Pharmacological Mechanisms of Low-intensity Focused Ultrasound for Motor Cortex Neuroplasticity (LIFUS-Pharma)

July 30, 2025 updated by: Robert Chen, University Health Network, Toronto
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

In the current study investigators aim to describe how common neurotransmitter receptors and ion channels in the brain, particularly the motor cortex, are dynamically involved in the mechanisms generated by LIFUS. By selectively modulating the activity of these receptors and channels with previously studied and known drugs, it can be empirically determined how common components of signal propagation and prolonged neuroplasticity are being affected by the sonication waves induced by LIFUS. This will be done through baseline recording of FUS-induced neuroplasticity, and then compared within-subject to FUS-induced neuroplasticity after administration of pharmacological agents of interest. Random double-blinded administration of four drugs and a placebo will ensure that results are accurate and reduce any effects of expectation. Its predicted that online FUS will lead to a reduction in motor excitation and an increase in intracortical inhibition, and offline FUS will lead to an increase in motor excitation, an increase in intracortical facilitation, and a reduction in intracortical inhibition. Its predicted that drugs of interest to similarly replicate previous work; that is, carbamazepine, lorazepam, dextromethorphan, and nimodipine will all reduce cortical excitation and increase intracortical inhibition compared to placebo. Its predicted that carbamazepine, lorazepam, nimodipine and dextromethorphan will all further reduce motor excitation in conjunction with online FUS in an additive manner, compared to placebo. Its predicted that carbamazepine will have no effect on the prolonged effects of offline FUS on the motor cortex, but that lorazepam, nimodipine, and dextromethorphan will all interfere with the offline effects of FUS on motor cortex, compared to placebo.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5T 2S8
        • Toronto Western Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Right-handed healthy subjects between the ages of 18-65 will be included for recruitment.

Exclusion Criteria:

  • Diagnosed with any gait or postural disorders
  • Major neurological disease or disorder
  • Major musculoskeletal or nerve disorder, or disorder of hands, wrists and upper limbs
  • History of stroke or seizure
  • Diagnosed with dementia
  • Diagnosed with myasthenia gravis or acute narrow angle glaucoma
  • Has intracranial implant(s) or device(s)
  • Has an implanted cardiac pacemaker or implantable cardioverter-defibrillator (ICD)
  • Presence of metal implanted in body that is contraindicated in TMS
  • Caffeine or chocolate consumption 1-2 hours before study sessions
  • Consumption of grapefruit juice 24 hours before study sessions
  • Alcohol consumption 24 hours before study sessions
  • Pregnancy*
  • Major depression/psychiatric disorder that in the opinion of the Investigator will affect patient's understanding of study procedures and willingness to abide by all procedures during the course of the study
  • Regular usage of CNS active drugs or calcium channel blockers during or up to 2 weeks before participating in the study**
  • Is on antipsychotics, marijuana, or other recreational drugs (including tobacco) that affect the nervous system
  • Major cardiac, hematopoietic, liver, or kidney disease or infection
  • Treated hypertension
  • Hypersensitivity to benzodiazepines
  • Hypersensitivity to calcium channel blockers
  • Hypersensitivity to antitussives
  • Hypersensitivity to anticonvulsants
  • Regular usage of androgens, antibiotics, antifungals, antivirals, cardiovascular/gastrointestinal drugs, muscle relaxants, and platelet aggregation inhibitors during or up to 2 weeks before participating in the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: LIFUS
Low Intensity Focussed ultrasound.
Drug: Carbamazepine
600 mg reconstituted as one table. Administered once
Other Names:
  • Tegretol
Drug: Lorazepam
2.5 mg mg reconstituted as one table. Administered once
Other Names:
  • Ativan
Drug: Dextromethorphan
150 mgmg reconstituted as one table. Administered once
Other Names:
  • Robitussin
Drug: Nimodipine
30 mg reconstituted as one table. Administered once
Other Names:
  • Nimotop
Drug: Placebo
Administered once
Other Names:
  • Sugar

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Motor Evoked Potential
Time Frame: 2 years
1 mV peak-to-peak MEP (motor evoked potential), defined as the average TMS stimulation intensity required to elicit a 1-mV EMG response in the right hand muscle. We will compare the intensities required to elicit this response within all of our pharmacological and FUS interventions, compared to our sham/placebo FUS intervention.
2 years
Resting Motor Threshold
Time Frame: 2 years
• The resting motor threshold (RMT) is defined as the minimum stimulus intensity that elicits an MEP greater than or equal to 50 microvolts in at least 5 out of 10 trials in the relaxed right FDI. We will compare the RMT required to elicit this response within all of our pharmacological and FUS interventions, compared to our sham/placebo FUS intervention.
2 years
Recruitment Curve
Time Frame: 2 years
• The MEP recruitment curve is a dose-response curve for assessing the effects of TMS stimulation intensity on recorded MEP. TMS stimulation begin at sub-RMT levels (80-90%) and is increased in increments of 10%. During this, MEP response is recorded from the right FDI, and a graph may then be created by fitting data-points into a sigmoidal curve. Recruitment curves will be compared in-between sham and real FUS, and in-between our various pharmacological interventions to observe changes in cortical neuron activation.
2 years
Short Interval Intracortical Inhibition
Time Frame: 2 years
• Short Interval Intracortical Inhibition (SICI) will be obtained on a relaxed right FDI muscle using paired-pulse TMS. SICI involves a subthreshold conditioning stimulus (CS) at 80% of RMT followed by a suprathreshold test stimulus (TS) at an intensity able to evoke an average MEP of ~1mV, at an interstimulus interval of 2ms. The magnitude of SICI will be indexed by the ratio of the mean conditioned MEP amplitude over the mean unconditioned MEP amplitude. A ratio less than 1 indicates greater inhibition and less facilitation.
2 years
Intracortical Facilitation
Time Frame: 2 years
• Intracortical Facilitation (ICF) will be obtained on a relaxed right FDI muscle using paired-pulse TMS. ICF involves a subthreshold conditioning stimulus (CS) at 80% of RMT followed by a suprathreshold test stimulus (TS) at an intensity able to evoke an average MEP of ~1mV, at an interstimulus interval of 10ms. The magnitude of ICF will be indexed by the ratio of the mean conditioned MEP amplitude over the mean unconditioned MEP amplitude. A ratio greater than 1 indicates greater facilitation and less inhibition.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Health Network, Toronto

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Robert Chen, MBBS, University Health Network, Toronto

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 25, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 10, 2022

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 25, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 10, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 11, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 3, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 30, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • YS609220

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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