id1585394.pdf

Exposure therapy for PTSD: A meta-analysis Findings support the overall efficacy of exposure therapy and highlight that there are a number of efficacious exposure-based therapies ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1077722925000458

Inhibitory Retrieval-Based Exposure Therapy for Patients ... Results showed that PTSD symptoms significantly decreased over treatment compared to baseline (b = −0.22, p < .001). Clinically meaningful ...

5. nature.com nature.com/articles/s41398-022-02066-x

a randomized clinical trial of virtual reality and imaginal ... We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11034887/

To Expose or Not to Expose: A Comprehensive Perspective ... Exposure therapy seeks to correct pathological anxiety by repeatedly exposing the patient to the feared stimulus, using imaginal and in vivo exposure. Prolonged ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0149763424004524

Fear and safety learning in anxiety- and stress-related ... Fear learning processes are believed to play a crucial role in the development and maintenance of anxiety and stress-related disorders.

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK559129/

Posttraumatic Stress Disorder - StatPearls - NCBI Bookshelf Posttraumatic stress disorder (PTSD) is a prevalent and complex psychiatric condition that arises in response to exposure to traumatic events.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT00057629

Prolonged Exposure Therapy for Post Traumatic Stress ... This study will evaluate the effectiveness of a brief cognitive behavioral therapy, administered by community agencies, for the treatment of patients with Post ...