Focused Ultrasound for Tobacco Use Disorder

(LIFU_TUD Trial)

Overseen By Evan Lindeman, BS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Washington D.C. Veterans Affairs Medical Center

Must not be taking: Psychotropics, Antibiotics, Antihistamines, others

Disqualifiers: Head injury, Seizures, Neurologic disorders, others

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

Compensation: Varies

Number of Visits: 2

Duration: 1 session each for LIFU and sham

44 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you will need to stop taking any psychotropic medications (like antidepressants, anxiolytics, and antipsychotics) and any other medications that can affect brain activity, such as certain antibiotics, antihistamines, or muscle relaxants.

What data supports the effectiveness of the treatment Low Intensity Focused Ultrasound (LIFU) for tobacco use disorder?

Research suggests that non-invasive brain stimulation (NIBS), which includes techniques like LIFU, shows promise in treating tobacco use disorder by reducing cravings and improving cognitive functions. Studies indicate that NIBS could be a potential intervention for smoking cessation by influencing brain activity related to smoking behavior. ^{1 2 3 4 5}

Is Low Intensity Focused Ultrasound (LIFU) safe for humans?

A study on Low Intensity Focused Ultrasound (LIFU) targeting the brain area called the nucleus accumbens in people with substance use disorders found it to be safe and feasible, suggesting it may be safe for humans. ^{1 2 3 6 7}

How is Low Intensity Focused Ultrasound (LIFU) different from other treatments for tobacco use disorder?

Low Intensity Focused Ultrasound (LIFU) is a non-invasive brain stimulation technique that targets specific brain areas to reduce cravings and improve cognitive functions, unlike traditional treatments like nicotine-replacement therapies or medications that work by altering neurotransmitter systems. This approach is unique because it directly influences brain activity without the need for drugs. ^{1 2 3 5 8}

What is the purpose of this trial?

The goal of this clinical trial is to to inhibit the dorsal anterior insula (dAI) with low intensity focused ultrasound (LIFU) to determine the causal role for the dAI in smoking cue induced craving in individuals with tobacco use disorder (TUD); smoking cue induced craving is a clinically important behavior which has been associated with the severity of nicotine addiction. The main question\[s\] it aims to answer are: * the safety and tolerability of dAI LIFU compared to sham stimulation in individuals with TUD * the effects of LIFU vs sham to left dAI functional magnetic resonance imaging (fMRI) BOLD activity and craving in response to smoking cue exposure. Participants will undergo anatomical MRI, neurological assessment, clinical assessment and patient query to assess the safety and tolerability of LIFU vs sham. Participants will undergo functional magnetic resonance imaging where we will measure the effect of LIFU vs sham on 1) dAI blood-oxygen-level-dependent (BOLD) activation in response to smoking (compared to neutral) cue exposure and 2) cue-induced craving in individuals with TUD. Each participant will receive LIFU and sham stimulation.

Research Team

Mary R Lee, MD

Principal Investigator

Veterans Affairs Medical Center, Washington DC

Eligibility Criteria

This trial is for individuals with Tobacco Use Disorder who want to explore a new treatment. Participants must be able to undergo MRI scans and neurological assessments. The study excludes those with certain medical conditions or metal implants that could interfere with MRI, pregnant women, and people unable to give informed consent.

Inclusion Criteria

I am a veteran between 18 and 65 years old.

Meet the DSM-5 criteria for current Tobacco Use Disorder (moderate to severe) as diagnosed by the Structured Clinical Interview for DSM-5

I currently smoke more than 10 cigarettes daily without quitting for more than 3 months in the past year.

Exclusion Criteria

Not under current treatment for smoking cessation

Ferromagnetic implants or other contraindications for MRI

I have no history of major brain or neurological conditions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LIFU and sham stimulation to assess the effects on dAI BOLD activity and craving in response to smoking cues

1 session each for LIFU and sham

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 hour post each session

Treatment Details

Interventions

• Low Intensity Focused Ultrasound

Trial Overview The trial tests if low intensity focused ultrasound (LIFU) can reduce cravings in smokers by targeting a brain area called the dorsal anterior insula. It compares LIFU's effects on brain activity and craving responses against sham (fake) treatments using functional magnetic resonance imaging (fMRI).

Participant Groups

Group I: Sham/LIFU Experimental Treatment 1 Intervention

double-blind, sham-controlled, crossover study in N=44 individuals with Tobacco Use Disorder

Group II: LIFU/Sham Experimental Treatment 1 Intervention

double-blind, sham-controlled, crossover study in N=44 individuals with Tobacco Use Disorder

Who Is Running the Clinical Trial?

Washington D.C. Veterans Affairs Medical Center

Lead Sponsor

Trials

45

Recruited

18,500+

Findings from Research

Non-invasive brain stimulation (NIBS) methods, particularly repetitive transcranial magnetic stimulation (rTMS), have shown a significant increase in sustained smoking abstinence rates, with a risk ratio of 2.39 compared to sham treatments, based on a meta-analysis of 7 studies involving 699 participants.

The effectiveness of NIBS was even greater when targeting specific brain areas, such as the left dorsolateral prefrontal cortex, with a risk ratio of 4.34, indicating that certain stimulation techniques may enhance the likelihood of long-term smoking cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive brain stimulation for smoking cessation: a systematic review and meta-analysis. Petit, B., Dornier, A., Meille, V., et al.[2023]

A systematic review of 26 randomized sham-controlled trials suggests that non-invasive brain stimulation (NIBS) may effectively reduce cravings and improve cognitive functions in patients with alcohol and tobacco use disorders.

NIBS shows promise as a new treatment approach for substance use disorders, indicating its potential therapeutic effects in managing addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of Non-Invasive Brain Stimulation in Substance Use Disorders: A Review of Randomized Sham-Controlled Clinical Trials. Trojak, B., Sauvaget, A., Fecteau, S., et al.[2018]

Cigarette smoking is the leading preventable cause of death globally, with nearly 4 million deaths each year, highlighting the urgent need for effective smoking cessation treatments.

Current smoking cessation medications often fail for many smokers, prompting research into new treatments targeting various neurotransmitter systems involved in nicotine dependence, which could help those who struggle to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current pharmacological treatments for nicotine dependence. George, TP., O'Malley, SS.[2015]

Nicotine intake positively affects cortical excitability and plasticity in deprived smokers, but this effect is reversed in non-smokers, indicating that smoking status influences how nicotine impacts brain activity.

Non-invasive brain stimulation (NIBS) shows promise as a potential intervention for smoking cessation, suggesting that modifying cortical excitability could help change smoking behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The two-way relationship between nicotine and cortical activity: a systematic review of neurobiological and treatment aspects. de Miquel, C., Pross, B., Papazova, I., et al.[2022]

Nicotine positively affects attention and mood by altering regional cerebral blood flow (rCBF) in specific brain areas, such as decreasing activity in the anterior cingulate cortex and cerebellum while increasing it in the occipital cortex.

These effects were consistent in both smokers and non-smokers, suggesting that nicotine's impact on cognitive function is related to its influence on brain activity, which may explain the cognitive impairments and irritability experienced during nicotine withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral effects of nicotine during cognition in smokers and non-smokers. Ghatan, PH., Ingvar, M., Eriksson, L., et al.[2022]

Low Intensity Focused Ultrasound (LIFU) targeting the nucleus accumbens was found to be safe and well-tolerated in a pilot study with four participants undergoing treatment for opioid use disorder, showing no adverse structural changes in MRI scans.

Participants receiving the higher dose of LIFU (90 W) experienced significant reductions in craving for their primary substances, with effects lasting up to 90 days post-treatment, indicating potential for LIFU as a novel intervention for substance use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial. Mahoney, JJ., Haut, MW., Carpenter, J., et al.[2023]

Deep brain stimulation (DBS) targeting the nucleus accumbens (NAc) in six patients with severe alcohol use disorder (AUD) led to significant reductions in cravings, alcohol consumption, and alcohol-related compulsivity over 12 months, demonstrating its potential as a safe and effective treatment.

Improvements in compulsive drinking behaviors were linked to reduced glucose metabolism in the NAc and decreased functional connectivity between the NAc and the visual association cortex, suggesting a mechanism by which NAc-DBS may help mitigate the effects of alcohol-related cues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial. Davidson, B., Giacobbe, P., George, TP., et al.[2023]

Chronic smokers exhibit significant changes in brain activity during resting state, with increased activity in areas related to addiction and decreased activity in regions associated with memory and smoking sensations, as shown by fMRI in a study of 20 smokers and 19 nonsmokers.

The study found that both the amount of nicotine consumed and the severity of nicotine dependence correlate with these changes in brain activity, indicating a neurobiological mechanism underlying smoking addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spontaneous brain activity in chronic smokers revealed by fractional amplitude of low frequency fluctuation analysis: a resting state functional magnetic resonance imaging study. Chu, S., Xiao, D., Wang, S., et al.[2014]

References

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

Non-invasive brain stimulation for smoking cessation: a systematic review and meta-analysis. [2023]

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

Outcome of Non-Invasive Brain Stimulation in Substance Use Disorders: A Review of Randomized Sham-Controlled Clinical Trials. [2018]

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

Current pharmacological treatments for nicotine dependence. [2015]

4. Germany pubmed.ncbi.nlm.nih.gov

The two-way relationship between nicotine and cortical activity: a systematic review of neurobiological and treatment aspects. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Cerebral effects of nicotine during cognition in smokers and non-smokers. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial. [2023]

8. China pubmed.ncbi.nlm.nih.gov

Spontaneous brain activity in chronic smokers revealed by fractional amplitude of low frequency fluctuation analysis: a resting state functional magnetic resonance imaging study. [2014]