Pharmacological Agents for Enhancing Low-Intensity Focused Ultrasound Effects

(LIFUS-Pharma Trial)

Overseen By Tasnuva Hoque, BSc

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University Health Network, Toronto

Must not be taking: Antipsychotics, Marijuana, Tobacco, others

Disqualifiers: Neurological, Musculoskeletal, Stroke, Seizure, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 5 sessions

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how low-intensity focused ultrasound (LIFUS), combined with certain brain-active drugs, affects brain signaling. Researchers aim to understand changes in brain receptors and channels related to neurological functions. The study involves administering four different medications known to influence the brain, along with a placebo, to observe their interaction with LIFUS. Right-handed, healthy individuals without neurological disorders might be suitable candidates for this trial. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants a unique opportunity to contribute to groundbreaking neurological research.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications. The trial excludes participants who regularly use CNS active drugs, calcium channel blockers, antipsychotics, recreational drugs, and several other types of medications during or up to 2 weeks before the study.

What prior data suggests that low-intensity focused ultrasound is safe?

Research has shown that low-intensity focused ultrasound (LIFUS) safely and non-invasively stimulates the brain. One study found that LIFUS was safe and well-tolerated in stroke patients, even at higher levels than typically used. Another study showed that the FDA considers LIFUS a Non-Significant Risk when used at or below certain levels, indicating it is low-risk for participants.

In this trial, LIFUS is used with drugs already known to safely affect the brain, including carbamazepine, lorazepam, nimodipine, and dextromethorphan. Each of these drugs has been studied and is known to safely alter brain activity. Therefore, based on current research, LIFUS combined with these drugs should be well-tolerated by participants. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Low-intensity Focused Ultrasound (LIFUS) is unique because it uses sound waves to target tissues non-invasively, unlike many standard treatments that might involve surgery or medication. This approach allows for precision in treating specific areas without affecting surrounding tissues. Researchers are excited because LIFUS has the potential to enhance drug delivery and stimulate healing processes at a cellular level, which could lead to faster and more effective treatments with fewer side effects.

What evidence suggests that this trial's treatments could be effective for neurological disorders?

Research has shown that low-intensity focused ultrasound (LIFUS) can safely and effectively alter brain activity. It reaches deeper and more specific brain areas than other methods. Studies have found that LIFUS can influence the motor cortex, the brain region controlling movement, by aiding the brain's adaptation and reorganization. This trial tests LIFUS with pharmacological agents such as carbamazepine, lorazepam, nimodipine, and dextromethorphan. These drugs affect brain signaling and may reveal how LIFUS interacts with brain receptors and ion channels, crucial for nerve cell communication. Overall, using LIFUS with these drugs could enhance understanding of its potential in treating neurological disorders. ^{6 7 8 9 10}

Who Is on the Research Team?

Robert Chen, MBBS

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

Healthy right-handed individuals aged 18-65 can join this trial. They must not be using antipsychotics, recreational drugs, CNS active drugs, or certain other medications recently. People with major diseases (cardiac, liver, kidney), neurological disorders, gait issues, mental health conditions that affect study compliance or those who are pregnant cannot participate.

Exclusion Criteria

Caffeine or chocolate consumption 1-2 hours before study sessions

Hypersensitivity to anticonvulsants

I have been using medications like antibiotics or muscle relaxants regularly up to 2 weeks before the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 5 in-lab sessions with double-blinded administration of four pharmacological agents and a placebo, combined with online and offline LIFUS stimulation.

5 sessions

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Low-intensity Focused Ultrasound
• Pharmacological Agents

Trial Overview The trial is testing how low-intensity focused ultrasound affects the motor cortex when combined with different brain-active drugs: Carbamazepine, Lorazepam, Dextromethorphan, Nimodipine and a placebo. Each participant will undergo five sessions to see how these substances influence brain stimulation outcomes.

How Is the Trial Designed?

Group I: LIFUS Experimental Treatment 5 Interventions

Low Intensity Focussed ultrasound.

Low-intensity Focused Ultrasound is already approved in United States, European Union for the following indications:

Approved in United States as LIFU for:

• Research purposes for neurological conditions such as depression, addiction, and pain management

Approved in European Union as LIFU for:

• Research purposes for neurological conditions such as depression, addiction, and pain management

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

High-density gel polymer matrices are effective couplants for low-intensity focused ultrasound (LIFU) neuromodulation, showing low acoustic attenuation (3.3%) and minimal beam distortion, making them suitable for clinical use.

The study highlights the importance of using standardized methods for preparing these gels to ensure consistent performance, as factors like thickness and de-gassing can significantly affect acoustic transmission and pressure attenuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of a Novel Acoustic Coupling Medium for Human Low-Intensity Focused Ultrasound Neuromodulation Applications. Strohman, A., In, A., Stebbins, K., et al.[2023]

A study involving 120 participants evaluated the safety of low intensity transcranial focused ultrasound (LIFU) for neuromodulation, finding no serious adverse effects and only mild to moderate symptoms reported by 7 participants, which were generally transient.

The symptom profile from LIFU was similar to other non-invasive brain stimulation methods, suggesting that LIFU is a safe option for neuromodulation with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Legon, W., Adams, S., Bansal, P., et al.[2021]

Low intensity focused ultrasound (LIFU) is a promising non-invasive technology that can precisely modulate brain activity, offering a new approach to studying and potentially treating psychiatric illnesses.

LIFU has been shown to safely affect both cortical and subcortical brain regions, distinguishing it from other neuromodulatory techniques due to its spatial precision and reversible effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. Arulpragasam, AR., van 't Wout-Frank, M., Barredo, J., et al.[2022]

Low-intensity transcranial ultrasound stimulation (LITUS) has shown therapeutic efficacy in treating various conditions, including neurological and psychiatric disorders, pain, sleep disorders, and hypertension, based on a systematic review of 11 human studies and 44 animal studies.

LITUS appears to be safe, with no adverse effects reported in animal studies and only minor side effects like headaches and nausea in a few human subjects, while also promoting neurogenesis and reducing inflammation in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness and safety of low-intensity transcranial ultrasound stimulation: A systematic review of human and animal studies. Qin, PP., Jin, M., Xia, AW., et al.[2023]

The study found that the timing of intravenous injection of large molecular agents, like Evans blue, significantly affects their delivery efficiency across the blood-brain barrier (BBB) when using focused ultrasound (FUS) to induce disruption, with better results when the agent is administered before sonication.

Optimizing ultrasound parameters, such as using lower acoustic power and ultrasound contrast agent doses, can enhance the delivery of therapeutic agents while minimizing damage to normal brain tissue, making this approach safer and more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficiency of drug delivery enhanced by acoustic pressure during blood-brain barrier disruption induced by focused ultrasound. Yang, FY., Lee, PY.[2021]

Low intensity focused ultrasound (LIFU) is a promising non-invasive technology for neuromodulation, offering better spatial specificity than traditional methods like transcranial electrical or magnetic stimulation.

The review suggests that a neuronal intramembrane cavitation excitation model may explain the varying excitatory effects of LIFU, but further research is needed to clarify the mechanisms behind its suppressive effects and how they relate to specific sonication parameters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current State of Potential Mechanisms Supporting Low Intensity Focused Ultrasound for Neuromodulation. Dell'Italia, J., Sanguinetti, JL., Monti, MM., et al.[2022]

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]

Researchers have created biodegradable nanoparticles that can noninvasively release the anesthetic propofol in the brain using focused ultrasound, which could change how we approach brain treatments.

In tests on rats, these nanoparticles effectively silenced seizures without causing any damage to brain tissue or disrupting the blood-brain barrier, indicating a safe method for neuromodulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions. Airan, RD., Meyer, RA., Ellens, NP., et al.[2022]

Low-intensity focused ultrasound (LIFU) treatment significantly improved spasticity in male Sprague-Dawley rats with spinal cord injury after 4 weeks of daily sessions, indicating its potential as an effective therapy.

The mechanism of LIFU's efficacy may involve a reduction in the expression of growth associated protein 43 (Gap43), suggesting it helps to modulate neuroplasticity and axon regeneration below the injury site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteomics Reveals the Effect of Low-Intensity Focused Ultrasound on Spasticity After Spinal Cord Injury. Wang, B., Zhao, H., Chen, M., et al.[2023]

Researchers developed nanoparticles that can noninvasively release neuromodulatory drugs using focused ultrasound, which could allow precise control of brain activity in a clinical setting.

The study demonstrated that the effects of this ultrasonic drug release are spatially and temporally limited, but can also influence connected brain regions, suggesting potential for mapping brain connectivity changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Ultrasonic Drug Uncaging Maps Whole-Brain Functional Networks. Wang, JB., Aryal, M., Zhong, Q., et al.[2023]

A prototype Low Intensity Focused Ultrasound (LIFU) stimulator was successfully developed and tested on a Göttingen minipig, showing its potential for non-invasive neuromodulation.

The study demonstrated that targeted stimulation of the hypothalamus using LIFU resulted in reversible increases in heart rate and blood pressure, indicating a direct physiological effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prototype stimulator system for noninvasive Low Intensity Focused Ultrasound delivery. Mulgaonkar, AP., Singh, RS., Babakhanian, M., et al.[2016]

The dual-crossed transducer system achieved high spatial resolution in targeting small brain regions in mice, with a focal volume of under 0.52 μm³ and a focal diameter of 1 mm, making it effective for precise neuromodulation.

In vivo experiments demonstrated successful brain stimulation in wild-type mice, evidenced by observable movements, confirming the system's capability for noninvasive and specific targeting of brain circuits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial focused ultrasound stimulation with high spatial resolution. Kim, S., Jo, Y., Kook, G., et al.[2021]

Transcranial focused ultrasound (tFUS) can precisely target specific brain areas with low acoustic intensity, effectively modulating brain excitability and potentially promoting neural plasticity for neurorehabilitation.

The review highlights the excellent safety profile of tFUS, but emphasizes the need for new safety guidelines and recommendations for its use in healthy volunteers and clinical settings, based on a comprehensive analysis of acoustic parameters and their effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. Lee, W., Weisholtz, DS., Strangman, GE., et al.[2023]

This study involving 94 rats demonstrated that weak transcranial focused ultrasound (tFUS) can induce long-lasting neuromodulatory effects in the motor cortex, with significant changes in motor-evoked potentials (MEPs) observed for up to 30 minutes after stimulation.

The results indicated that higher intensities of tFUS suppressed excitatory neuron activity while enhancing inhibitory GABAergic neuron expression, suggesting a specific mechanism of action involving PIEZO-1 proteins in GABAergic neurons for neuromodulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weak Ultrasound Contributes to Neuromodulatory Effects in the Rat Motor Cortex. Chu, PC., Huang, CS., Chang, PK., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11700779/

A Comprehensive Review of Low-Intensity Focused ... In this study, we provide a review of the most recent LIFU literature covering three key domains: 1) the history of focused ultrasound ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06906211

Low Intensity Focused Ultrasound for Chronic Pain: High ... The preliminary data indicate that LIFU to PI reduces laboratory measures of central sensitization and evoked pain in healthy controls but there was no such ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11612502/

The therapeutic potential of low-intensity focused ultrasound ... LIFU is a promising modality for precise and invasive modulation of brain activity, capable of redefining the landscape of SUD treatment.

4. withpower.com withpower.com/trial/pharmacological-agents-for-enhancing-low-intensity-focused-ultrasound-effects-28413

Pharmacological Agents for Enhancing Low-Intensity ... What data supports the effectiveness of this treatment? Research shows that focused ultrasound can noninvasively modulate brain activity and enhance drug ...

5. thejournalofheadacheandpain.biomedcentral.com thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-025-02096-y

The efficacy and mechanisms of low-intensity transcranial ... The efficacy and mechanisms of low-intensity transcranial ultrasound stimulation on pain: a systematic review of human and animal studies. Hao- ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05467085

Imaging-Guided Low Intensity Focused Ultrasound (LIFU) LIFU intensity will be at or below FDA safety limit of 720 mW/cm^2 Ispta, which resulted in an IRB/FDA determination of Non-Significant Risk (NSR) in our study ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X25000178

Low intensity focused ultrasound stimulation in stroke Our phase-I safety study suggests that one session of LIFUS up to 8 W/cm2 ISPPA is safe and feasible in stroke patients, and LIFUS at high intensity induces ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9599299/

Safety of Clinical Ultrasound Neuromodulation - PMC Transcranial ultrasound holds much potential as a safe, non-invasive modality for navigated neuromodulation, with low-intensity focused ultrasound (FUS) and ...

9. nature.com nature.com/articles/s41598-020-62265-8

A retrospective qualitative report of symptoms and safety ... We provide an evaluation of the safety of LIFU for human neuromodulation through participant report and neurological assessment with a comparison of ...

10. fusfoundation.org fusfoundation.org/posts/clinical-trial-investigates-low-intensity-focused-ultrasound-for-depression/

Clinical Trial Investigates Low-Intensity ... A clinical trial is investigating the safety and feasibility of using low-intensity focused ultrasound to address anxiety and depression.