Brain Study for Irritability

Recruiting at 1 trial location

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

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the brain reacts to frustration, as irritability is a common symptom in many mental health issues. Participants will engage in a "frustration task," performing an activity designed to evoke feelings of frustration. The study involves several visits, including brain scans like MRI and MEG to track brain activity. Healthy adults who have been screened in certain NIH studies and can speak and read English are eligible to participate. As an Early Phase 1 trial, this research focuses on understanding how the brain processes frustration, offering participants a unique opportunity to contribute to foundational mental health research.

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 prior data suggests that this frustration task is safe for participants?

Previous research lacks specific safety information for the Frustration Task, but these studies did not report any negative effects. The task is designed to induce frustration without causing harm. Participants press buttons to open doors on a screen, sometimes receiving rewards and sometimes not. This method is a standard way to study responses to frustration.

As this trial is in an early phase, researchers closely monitor safety. Early trials prioritize participant safety. So far, no harm from the task itself has been reported. However, as this is an early study, researchers continue to learn about any potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a unique approach to managing irritability through a psychological technique called the frustration task. Unlike traditional treatments for irritability, which might involve medication or behavioral therapy, this task directly engages participants in a controlled situation designed to provoke and study frustrative non-reward (FNR). By immersing participants in a scenario where they experience frustration in a safe and structured environment, researchers hope to better understand the emotional and neurological responses involved. This could lead to insights that improve how we address irritability, potentially offering new therapeutic avenues beyond conventional methods.

What evidence suggests that the frustration task is effective for studying irritability?

Research has shown that the frustration task, which participants in this trial will undergo, effectively induces frustration, aiding in the study of irritability. Studies have found that people feel more frustrated during certain parts of the task, proving it can accurately measure emotional responses. The task has been confirmed as a way to observe how frustration affects cognitive control, which refers to how well the brain manages tasks and emotions. Another study found that frustration can lead to increased movement and aggression, similar to irritability symptoms. These findings suggest that the task is a useful tool for understanding how the brain reacts to frustration, potentially aiding in the development of better treatments for irritability in the future. ^{6 7 8 9 10}

Who Is on the Research Team?

Zheng Li, Ph.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Are You a Good Fit for This Trial?

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

Any current psychiatric diagnosis

Pregnancy

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11450524/

Frustrative Nonreward: Behavior, Circuits, Neurochemistry ... Frustration affects motivation in many circumstances, and, since SUDs are often a function of unchecked motivation, FNR should be a component of ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7523008/

The Validity of a Frustration Paradigm to Assess the Effect ... These results support the construct validity of the Frustration GNG task as a means of assessing the effect of frustration on cognitive control.

3. nature.com nature.com/articles/s41386-020-00954-8

Functional connectivity during frustration: a preliminary ... Overall, participants reported feeling more frustrated during frustration than nonfrustration blocks, supporting the task's validity as a ...

4. bpsgos.org bpsgos.org/article/S2667-1743(23)00137-4/fulltext

A New Behavioral Paradigm for Frustrative Nonreward in ... Results. FNR increased locomotion and aggression regardless of sex. These behavioral changes elicited by FNR resemble the symptoms observed in ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2667174324001332

Neural Correlates of Irritability and Potential Moderating ... During frustration-inducing tasks, irritable adolescents (10–15 years old) (13,14) performed slower than their TD peers (e.g., reaction time during loss trials) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10002733/

A New Behavioral Paradigm for Frustrative Non-reward ... It is noted that APRO has more selective behavioral effects than frustration induced by extinction tasks that completely omit reward (44).

7. sciencedirect.com sciencedirect.com/science/article/pii/S0890856722012278

Task-based fMRI Studies in Youths With Irritability Most evidence for the reward processing pathway was grounded in frustrative nonreward, a negative valence construct in the Research Domain Criteria (RDoC) ...

8. link.springer.com link.springer.com/article/10.1007/s00787-024-02591-8

Understanding irritability through the lens of self-regulatory ... Irritability refers to a specific form of emotional and behavioural dysregulation. While anger is a normative response to frustrative non-reward ...

9. withpower.com withpower.com/trial/early-phase-1-irritability-8-2024-2e87c

Brain Study for Irritability · Recruiting Participants for Phase ... 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 ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4628903/

How does Reactivity to Frustrative Non-Reward Increase ... Disproportionate increases in arousal in response to frustration may exceed normal regulatory capacity, thus precipitating aggressive or antisocial responses.