Focused Ultrasound for Bipolar Disorder

Overseen By Darin Dougherty, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Massachusetts General Hospital

Disqualifiers: Neurological disorder, Psychosis, MRI contraindications, others

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

Compensation: Varies

Number of Visits: 8

Duration: 4 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

The specific aim of this proposed study is to investigate the feasibility and therapeutic potential of transcranial focused ultrasound (tFUS) as a treatment for bipolar disorder (BD). Specifically, the investigators will study the effects of amygdala tFUS on corticolimbic activation during an emotion regulation task in BD, the effects of amygdala tFUS on corticolimbic resting-state functional connectivity in BD, and explore the relationship between tFUS-associated changes in amygdala activity and mood symptoms. The investigators hypothesize that transcranial focused ultrasound (tFUS) of the amygdala will be associated with decreased amygdala activation and increased ventromedial prefrontal cortex activation during a modified version of the Multi-Source Interference Task (MSIT) paired with affective pictures from the International Affective Picture System (IAPS). The investigators also hypothesize that tFUS of the amygdala will be associated with increased resting-state functional connectivity between the amygdala and ventromedial prefrontal cortex. Finally, the investigators hypothesize that tFUS-associated reductions in amygdala activity could be positively correlated with reductions in depressive symptom scores and global improvement.

Do I have to stop taking my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Low-Intensity Focused Ultrasound of the Amygdala for Bipolar Disorder?

The research highlights that the amygdala plays a critical role in mood regulation and is often abnormal in individuals with bipolar disorder, suggesting that targeting the amygdala with focused ultrasound could potentially help in managing mood symptoms. ^{1 2 3 4 5}

Is focused ultrasound generally safe for humans?

Research shows that low-intensity focused ultrasound can safely be used on the brain without causing significant damage, as it can deliver small doses through the skull without major thermal injury. This technique has been tested in humans and animals, showing potential for safe use in treating neurological conditions. ^{6 7 8 9 10}

How does the treatment Low-Intensity Focused Ultrasound of the Amygdala differ from other treatments for bipolar disorder?

This treatment is unique because it uses focused ultrasound waves to target the amygdala, a brain region involved in emotion regulation, without the need for surgery or medication. Unlike traditional treatments that often involve drugs, this non-invasive approach aims to directly alter brain activity associated with mood regulation. ^{1 2 4 11 12}

Eligibility Criteria

This trial is for individuals with bipolar disorder. Participants should be able to undergo an emotion regulation task and have their brain activity monitored. Details on specific inclusion or exclusion criteria are not provided, but typically these would involve age, health status, and severity of bipolar disorder.

Inclusion Criteria

YMRS ≤ 12

I am between 18 and 64 years old.

BDI ≥ 14

Exclusion Criteria

Current psychosis symptoms

MRI scan contraindications (e.g., metal implant, claustrophobia, weigh over 250 pounds, etc.)

YMRS > 13

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Baseline Assessment

Participants complete clinical assessments and practice sessions of the MSIT task, undergo MRI scans, and receive initial tFUS sonication

1 week

1 visit (in-person)

Treatment

Participants receive tFUS sonication and complete clinical assessments over multiple visits

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for changes in mood symptoms and corticolimbic network connectivity

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Low-Intensity Focused Ultrasound of the Amygdala

Trial Overview The study is testing the use of a device called BrainSonix Pulsar 1002 to apply low-intensity focused ultrasound (tFUS) to the amygdala in the brain. The goal is to see if this can affect emotional regulation and improve mood symptoms in people with bipolar disorder.

Participant Groups

Group I: Active transcranial focused ultrasound (tFUS) Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

Children with pediatric bipolar disorder had significantly smaller overall brain sizes compared to healthy controls, suggesting potential structural differences associated with the disorder.

However, the study found no significant differences in the volumes of key brain regions like the amygdala, thalamus, or hippocampus among the pediatric bipolar disorder group, risk group, and healthy controls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative analysis of the amygdala, thalamus and hippocampus on magnetic resonance images in paediatric bipolar disorders and compared with the children of bipolar parents and healthy control. Akbaş, S., Nahir, M., Pirzirenli, ME., et al.[2018]

Unmedicated bipolar disorder (BD) patients showed significantly smaller amygdala volumes compared to healthy controls, suggesting a potential structural brain difference associated with the disorder.

Medicated BD patients (treated with lithium or divalproex) exhibited larger amygdala volumes than unmedicated patients, indicating that mood stabilizing medications may promote neuroplastic changes in the amygdala.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication. Savitz, J., Nugent, AC., Bogers, W., et al.[2021]

In a study of 54 bipolar disorder patients and 41 healthy controls, it was found that bipolar patients experienced a reduction in amygdala volume as they aged, while healthy controls did not show this change.

The findings suggest that dysfunction in the amygdala may play a significant role in bipolar disorder, particularly in older patients, potentially contributing to mood regulation issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-dependent reduction of amygdala volume in bipolar disorder. Doty, TJ., Payne, ME., Steffens, DC., et al.[2021]

Youths with bipolar disorder showed significantly smaller hippocampal volumes compared to healthy peers, particularly among female participants, suggesting a potential link between hippocampal abnormalities and the disorder's pathophysiology.

Both male and female youths with bipolar disorder also exhibited reduced overall cerebral volumes, indicating broader brain structural changes associated with the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Frazier, JA., Chiu, S., Breeze, JL., et al.[2022]

Individuals diagnosed with bipolar spectrum disorders (BSD) have larger overall amygdala volumes compared to those at low risk for the disorder, indicating a potential biomarker for BSD.

Examining specific amygdala subnuclei revealed that those with BSD had larger volumes in certain subnuclei compared to high-risk individuals, suggesting that these subnuclei may play a critical role in the disorder's development and progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amygdala subnuclei volume in bipolar spectrum disorders: Insights from diffusion-based subsegmentation and a high-risk design. Damme, KSF., Alloy, LB., Young, CB., et al.[2021]

A wearable low-intensity pulsed ultrasound (LIPUS) device was developed and tested, showing it can safely deliver ultrasound to the brain without causing significant thermal injury.

The study suggests that LIPUS has potential as a safe transcranial treatment for neurological diseases, which could help alleviate symptoms of mental illnesses like depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of a Wearable Low-Intensity Pulsed Ultrasound Device for Relieving Mental Illness Symptoms. Qi, S., Chen, J.[2020]

Focused ultrasound ablation (FUSA) of the anterior nucleus of the thalamus (ANT) is a promising treatment for patients with treatment-refractory epilepsy, showing significant reduction in seizure frequency in a pilot study of two adult subjects.

The procedure was well-tolerated with no serious adverse events, although one patient experienced a decline in certain cognitive functions, highlighting the need for careful monitoring of potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 open-label trial evaluating focused ultrasound unilateral anterior thalamotomy for focal onset epilepsy. Krishna, V., Mindel, J., Sammartino, F., et al.[2023]

Transcranial focused ultrasound technology can temporarily and reversibly disrupt the blood-brain barrier in a highly controlled, noninvasive manner, which is promising for delivering therapies to treat neurological and psychiatric conditions.

This technique is being studied in both nonhuman primates and humans, indicating its potential for clinical applications, as it may allow for the transfer of therapeutic agents across the blood-brain barrier to modulate brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Potentials of Localized Blood-Brain Barrier Disruption by Noninvasive Transcranial Focused Ultrasound: A Technical Review. Cammalleri, A., Croce, P., Lee, W., et al.[2022]

In a study involving 36 patients with essential tremor, the accumulated thermal dose (ATD) during MR-guided focused ultrasound (MRgFUS) thalamotomy was found to correlate with the size of brain lesions, helping to predict treatment outcomes.

The optimal ATD values for predicting lesion size were identified as 100 and 200 cumulative equivalent minutes at 43°C, providing valuable insights for determining effective treatment endpoints in future MRgFUS procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting lesion size by accumulated thermal dose in MR-guided focused ultrasound for essential tremor. Huang, Y., Lipsman, N., Schwartz, ML., et al.[2019]

MR-guided focused ultrasound (MRgFUS) shows promise in treating neuropsychiatric disorders like obsessive-compulsive disorder (OCD) and depression, with preliminary studies indicating improvements in symptoms, although more rigorous trials are needed.

Low-intensity MRgFUS may help open the blood-brain barrier and modulate brain activity, but current evidence is limited, necessitating further comparative studies to evaluate its effectiveness against other treatment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incisionless MR-guided focused ultrasound: technical considerations and current therapeutic approaches in psychiatric disorders. Kinfe, T., Stadlbauer, A., Winder, K., et al.[2021]

In a study of 16 adolescents and young adults with bipolar disorder compared to 21 healthy controls, there was a trend indicating smaller left amygdala volumes in bipolar patients, suggesting potential neurodevelopmental abnormalities associated with the disorder.

The study found a unique correlation in bipolar patients where left amygdala volume increased with age, contrasting with healthy controls who showed a decrease, indicating that bipolar disorder may involve atypical brain development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Chen, BK., Sassi, R., Axelson, D., et al.[2007]

Children and adolescents with bipolar disorder have smaller amygdala volumes compared to their peers without the disorder, indicating potential structural abnormalities associated with mood dysregulation.

In contrast, adults with bipolar disorder do not show significant differences in amygdala size compared to control adults, suggesting that these structural changes may be more pronounced in younger populations and could serve as biomarkers for the illness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder. Pfeifer, JC., Welge, J., Strakowski, SM., et al.[2008]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Quantitative analysis of the amygdala, thalamus and hippocampus on magnetic resonance images in paediatric bipolar disorders and compared with the children of bipolar parents and healthy control. [2018]

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

Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication. [2021]

3. Ireland pubmed.ncbi.nlm.nih.gov

Age-dependent reduction of amygdala volume in bipolar disorder. [2021]

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

Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. [2022]

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

Amygdala subnuclei volume in bipolar spectrum disorders: Insights from diffusion-based subsegmentation and a high-risk design. [2021]

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

Safety Assessment of a Wearable Low-Intensity Pulsed Ultrasound Device for Relieving Mental Illness Symptoms. [2020]

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

A phase 1 open-label trial evaluating focused ultrasound unilateral anterior thalamotomy for focal onset epilepsy. [2023]

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

Therapeutic Potentials of Localized Blood-Brain Barrier Disruption by Noninvasive Transcranial Focused Ultrasound: A Technical Review. [2022]

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

Predicting lesion size by accumulated thermal dose in MR-guided focused ultrasound for essential tremor. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Incisionless MR-guided focused ultrasound: technical considerations and current therapeutic approaches in psychiatric disorders. [2021]

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

Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. [2007]

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

Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder. [2008]