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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

Low-intensity focused ultrasound (LIFUS) has been shown to be an effective and safe non-invasive brain stimulation technique, capable of reaching greater brain depth and a greater spatial resolution than other brain stimulation tools. Its use as a potential clinical tool for treatment of neurological disorders is reliant on an understanding of its mechanisms of action. Although it has been shown to induce immediate (online) and prolonged (offline) changes in plasticity in the motor cortex, researchers have not studied its effects on neurotransmitter receptors and ion channels responsible for neuronal signaling in humans. The purpose of this study is to explore the effects of online and offline LIFUS stimulation in tandem with administration of various brain-active drugs, to elucidate the effects of this technique on specific cortical receptors and channels. 20 healthy, screened subjects will be recruited to participate in 5 sessions in-lab. Each session will represent the double-blinded administration of four known and studied pharmacological agents known to safely induce changes in the motor cortex, as well as a placebo. Investigators will use carbamazepine (sodium channel blocker), lorazepam (GABAA positive allosteric modulator), nimodipine (calcium channel blocker), and dextromethorphan (glutamate N-Methyl-D-aspartate receptor antagonist). Single- and paired-pulse transcranial magnetic stimulation (TMS) measures will be recorded for online LIFUS before and after drug intervention, and induction of offline LIFUS during placebo will be compared with its induction following the various drug interventions. Investigators predict that due to the differential effects of online and offline LIFUS on motor parameters, the mechanisms in which it alters the receptors and channels of interest will also be differentially modulated.

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 data supports the effectiveness of this treatment?

Research shows that focused ultrasound can noninvasively modulate brain activity and enhance drug delivery by temporarily disrupting the blood-brain barrier, which could help treat neurological conditions. Additionally, weak ultrasound has been shown to induce long-lasting neuromodulatory effects in the brain, suggesting potential for clinical applications. ^{1 2 3 4 5}

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

Research shows that Low-Intensity Focused Ultrasound (LIFU) is generally safe for humans, with no serious adverse effects reported. Some participants experienced mild symptoms like neck pain, attention problems, and headaches, but these were temporary and similar to other non-invasive brain stimulation methods. ^{6 7 8 9 10}

How is Low-intensity Focused Ultrasound (LIFU) treatment different from other treatments?

Low-intensity Focused Ultrasound (LIFU) is unique because it is a non-invasive treatment that uses sound waves to precisely target and modulate specific brain areas, unlike other treatments that may involve surgery or less targeted methods. It offers high spatial resolution and can induce both excitatory and inhibitory effects on neurons, making it a promising option for neuromodulation. ^{2 11 12 13 14}

Research Team

Robert Chen, MBBS

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

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.

Inclusion Criteria

I am right-handed, healthy, and aged between 18-65.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Noninvasive Ultrasonic Drug Uncaging Maps Whole-Brain Functional Networks. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Weak Ultrasound Contributes to Neuromodulatory Effects in the Rat Motor Cortex. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

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

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

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions. [2022]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. [2023]

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

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A prototype stimulator system for noninvasive Low Intensity Focused Ultrasound delivery. [2016]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. [2022]

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

The effectiveness and safety of low-intensity transcranial ultrasound stimulation: A systematic review of human and animal studies. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Current State of Potential Mechanisms Supporting Low Intensity Focused Ultrasound for Neuromodulation. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Evaluation of a Novel Acoustic Coupling Medium for Human Low-Intensity Focused Ultrasound Neuromodulation Applications. [2023]

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

Transcranial focused ultrasound stimulation with high spatial resolution. [2021]

14. Turkey pubmed.ncbi.nlm.nih.gov

Proteomics Reveals the Effect of Low-Intensity Focused Ultrasound on Spasticity After Spinal Cord Injury. [2023]