Low Intensity Focussed UltrasoundEarly Phase 1LIFUS-PharmaNCT04923659
Pharmacological Mechanisms of Low-intensity Focused Ultrasound for Motor Cortex Neuroplasticity
A Early Phase 1 study testing Carbamazepine, Lorazepam and Dextromethorphan in people with Low Intensity Focussed Ultrasound, run by University Health Network, Toronto at 1 site in Canada.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Low Intensity Focussed Ultrasound
- What is being tested?
- Carbamazepine, Lorazepam and Dextromethorphan
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- 25 May 2021to May 2026
- Phase
- Early Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Right-handed healthy subjects between the ages of 18-65 will be included for recruitment.
Who cannot join
- 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
Show all 23Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Low Intensity Focussed Ultrasound
- Being tested
- Carbamazepine, Lorazepam, Dextromethorphan, Nimodipine, Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CarbamazepineDrug
Also called Tegretol
600 mg reconstituted as one table. Administered once
LorazepamDrug
Also called Ativan
2.5 mg mg reconstituted as one table. Administered once
DextromethorphanDrug
Also called Robitussin
150 mgmg reconstituted as one table. Administered once
NimodipineDrug
Also called Nimotop
30 mg reconstituted as one table. Administered once
PlaceboDrug
Also called Sugar
Administered once
| Study group | Role | What they receive |
|---|---|---|
| LIFUS | Experimental | Low Intensity Focussed ultrasound. Receives: Drug: Carbamazepine; Drug: Lorazepam; Drug: Dextromethorphan; Drug: Nimodipine; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Motor Evoked Potential
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.
Measured: 2 years
Resting Motor Threshold
- 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.
Measured: 2 years
Recruitment Curve
- 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.
Measured: 2 years
Short Interval Intracortical Inhibition
- 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.
Measured: 2 years
Intracortical Facilitation
- 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.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2021
- Study start25 May 2021
- Primary completion10 Jul 2022
- Study completionMay 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Low Intensity Focussed UltrasoundStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Robert Chen, University Health Network, Toronto
- Investigators
- Robert Chen, MBBS, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04923659
- Sponsor's protocol ID
- YS609220
- Acronym
- LIFUS-Pharma
- Status last verified
- Jul 2025
- First submitted
- 25 May 2021
- Last updated
- 3 Aug 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacological Mechanisms of Low-intensity Focused Ultrasound for Motor Cortex Neuroplasticity
- ClinicalTrials.gov ID
- NCT04923659
- Acronym / sponsor ID
- LIFUS-Pharma / YS609220
- Conditions
- Low Intensity Focussed Ultrasound
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- 25 May 2021 (actual)
- Primary completion
- 10 Jul 2022 (actual)
- Study completion
- May 2026 (estimated)
- First posted
- 11 Jun 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| LIFUS | Experimental | Drug: Carbamazepine, Drug: Lorazepam, Drug: Dextromethorphan, Drug: Nimodipine, Drug: PlaceboLow Intensity Focussed ultrasound. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Right-handed healthy subjects between the ages of 18-65 will be included for recruitment.
Key exclusion criteria (23 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CarbamazepineAlso: Tegretol600 mg reconstituted as one table. Administered once | Drug | LIFUS |
| LorazepamAlso: Ativan2.5 mg mg reconstituted as one table. Administered once | Drug | LIFUS |
| DextromethorphanAlso: Robitussin150 mgmg reconstituted as one table. Administered once | Drug | LIFUS |
| NimodipineAlso: Nimotop30 mg reconstituted as one table. Administered once | Drug | LIFUS |
| PlaceboAlso: SugarAdministered once | Drug | LIFUS |
Primary outcome
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.
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.
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.
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.
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.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Aug 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert Chen, MBBS principal investigator
University Health Network, Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Carbamazepine, Lorazepam and Dextromethorphan in people with Low Intensity Focussed Ultrasound, run by University Health Network, Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 3 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Motor Evoked Potential (time frame: 2 years). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2025.