Amygdala Neurofeedback for Depression

Overseen By Scott Barb

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Kymberly Young

Must be taking: SSRI antidepressants

Must not be taking: Antipsychotics, Anticonvulsants, Stimulants, others

Disqualifiers: Cardiovascular, Substance dependence, Brain injury, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method called amygdala neurofeedback to assist people with depression who haven't found relief from typical treatments. The study aims to determine if real-time brain imaging can boost positive emotions by focusing on happy memories. Researchers will divide participants into two groups: one focusing on the amygdala (a brain area tied to emotions) and the other on a part of the brain not usually linked to emotions. Ideal participants are right-handed adults diagnosed with depression who haven't improved after trying at least two different antidepressants.

As an unphased trial, this study provides a unique opportunity to explore innovative treatment options for depression.

Will I have to stop taking my current medications?

You can continue taking your current SSRI antidepressant if it's stable for at least 3 weeks. However, you must stop taking any antipsychotics, anticonvulsants, stimulants, benzodiazepines, beta-blockers, or other medications that might affect brain blood flow at least 3 weeks before the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using real-time brain imaging feedback to target the amygdala is generally safe. One study found that this method helped reduce depression by boosting the amygdala's response to positive memories, and participants tolerated it well. These studies reported no serious side effects.

For the parietal neurofeedback, used for comparison in this trial, safety data is also encouraging. Reviews have shown that neurofeedback has been used for various conditions without serious side effects. It is noninvasive and painless, making it a gentle option for many people.

Both treatments have demonstrated positive results in previous research with no major safety issues. However, as with any medical treatment, consulting healthcare professionals and considering personal health conditions is important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about Amygdala Neurofeedback because it offers a novel approach to treating depression. Unlike standard antidepressants and therapies that often take weeks to show effects, this treatment uses real-time fMRI neurofeedback to potentially enhance emotional processing by targeting the amygdala directly. By focusing on positive autobiographical memory recall, it aims to produce faster mood improvements. Additionally, the Parietal Neurofeedback arm targets a different brain region, the intraparietal sulcus, which is not directly involved in emotional processing, to provide a unique comparison in how different brain areas can influence mood. This trial could reveal new insights into how brain activity modulation can be used in depression treatment.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that amygdala neurofeedback, which participants in this trial may receive, can help reduce symptoms of depression. By increasing activity in the amygdala—a part of the brain—when recalling positive memories, individuals can experience a significant decrease in depression symptoms over time. Some studies suggest that after just a few sessions, the benefits can last up to 12 weeks.

In this trial, another group of participants will receive parietal neurofeedback, which has also shown promise. This technique has been used to treat various conditions, including depression, and has been reported to improve brain functions and reduce symptoms related to depression. Both treatments offer new ways to potentially help those with depression that hasn't responded to other treatments. ^{1 3 6 7 8}

Who Is on the Research Team?

Kymberly Young, PhD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for right-handed adults aged 18-55 with Major Depressive Disorder (MDD) who haven't improved after two SSRI treatments. Participants can be unmedicated or on a stable SSRI regimen, must experience anhedonia, and have difficulty recalling specific positive memories. Exclusions include other major psychiatric disorders, recent substance dependence, traumatic brain injury, MRI incompatibility (like claustrophobia), pregnancy, breastfeeding, non-English speakers, vision issues without correction, and certain unstable medical conditions.

Inclusion Criteria

must have fewer than 45% memories categorized as specific on the Autobiographical Memory Test

I have tried two SSRI medications without success.

I am not on antidepressants or have been stable on SSRI antidepressants for at least 3 weeks.

Exclusion Criteria

are unable to complete questionnaires written in English

You cannot have an MRI scan due to feeling very uncomfortable in small or enclosed spaces (claustrophobia) or having certain metal objects inside your body.

I do not have any serious or unstable health conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 5 sessions of real-time fMRI neurofeedback training over a 2-month period

8 weeks

Follow-up

Participants are monitored for changes in amygdala activity and clinical symptoms after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amygdala Neurofeedback
• Parietal Neurofeedback

Trial Overview The study tests if neurofeedback using real-time fMRI can help patients with treatment-resistant depression by enhancing the amygdala's response to positive memories. It involves two types of neurofeedback: one targeting the parietal region and another focusing on the amygdala of the brain.

How Is the Trial Designed?

Group I: Amygdala Neurofeedback Experimental Treatment 1 Intervention

attempt to up regulate the left amygdala during positive autobiographical memory recall via real time fMRI neurofeedback from the amygdala. Five sessions will be performed within a 2 month period.

Group II: Parietal Neurofeedback Active Control 1 Intervention

attempt to upregulate the left horizontal segment of the intraparietal sulcus, a region not involved in emotional processing, during positive autobiographical memory recall via real time fMRI neurofeedback. Five sessions will be performed within a 2 month period.

Who Is Running the Clinical Trial?

Kymberly Young

Lead Sponsor

Trials

4

Recruited

440+

University of Pittsburgh

Lead Sponsor

Trials

1,820

Recruited

16,360,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The study demonstrated that healthy participants could effectively down-regulate activity in the right amygdala using real-time functional MRI (rtfMRI) neurofeedback while exposed to negative emotional stimuli, suggesting a potential method for emotion regulation.

This approach, which involved four training sessions with six participants, indicates that rtfMRI neurofeedback could be a promising tool for treating emotional disorders by targeting the overactive amygdala, which is often dysregulated in such conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-time neurofeedback using functional MRI could improve down-regulation of amygdala activity during emotional stimulation: a proof-of-concept study. Brühl, AB., Scherpiet, S., Sulzer, J., et al.[2021]

Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training targeting the left amygdala can reverse abnormal brain connectivity in individuals with major depressive disorder (MDD), leading to significant improvements in mood and depression severity.

The study found that the positive effects of rtfMRI-nf training are associated with increased connectivity between the amygdala and other brain regions, such as the hippocampus, suggesting that this approach may help rehabilitate emotion regulation in depressed individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resting-state functional connectivity modulation and sustained changes after real-time functional magnetic resonance imaging neurofeedback training in depression. Yuan, H., Young, KD., Phillips, R., et al.[2022]

Healthy individuals can learn to self-regulate the activity of the amygdala using real-time fMRI neurofeedback, leading to significant increases in blood oxygen level dependent (BOLD) signals during training.

This training not only enhances amygdala activation but also improves functional connectivity within a broader brain network, indicating potential therapeutic applications for neuropsychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-regulation of amygdala activation using real-time FMRI neurofeedback. Zotev, V., Krueger, F., Phillips, R., et al.[2021]

Real-time functional MRI neurofeedback (rtfMRI-nf) training has shown promise in helping individuals, both healthy and those with depression, to regulate brain activity in the amygdala, which may enhance positive memory recall.

While initial studies indicate that rtfMRI-nf could help alleviate symptoms of major depressive disorder, further research with larger participant groups is needed to confirm its effectiveness as a clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amygdala real-time functional magnetic resonance imaging neurofeedback for major depressive disorder: A review. Young, KD., Zotev, V., Phillips, R., et al.[2020]

Training patients with major depressive disorder to enhance their amygdalar responses to positive memories using real-time fMRI neurofeedback led to increased amygdalar activity when viewing happy faces and decreased activity for sad faces, indicating a shift in emotional processing.

The training also improved participants' ability to identify positive emotional stimuli and reduced their reaction times to positive faces, suggesting that this neurofeedback approach may have effects similar to those of antidepressant medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Time Functional Magnetic Resonance Imaging Amygdala Neurofeedback Changes Positive Information Processing in Major Depressive Disorder. Young, KD., Misaki, M., Harmer, CJ., et al.[2019]

In a study involving 10 individuals with a history of major depressive disorder (MDD) and 12 healthy controls, real-time fMRI neurofeedback (rtfMRI-nf) targeting the connectivity between the amygdala and prefrontal regions showed potential for enhancing emotional regulation, particularly in healthy individuals who exhibited increased frontal cortex activation during training.

Participants with a history of MDD demonstrated a trend towards decreased functional connectivity over the training runs, and while the overall group experienced a reduction in negative emotions, the MDD group specifically showed a significant decrease in positive emotions after the neurofeedback sessions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Connectivity based Real-Time fMRI Neurofeedback Training in Youth with a History of Major Depressive Disorder. He, X., Moreno, DR., Hou, Z., et al.[2023]

Real-time functional magnetic resonance imaging-based neurofeedback (rt-fMRI NF) is a promising technique for treating depression by training individuals to self-regulate brain areas like the amygdala, which is often overactive in response to negative stimuli.

Initial randomized controlled trials show promising results for rt-fMRI NF in improving emotional processing, but further research is needed to determine the best methods, target regions, and training durations for lasting clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Application of Real-Time fMRI-Based Neurofeedback for Depression. Mathiak, K., Keller, M.[2021]

In a study involving 35 adults with major depressive disorder, real-time fMRI neurofeedback (rtfMRI-nf) training to enhance amygdala responses during positive memory recall led to significant reductions in depressive symptoms and higher remission rates at 6 months and 1 year follow-up compared to a control group.

The combination of rtfMRI-nf and cognitive behavioral therapy (CBT) encouraged participants to focus more on positive thoughts and behaviors, suggesting that this approach may enhance the effectiveness of standard CBT in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced efficacy of CBT following augmentation with amygdala rtfMRI neurofeedback in depression. Compère, L., Siegle, GJ., Riley, E., et al.[2023]

Real-time fMRI neurofeedback (rtfMRI NF) allows individuals to voluntarily down-regulate the amygdala, which is linked to improved connectivity with the ventromedial prefrontal cortex (vmPFC) during emotional processing, as shown in a study with 16 healthy participants.

The study suggests that this increased connectivity may enhance emotion regulation, indicating that rtfMRI NF could be a promising tool for helping patients with severe emotion dysregulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

fMRI neurofeedback of amygdala response to aversive stimuli enhances prefrontal-limbic brain connectivity. Paret, C., Ruf, M., Gerchen, MF., et al.[2017]

In a study involving 48 healthy female participants, real-time functional MRI neurofeedback (rt-fMRI-NF) training showed that providing feedback on amygdala activation during exposure to aversive scenes can help improve the down-regulation of amygdala activity.

Participants who received amygdala feedback demonstrated a significant ability to down-regulate amygdala activation in a subsequent test without feedback, suggesting that this neurofeedback training may be beneficial for individuals with emotion dysregulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Down-regulation of amygdala activation with real-time fMRI neurofeedback in a healthy female sample. Paret, C., Kluetsch, R., Ruf, M., et al.[2021]

Citations

1. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/abs/10.1111/pcn.12665

Amygdala real‐time functional magnetic resonance ... In this review, we summarize the results of several studies that have developed and applied neurofeedback training to healthy and depressed ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29687527/

Amygdala real-time functional magnetic resonance imaging ... In this review, we summarize the results of several studies that have developed and applied neurofeedback training to healthy and depressed individuals with the ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0005796724000500

Amygdala real-time fMRI neurofeedback upregulation in ... Amygdala rtfMRI-nf was associated with reduced depressive symptomatology from the 3rd session to 12 weeks follow-up. •. Results suggest that two neurofeedback ...

4. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.2017.16060637

Randomized Clinical Trial of Real-Time fMRI Amygdala ... Conclusions: rtfMRI-nf training to increase the amygdala hemodynamic response to positive memories significantly decreased depressive symptoms ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02709161

Effects of Amygdala Neurofeedback on Depressive ... Real-time functional magnetic resonance imaging neurofeedback training of amygdala upregulation increases affective flexibility in depression. J Psychiatry ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28476207/

Real-Time Functional Magnetic Resonance Imaging ... This study tested whether amygdalar rtfMRI-nf also changes emotional processing of positive and negative stimuli in a variety of behavioral and imaging tasks.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0149763420306953

The efficacy of real-time functional magnetic resonance ... We present the first meta-analysis of rtfMRI-NF for psychiatric disorders, evaluating its impact on brain and behavioral outcomes.

8. bmcpsychiatry.biomedcentral.com bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-025-07000-1

A randomised controlled trial of amygdala fMRI ... Many original articles and meta-analyses show that fMRI-neurofeedback can improve psychiatric symptoms. In contrast, there is a lack of ...