Brain Study for Irritability

Overseen By Zheng Li, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Psychoactive medications

Disqualifiers: Serious medical condition, Psychiatric diagnosis, Pregnancy, Night shifts, others

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

Compensation: Varies

Number of Visits: 3

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Irritability can be defined as an unusually strong response to frustration; these responses may include severe temper outbursts and a constant grumpy mood. Irritability is a common symptom of many mental health disorders. Little is known about how the brain responds to frustration, and few treatments are available for this problem. Researchers want to know more about how the brain responds to frustration. Objective: To learn how the brain responds to frustration. Eligibility: Healthy adults aged 18 to 55 years. They must have been screened through studies 01-M-0254 or 17-M-0181. Design: Participants will have up to 3 study visits in 2 months. Each visit will last up to 4 hours. Visit 1: Participants will be screened. They will have a physical exam. They will complete questionnaires about how often and how easily they get angry or grumpy. They will be trained to use a device that measures hand grip. Visit 2: Participants will have a magnetic resonance imaging (MRI) scan. They will lie on a table that slides into a tube. Padding will hold their head still. Visit 3: Participants will undergo magnetoencephalography (MEG). A cone with detectors will be lowered over their head while they are seated. The MEG will measure the magnetic fields in the participant s brain both while they are resting and while they are doing the frustration task. For the task, they will hold a grip device in each hand. They will use the devices to pick 1 of 2 doors on a computer screen. The task has 3 parts. The participant s face will be filmed during this task....

Will I have to stop taking my current medications?

The trial requires that participants do not take any prescription or over-the-counter medications and dietary supplements with psychoactive properties (substances that affect the mind, such as St. John's Wort, Melatonin, or Valerian).

What data supports the effectiveness of the Frustration Task treatment for irritability?

Research shows that frustration tasks can effectively measure and predict irritability by examining how frustration affects brain activity and behavior. These tasks have been used to identify neural patterns and connectivity changes associated with irritability, suggesting they could be useful in understanding and potentially treating irritability. ^{1 2 3 4 5}

Is the Frustration Task safe for humans?

The studies reviewed do not provide specific safety data for the Frustration Task, but they do not report any adverse effects, suggesting it is generally safe for use in research settings. ^{1 3 5 6 7}

How does this treatment for irritability differ from other treatments?

This treatment is unique because it focuses on understanding and predicting irritability through brain connectivity during frustration, rather than directly targeting symptoms with medication. It uses advanced imaging techniques to identify neural patterns associated with irritability, which could lead to more personalized and effective interventions. ^{1 2 3 4 8}

Research Team

Zheng Li, Ph.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Healthy adults aged 18 to 55 who have been previously screened through specific studies. Participants will undergo a physical exam and answer questionnaires about their mood and anger. They must be able to commit to up to three visits over two months, each lasting up to four hours.

Inclusion Criteria

Can give consent

Speak and read English

I am between 18 and 55 years old and in good health.

Exclusion Criteria

I don't have conditions that affect MRI or MEG scans.

Any current psychiatric diagnosis

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

MRI Scan

Participants will have a magnetic resonance imaging (MRI) scan to study brain mechanisms underlying frustration

1 visit

1 visit (in-person)

MEG and Frustration Task

Participants undergo magnetoencephalography (MEG) and perform a frustration task to measure brain responses

1 visit

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the MEG and frustration task

2 months

Treatment Details

Interventions

• Frustration Task

Trial Overview The study aims to understand how the brain reacts when people feel frustrated. It involves an MRI scan, magnetoencephalography (MEG), and a frustration task using hand grip devices during the third visit, with participants' facial reactions being recorded.

Participant Groups

Group I: Frustration task Experimental Treatment 1 Intervention

The experimental manipulation for this study is the frustration task. The frustration task is designed to elicit the emotional state of frustrative non-reward (FNR). During the task, participants are asked to use button press (left or right) to alternately press one of the two doors displayed on the monitor. The task has two non-frustration blocks (Block 1 and 2) and one frustration block (Block 3). During the non-frustration blocks, participants earn money for correct press on a fixed schedule. During the frustrative block, participants will not always receive reward for correct press.

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a preliminary fMRI study of 69 youths, functional connectivity during frustrating tasks was found to predict levels of irritability, suggesting a neural basis for this emotional response.

The study identified specific brain networks, particularly within motor-sensory and salience networks, that are associated with irritability during experiences of frustration, highlighting the importance of these networks in understanding irritability across various pediatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth. Scheinost, D., Dadashkarimi, J., Finn, ES., et al.[2023]

This preliminary study involving 31 non-White adolescents identified specific neural patterns associated with irritability, particularly changes in amygdala connectivity with other brain regions during a frustrative nonreward task.

The findings suggest that irritability is linked to difficulties in recovering from frustration, highlighting the amygdala's role in this process and pointing to potential new treatment targets for managing irritability in diverse youth populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irritability-related neural responses to frustrative nonreward in adolescents with trauma histories: A preliminary investigation. Hodgdon, EA., Yu, Q., Kryza-Lacombe, M., et al.[2022]

The study validated a new behavioral frustration task, the Frustration Go/No-Go (GNG) task, for assessing cognitive control in children aged 8-12, including those with ADHD and typically developing peers, highlighting its effectiveness in measuring irritability-related responses.

Results indicated that self-reported irritability was a stronger predictor of frustration during the task than ADHD symptoms, suggesting that irritability significantly impacts cognitive control and may be a key focus for interventions in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Validity of a Frustration Paradigm to Assess the Effect of Frustration on Cognitive Control in School-Age Children. Seymour, KE., Rosch, KS., Tiedemann, A., et al.[2021]

Children aged 6-9 with extreme irritability showed increased brain activation in areas related to reward processing but decreased activation during frustration compared to healthy peers, indicating a potential neural dysfunction in emotion regulation.

The study found a correlation between parent-reported irritability and reduced activation in the anterior cingulate and striatum during frustration, suggesting that these brain regions may play a critical role in understanding and diagnosing irritability in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neural substrates of child irritability in typically developing and psychiatric populations. Perlman, SB., Jones, BM., Wakschlag, LS., et al.[2020]

The study involving 58 young adult females found that higher levels of trait irritability were linked to reduced brain response (smaller FRN amplitudes) to loss feedback, suggesting a connection between irritability and how individuals process frustration.

Similar to findings in children, the frustration manipulation in this study led to increased self-reported frustration and decreased task performance, indicating that irritability may affect attention and emotional responses in adults as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reward processing and irritability in young adults. Deveney, CM.[2019]

In a study involving 39 males with high and low trait aggression, those with high aggression reported greater negative emotions and anger after experiencing frustration, despite similar task performance.

fMRI results showed that individuals with high trait aggression had reduced activation in key brain areas, such as the frontal regions and the dorsal anterior cingulate cortex, suggesting distinct neural processing patterns related to frustration that may be linked to aggressive behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anger under control: neural correlates of frustration as a function of trait aggression. Pawliczek, CM., Derntl, B., Kellermann, T., et al.[2021]

In a study using functional near infrared spectroscopy (fNIRS) with 3-5-year-old children, increased activity in the lateral prefrontal cortex was observed during moments of frustration, suggesting its role in emotional regulation.

The level of activation in the lateral prefrontal cortex during frustration was positively correlated with parent-reported frustration tolerance, indicating that this brain region may help children manage their emotional responses to frustrating situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

fNIRS evidence of prefrontal regulation of frustration in early childhood. Perlman, SB., Luna, B., Hein, TC., et al.[2021]

Irritability in children is a significant symptom of psychopathology that requires more systematic assessment and understanding, particularly in differentiating between normative and pathological irritability.

The paper suggests that subtyping irritability and using specific behavioral paradigms can enhance research on its causes and effects, while also highlighting the need for better measurement scales for irritability severity in children with mood and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irritability in pediatric mania and other childhood psychopathology. Leibenluft, E., Blair, RJ., Charney, DS., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Irritability-related neural responses to frustrative nonreward in adolescents with trauma histories: A preliminary investigation. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The Validity of a Frustration Paradigm to Assess the Effect of Frustration on Cognitive Control in School-Age Children. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Neural substrates of child irritability in typically developing and psychiatric populations. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Reward processing and irritability in young adults. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Anger under control: neural correlates of frustration as a function of trait aggression. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

fNIRS evidence of prefrontal regulation of frustration in early childhood. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Irritability in pediatric mania and other childhood psychopathology. [2019]