Pharmacological Mechanisms of Low-intensity Focused Ultrasound for Motor Cortex Neuroplasticity

NCT04923659 | Active Not Recruiting Early Phase 1

• 1 other identifier: YS609220
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Low Intensity Focussed Ultrasound

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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.

  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.

  2 years

Study Arms (1)

LIFUS

EXPERIMENTAL

Low Intensity Focussed ultrasound.

Drug: Carbamazepine; Drug: Lorazepam; Drug: Dextromethorphan; Drug: Nimodipine; Drug: Placebo

Interventions

Carbamazepine DRUG

600 mg reconstituted as one table. Administered once

Also known as: Tegretol

LIFUS

Lorazepam DRUG

2.5 mg mg reconstituted as one table. Administered once

Also known as: Ativan

LIFUS

Dextromethorphan DRUG

150 mgmg reconstituted as one table. Administered once

Also known as: Robitussin

LIFUS

Nimodipine DRUG

30 mg reconstituted as one table. Administered once

Also known as: Nimotop

LIFUS

Placebo DRUG

Administered once

Also known as: Sugar

LIFUS

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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\*\*

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

Location

MeSH Terms

Interventions

Carbamazepine; Lorazepam; Dextromethorphan; Acetylcysteine; Nimodipine; Sugars

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Nicotinic Acids; Carbohydrates

Study Officials

• Robert Chen, MBBS

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: Healthy Controls 18-80 years
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Neurologist and Scientist

Study Record Dates

• First Submitted: May 25, 2021
• First Posted: June 11, 2021
• Study Start: May 25, 2021
• Primary Completion: July 10, 2022
• Study Completion: May 1, 2026
• Last Updated: August 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)