Depressive Disorder, Major
Conditions
Brief summary
In this project, the investigators use real-time fMRI neurofeedback (rtfMRI-nf) to causally relate dysfunction of right anterior insula (rAI) and right superior temporal sulcus (rSTS) connectivity with the intensity of repetitive negative thinking (RNT). The investigators hypothesize that rtfMRI-nf reducing rAI-rSTS connectivity would reduce RNT. The investigators propose a randomized double-blind, sham-controlled trial of rtfMRI-nf with 110 young adults (n=55/arm) with major depressive disorder (MDD) and high trait-RNT levels.
Detailed description
Young adult mental health is crucial, as 1 in 10 young adults (ages 18-25) suffer from major depressive disorder (MDD), impacting long-term outcomes such as comorbid mental disorders, unemployment and suicide . With increasing rates of MDD among young adults, new explanatory disease models focusing on targetable disease-modifying processes (DMPs) are needed. Repetitive negative thinking (RNT) is a key DMP in MDD, involving difficulty controlling distressing thoughts and past events , and predicting depression severity and suicidal ideation/attempts in early adulthood. Current treatments, such as medication and psychotherapy including cognitive-behavioral therapy (CBT), often have limited effectiveness for MDD, with higher levels of RNT associated with slower and poorer response rates. In theory, novel treatments designed to modify the neurobiological mechanisms underlying RNT could facilitate recovery in MDD. Real-time functional Magnetic Resonance Imaging neurofeedback (rtfMRI-nf) is a non-invasive method, providing individuals with feedback concerning their brain activity in order to facilitate one's self-control. Our preliminary studies identified a circuit with stronger connectivity between the right anterior insular (rAI, emotional salience processing hub) and the right superior temporal sulcus (rSTS, episodic memory/language processing area), correlating with the severity of RNT apart from depression. This finding aligns with the framework that views RNT as heightened evaluative and dialogic inner speech, resulting from an inability to disengage from self-critical and threatening interpretations of episodic memories. The investigators propose that excessive functional connectivity between the rAI and STS may contribute to RNT in young adults with MDD. This project is a research project at the Laureate Institute for Brain Research (LIBR). In this project, the investigators use rtfMRI-nf to causally relate dysfunction of rAI-rSTS connectivity with the intensity of RNT. The investigators hypothesize that rtfMRI-nf reducing rAI-rSTS connectivity would reduce RNT. The investigators propose a randomized double-blind, sham-controlled trial of rtfMRI-nf with 110 young adults (n=55/arm) with MDD and high trait-RNT levels. Primary outcome will be active vs. sham rtfMRI-nf's effect on rAI-rSTS connectivity. Secondary outcomes will be active vs. sham rtfMRI-nf's effect on state-RNT (Brief State Rumination Inventory, BSRI) and depression severity (Montgomery-Asberg Depression Rating Scale, MADRS). Exploratory outcomes will be the relationship between reducing rAI-rSTS connectivity and BSRI scores. Participants will perform a self-regulation task involving neurofeedback, receiving either real-time feedback on rAI-rSTS connectivity (active group) or artificial feedback unrelated to rAI-rSTS connectivity (sham group). The investigators will collect data across two visits, one week apart. The first visit will include five runs of the self-regulation task, the middle three containing the neurofeedback condition (Visit 1). The second visit will include one run of the self-regulation task without the neurofeedback condition 1-week later (Visit 2).
Interventions
BEHAVIORALActive neurofeedback
The session will be done on an individual basis. The active group will receive neurofeedback training from the repetitive negative thinking (RNT) related brain functional connectivity.
BEHAVIORALSham neurofeedback
The session will be done on an individual basis. The sham group will receive neurofeedback training from an artificially generated random feedback signal.
Sponsors
Laureate Institute for Brain Research, Inc.
National Institute of General Medical Sciences (NIGMS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Young adults ages 18-35 * Participants who are able to give written informed consent prior to participation * Meeting DSM-5 diagnostic criteria for MDD who are currently depressed defined by the MINI * Participants who have RNT symptoms (Brooding subscale of Ruminative Response Scale: RRS-B ≥ 13)
Exclusion criteria
* Moderate to severe traumatic brain injury (\>30 min. loss of consciousness or \>24 hours posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological deficits * Presence of co-morbid medical conditions not limited to but including cardiovascular (e.g., history of acute coronary event, stroke), pulmonary, endocrine, neurological diseases (e.g., Parkinson's disease), or gastrointestinal illness, as well as pain disorders * Current significant suicidal ideation or suicide attempt within the previous 12 months * Current psychosis * Schizophrenia or schizoaffective disorder * Substance use disorder within the previous 12 months, except for mild alcohol, cannabis, or tobacco use disorder defined as less than 4 symptoms of the criteria for substance use disorder according to the MINI * Current diagnosis of post-traumatic disorder (PTSD) defined by the MINI * Severe claustrophobia * Bodily implants of unsafe paramagnetic materials such as pacemakers and aneurysm clips * Pregnancy * Current regular use of cardiovascular medications with a direct vasomotor effect, namely beta- or alpha-beta-blockers, clonidine, and antianginal agents. * Current use of more than three psychotropic medications * Evidence of recreational drug use from a urine test * Commencement of psychotropic medication for depression and/or anxiety less than a month before the study enrollment * Commencement of psychological therapy less than a month before the study enrollment * Participants who have a clinically significant or unstable cardiovascular, pulmonary, endocrine, neurological, gastrointestinal illness or unstable medical disorder will be excluded * Participants who, on arrival to the study, have a temperature greater than 100.4°F will not be allowed to initiate the study * The majority of the assessments proposed for this study have not been translated from English, thus, non-English speaking volunteers will be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Connectivity Change Between Right Anterior Insular (rAI) and Right Superior Temporal Sulcus (rSTS) Within Visit1 | Immediately post-intervention during Visit 1 (day 1) | Functional connectivity between rAI and rSTS was assessed using psychophysiological interaction (PPI) analysis of fMRI BOLD signal. Beta-values derived from PPI analysis represent the strength of connectivity; higher positive values indicate stronger functional coupling between regions. Change scores were calculated as post-intervention beta-value minus pre-intervention beta-value within Visit 1. A negative value indicates reduced connectivity following neurofeedback. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Brief State Rumination Inventory (BSRI) Total Score From Pre- to Post-Intervention at Visit 1 | From baseline (pre-scan at Visit 1, Day 1) to immediately after neurofeedback intervention (post-scan at Visit 1, Day 1) | The BSRI is a self-report scale to measure state rumination. A higher score indicates higher state rumination with a maximum score of 800 and the minimum score of 0. Change scores were calculated as post-intervention score minus pre-intervention score at Visit 1. A negative change score indicates reduction in state rumination. |
| Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Follow-up | From baseline at Visit 1 (Day 1) to follow-up at Visit 2 (1 week after Visit 1) | The MADRS is an interviewer-rated scale to measure the severity of depressive symptoms. A higher score indicates severer depression with a maximum score of 60 and a minimum score of 0. Change scores were calculated as Visit 2 score minus Visit 1 score. A negative change score indicates improvement in depressive symptoms. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Tulsa metropolitan area through the Laureate Institute for Brain Research (LIBR). Recruitment methods included outreach by the LIBR clinical team, as well as newspaper, flyers, radio, and Facebook advertisements. The study targeted young adults (ages 18-35) with Major Depressive Disorder. Recruitment began in January 2024 and was terminated prematurely due to the Principal Investigator's departure.
Pre-assignment details
A total of 54 participants signed the informed consent form, but only 42 were randomized and assigned to study arms. The remaining 12 participants were excluded prior to group assignment due to screening failures (e.g., exclusionary psychiatric diagnoses, positive drug tests, pregnancy), loss to follow-up, or voluntary withdrawal before the first visit.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 27.3 years old STANDARD_DEVIATION 4.9 |
| Brief State Rumination Inventory (BSRI) Total Score at Baseline | 455.05 score STANDARD_DEVIATION 201.94 |
| Functional Connectivity between rAI and rSTS at baseline | 0.3170 beta-values STANDARD_DEVIATION 0.5142 |
| Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Baseline | 16.84 score STANDARD_DEVIATION 7.73 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 |
| other Total, other adverse events | 0 / 22 | 0 / 20 |
| serious Total, serious adverse events | 0 / 22 | 0 / 20 |
Outcome results
None listed