Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001688875
Ethics application status
Approved
Date submitted
27/09/2021
Date registered
10/12/2021
Date last updated
1/06/2024
Date data sharing statement initially provided
10/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Understanding tissue mechanics, architecture and function using a gravitational magnetic resonance elastography transducer.
Scientific title
Understanding tissue mechanics, architecture and function of healthy adults using a gravitational magnetic resonance elastography transducer.
Secondary ID [1] 305165 0
Nil known.
Universal Trial Number (UTN)
U1111-1269-7143
Trial acronym
Linked study record
Nil.

Health condition
Health condition(s) or problem(s) studied:
Tissue mechanics in healthy adults. 323740 0
Tissue architecture in healthy adults. 324086 0
Tissue function in healthy adults. 324087 0
Condition category
Condition code
Musculoskeletal 321267 321267 0 0
Normal musculoskeletal and cartilage development and function
Neurological 321268 321268 0 0
Studies of the normal brain and nervous system
Oral and Gastrointestinal 321269 321269 0 0
Normal oral and gastrointestinal development and function

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
We are applying for registration of a trial using an investigational medical device that is not currently registered on the Australian Register of Therapeutic Goods (ARTG).
The device in question is referred to as the gravitational magnetic resonance (MR) elastography transducer. Put simply, MR elastography is an MR imaging technology that uses the way that shear vibrations travel through in-vivo tissues (as imaged using an MR scanner) to provide information about tissue mechanical properties. The transducer produces a vibration that feels similar to an electric toothbrush through the rotation of an eccentric mass. The device is placed externally on the body of participants and is used to vibrate various body regions during MR scanning.

In this study, the device will be used as a means of producing painless shear wave vibrations in the target tissues of participants undergoing MR scanning. The scanning will take place during a single visit to the Imaging Facility at NeuRA, in Randwick NSW 2031.
Participants will undergo MR scanning of their brain, abdomen, spinal cord, adipose tissue or skeletal muscle.

During MR imaging, we will obtain images of:
- Tissue anatomy (T1 and T2 weighted imaging);
- Anisotropy (diffusion tensor imaging, DTI);
- Fat content (DIXON imaging);
- Real-time phase-contrast imaging of shear wave propagation (MR elastography);
- Real-time tissue strain during deformation (tagged MR).
If the tissue is able to be deformed by compression, joint rotation or active isometric contraction, the scans will be repeated while undergoing that deformation.
Post-processing of these scans will allow various anatomical measurements and the large deformation, anisotropic mechanical properties of the tissue to be reconstructed.
The reconstructed data will be quantitatively analysed using statistical methods to obtain group mechanical property data for the tissues, and how they vary during deformation.

Participants will be required to undergo MR scanning of – depending on the tissue being investigated – either their:
i. Head/neck (brain, tongue, spinal cord);
ii. Buttocks (adipose tissue);
iii. Abdomen (liver/kidney);
iv. Upper or lower extremity (skeletal muscle/tendon).
The participant will be asked to lie down on a comfortable padded table that goes inside the large tube that is the imaging magnet. They will have a series of pictures taken of their body using the MRI scanner.
While measurements of elasticity are being recorded, vibration will be transmitted into the tissue being investigated via a purpose built device, comprising a gravitational design that produces vibration through the rotation of an eccentric mass.
Vibration will be transmitted directly to the participant by placing the device directly over or on the tissue of interest. If the transducer is to be positioned over bone, a gel pad will be placed between the transducer and the participant for comfort.
We may also apply some compression to the body area to deform the tissue of interest (if possible and safe to do so), which will be a light to moderate pressure and should not be uncomfortable. This will allow us to measure how the tissue properties change during deformation.

The exposure of the gravitational MR elastography transducer lasts only as long as the scan itself, as the device is only activated when that particular scan is being acquired, and it lays dormant for the rest of the scan.

The anticipated duration of the scans is one and half hours, with the total study visit requiring 2 to 2.5 hours. This will include MR screening, completion of consent forms, participant positioning and MR scanning. Pilot studies for each body region will allow us to determine the total time required for scanning but will be no shorter than 60 minutes and no greater than 120 minutes, with the time required to position the testing apparatus predominately determining the length of the scan.
Participants will be recruited and enrolled into studies for each body region, one at a time. For example, the initial study will recruit participants for the study of extremity skeletal muscle and this will be disclosed at the time of recruitment. Recruitment drives for the other tissues will also specify which tissue is to be scanned in the initial advertisement.

Electromyographic recordings of neural drive will be measured in the participants recruited for the skeletal muscle MRI study so that regional neural drive across the muscle can be quantified. Data collection will occur in a single visit, following their MRI scan, with participants positioned in the same manner as in the MRI. The lab session will take an additional 30 – 60 minutes for completion.
The EMG recordings will occur immediately after the MRI scan, in a NeuRA laboratory upstairs from the NeuRA MRI scanner. The boundaries of the target muscles (e.g. in the calf – medial gastrocnemius, soleus, tibialis anterior; and in the tongue – genioglossus, geniohyoid, superior longitudinal muscle) will be identified with ultrasound. Fine-wire electrodes will be inserted intramuscularly into the muscle belly under ultrasound guidance to known depths and distances such that the EMG data can be mapped back to the 3D model. For the multi-unit recordings, sterile Teflon-coated stainless steel fine-wire electrodes with the ends of the wires bared for 2mm will be inserted along the midline of the muscle. For the single-unit recordings, the ends of the electrodes will be trimmed to reduce recording surface area. Surface electrodes will be positioned superficially to muscle in the upper and lower extremities, and to act as the ground for experiments.
Participants will be asked to perform the same voluntary tasks as they performed in the scanner and the neural input while doing so will be measured. This includes both passive recordings (e.g. in the calf at 4 muscle lengths achieved by rotating ankle joint, and tongue during quiet breathing and as the tongue is stretched anteriorly using dental tape) and during voluntary, isometric contractions (e.g. by pushing the foot against an immovable foot plate or protruding the tongue at levels 10 or 20% of the maximal).
Intervention code [1] 321795 0
Not applicable
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329049 0
Any differences in the shear moduli of adipose tissue under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography.
Timepoint [1] 329049 0
At the conclusion of the adipose tissue MR study.
Primary outcome [2] 329050 0
Any differences between the shear moduli of skeletal muscle in directions parallel to the microstructural tissue axes under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography.
Timepoint [2] 329050 0
At the conclusion of the skeletal muscle MR and EMG study.
Primary outcome [3] 329051 0
Any differences between the shear moduli of skeletal muscle in directions perpendicular to the microstructural tissue axes under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography.
Timepoint [3] 329051 0
At the conclusion of the skeletal muscle MR and EMG study.
Secondary outcome [1] 401274 0
(Primary outcome): The shear moduli of brain tissue in directions parallel to the microstructural tissue axes assessed by MR scanning and the technique of MR elastography.
Timepoint [1] 401274 0
At the conclusion of brain tissue MR study.
Secondary outcome [2] 401275 0
The shear moduli of brain tissue in directions perpendicular to the microstructural tissue axes assessed by MR scanning and the technique of MR elastography.
Timepoint [2] 401275 0
At the conclusion of brain tissue MR study.
Secondary outcome [3] 402269 0
(Primary Outcome): The shear moduli of spinal cord in directions parallel to the microstructural tissue axes assessed by MR scanning and the technique of MR elastography.
Timepoint [3] 402269 0
At the completion of the spinal cord MR study.
Secondary outcome [4] 402270 0
(Primary Outcome): The shear moduli of spinal cord in directions perpendicular to the microstructural tissue axes assessed by MR scanning and the technique of MR elastography.
Timepoint [4] 402270 0
At the completion of the spinal cord MR study.
Secondary outcome [5] 402271 0
(Primary Outcome): The shear moduli of abdominal soft tissue in directions parallel to the microstructural tissue axes under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography.
Timepoint [5] 402271 0
At the completion of the abdominal soft tissue MR study.
Secondary outcome [6] 402272 0
(Primary Outcome): The shear moduli of abdominal soft tissue in directions perpendicular to the microstructural tissue axes under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography.
Timepoint [6] 402272 0
At the completion of the abdominal soft tissue MR study.
Secondary outcome [7] 402273 0
Any differences between the shear moduli of tendon in directions parallel to the microstructural tissue axes under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography.
Timepoint [7] 402273 0
At the conclusion of the skeletal muscle MR and EMG study.
Secondary outcome [8] 402274 0
Any differences between the shear moduli of tendon in directions perpendicular to the microstructural tissue axes under physiological large deformation conditions assessed by MR scanning and the technique of MR elastography
Timepoint [8] 402274 0
At the conclusion of the skeletal muscle MR and EMG study.
Secondary outcome [9] 402275 0
Differences in principal Right Cauchy Green strain field components of adipose tissue as a result of physiological large deformation conditions assessed by MR scanning and the post-processing technique of non-rigid registration.
Timepoint [9] 402275 0
At the completion of the adipose tissue MR study.
Secondary outcome [10] 402276 0
Differences in principal Right Cauchy Green strain field components of skeletal muscle as a result of physiological large deformation conditions assessed by MR scanning and the post-processing technique of non-rigid registration.
Timepoint [10] 402276 0
At the conclusion of the skeletal muscle MR and EMG study.
Secondary outcome [11] 402277 0
Differences in principal Right Cauchy Green strain field components of tendon as a result of physiological large deformation conditions assessed by MR scanning and the post-processing technique of non-rigid registration.
Timepoint [11] 402277 0
At the conclusion of the skeletal muscle MR and EMG study.
Secondary outcome [12] 402278 0
Differences in principal Right Cauchy Green strain field components of abdominal soft tissue as a result of physiological large deformation conditions assessed by MR scanning and the post-processing technique of non-rigid registration.
Timepoint [12] 402278 0
At the completion of the abdominal soft tissue MR study.
Secondary outcome [13] 402279 0
The identification of motor units in the upper limb (deltoid and rotator cuff) recording sites of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [13] 402279 0
At the conclusion of the upper limb skeletal muscle MR and EMG study.
Secondary outcome [14] 402280 0
Time to onset relative to activation of motor units in the upper limb (deltoid and rotator cuff) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [14] 402280 0
At the conclusion of the upper limb skeletal muscle MR and EMG study.
Secondary outcome [15] 402281 0
The discharge frequency relative to activation of motor units in the upper limb (deltoid and rotator cuff) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [15] 402281 0
At the conclusion of the upper limb skeletal muscle MR and EMG study.
Secondary outcome [16] 402282 0
Any regional differences in the recruitment of motor units across upper limb (deltoid and rotator cuff) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [16] 402282 0
At the conclusion of the upper limb skeletal muscle MR and EMG study.
Secondary outcome [17] 402283 0
The local activation parameter alpha, for each motor unit territory in the upper limb (deltoid and rotator cuff) whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be derived as a composite outcome by EMG recording.
Timepoint [17] 402283 0
At the conclusion of the upper limb skeletal muscle MR and EMG study.
Secondary outcome [18] 403900 0
The identification of motor units in the tongue (genioglossus and geniohyoid) recording sites of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [18] 403900 0
At the conclusion of the tongue skeletal muscle MR and EMG study.
Secondary outcome [19] 403901 0
Time to onset relative to activation of motor units in the tongue (genioglossus and geniohyoid) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [19] 403901 0
At the conclusion of the tongue skeletal muscle MR and EMG study.
Secondary outcome [20] 403902 0
The discharge frequency relative to activation of motor units in the tongue (genioglossus and geniohyoid) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [20] 403902 0
At the conclusion of the tongue skeletal muscle MR and EMG study.
Secondary outcome [21] 403903 0
Any regional differences in the recruitment of motor units across tongue (genioglossus and geniohyoid) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [21] 403903 0
At the conclusion of the tongue skeletal muscle MR and EMG study.
Secondary outcome [22] 403904 0
The local activation parameter alpha, for each motor unit territory in the tongue (genioglossus and geniohyoid) whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be derived as a composite outcome by EMG recording.
Timepoint [22] 403904 0
At the conclusion of the tongue skeletal muscle MR and EMG study.
Secondary outcome [23] 403905 0
The identification of motor units in the lower limb (soleus, tibialis anterior and medial gastrocnemius) recording sites of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [23] 403905 0
At the conclusion of the lower limb skeletal muscle MR and EMG study.
Secondary outcome [24] 403906 0
Time to onset relative to activation of motor units in the lower limb (soleus, tibialis anterior and medial gastrocnemius) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [24] 403906 0
At the conclusion of the lower limb skeletal muscle MR and EMG study.
Secondary outcome [25] 403907 0
The discharge frequency relative to activation of motor units in the lower limb (soleus, tibialis anterior and medial gastrocnemius) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [25] 403907 0
At the conclusion of the lower limb skeletal muscle MR and EMG study.
Secondary outcome [26] 403908 0
Any regional differences in the recruitment of motor units across lower limb (soleus, tibialis anterior and medial gastrocnemius) recording sites whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be assessed as a composite outcome by EMG recording.
Timepoint [26] 403908 0
At the conclusion of the lower limb skeletal muscle MR and EMG study.
Secondary outcome [27] 403909 0
The local activation parameter alpha, for each motor unit territory in the lower limb (soleus, tibialis anterior and medial gastrocnemius) whilst undergoing physiological large deformations of participants enrolled in the skeletal muscle sub-study will be derived as a composite outcome by EMG recording.
Timepoint [27] 403909 0
At the conclusion of the lower limb skeletal muscle MR and EMG study.

Eligibility
Key inclusion criteria
Inclusion criteria for participants taking part in this study includes:
1. Being an adult (male or female) over the age of 18 years.
2. Being in good health with no known history of nervous system, skeletal or muscular disease or injury.
3. Having no known medical conditions or implantation that would preclude them from undergoing MRI scanning.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for those who are not eligible to participate in the study includes:
1. People under the age of 18 years (tissue mechanical properties change throughout development)
2. Women who are pregnant (there are risks to the unborn foetus of undergoing MRI while pregnant).
3. People with medical conditions, devices or implantation that cannot be safely imaged using MRI (MRI is a critical tool in the study).
4. A history of MRI related claustrophobia (there is no direct benefit to the participant for participating in the study that would warrant their partaking).
5. People weighing over 140 kg (to comply with the safe working limit of the MR scanner).
6. If participating in the EMG study, allergic reactions to skin preparation solutions, conductive gels/creams or medical tape; or an extreme aversion to needles such as a history of fainting as a result of the insertion of needles.
7. People with a history of skin disease or injury to the site where the MR elastography transducer will be positioned (as the vibration applied through this site may aggravate this condition).

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Convenience sample
Timing
Prospective
Statistical methods / analysis
The data from the MRI studies comprising electronic files of MR images will be analysed using validated custom-built and freely available analysis packages available in Matlab, ImageJ and ROOT. The data from the EMG studies comprising electronic motor unit recordings will similarly be analysed in Matlab.
These methods are appropriate as they have been specifically built to answer the aims of the project, which are threefold:
1. To measure the isotropic and anisotropic soft tissues in human subject;
2. To map the change (if any) in these properties in tissues undergoing physiological large deformations;
3. To determine how neural drive, muscle mechanical properties, and muscle architecture interact in individuals, thus providing the first personalised ‘neuromechanical’ understanding of muscle function.
4. Use the data from part 1 – 3 to develop constitutive, computational models of skeletal muscle.

The primary outcomes from large deformation, anisotropic MRE studies comprise the means and standard deviations of:
• The elastic component of the shear modulus, perpendicular to the fibre direction (G’perp, measured in Pascals);
• The elastic component of the shear modulus, parallel to the fibre direction (G’para, measured in Pascals);
• The viscous component of the shear modulus (G’’, measured in Pascals);
• The complex shear modulus (G*, measured in Pascals);
• Fractional anisotropy, a measure indicating the overall directionality of water diffusion in a tissue (FA);
• Mean diffusivity, a measure of the total diffusion within a voxel (MD);
• Total tissue deformation (measured in mm);
• Green strain field components (exx and eyy).
The mean values described above in each region of interest under each deformation condition are compared using paired t-tests or one-way ANOVA as appropriate. The effect of increasing deformation on the shear properties is then typically analysed using linear mixed models, to account for the repeated measures design. Finally, the effect of increasing strain on the shear properties is evaluated using regression models.

The following will be evaluated in the muscular neural input studies:
• Participants will be asked to perform the same voluntary tasks as in the MRI scan (e.g. maximal voluntary contraction, quiet breathing, tongue protrusion etc) and electromyography (EMG) recordings will be captured at various sites in the muscle;
• Motor units will be identified based on their shape and discharge pattern;
• Time to onset and discharge frequencies for all motor units relative to activation will be identified;
• Regional differences in the recruitment of motor units across recording sites will be identified;
• These factors will be used to derive the local activation parameter a, for each motor unit territory.

Statistical analysis of the EMG data is not a primary outcome of the study, rather the data will be used as input for the individual computational models for each participant’s muscle, adopting a phenomenological motor unit recruitment model, following the Henneman size principle. This simulates recruitment when a specific motor unit reaches a predefined threshold, and then firing rates increase linearly from their minimum to their maximum.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/06/2024
Actual
Date of last participant enrolment
Anticipated
1/12/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
160
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 35358 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 309553 0
Government body
Name [1] 309553 0
Australian Research Council
Country [1] 309553 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Neuroscience Research Australia
Address
NeuRA,
Margarete Ainsworth Building, Barker Street, Randwick, NSW 2031
Country
Australia
Secondary sponsor category [1] 311061 0
None
Name [1] 311061 0
Address [1] 311061 0
Country [1] 311061 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309333 0
University of New South Wales Human Research Ethics Committee A
Ethics committee address [1] 309333 0
Ethics committee country [1] 309333 0
Australia
Date submitted for ethics approval [1] 309333 0
30/08/2021
Approval date [1] 309333 0
22/10/2021
Ethics approval number [1] 309333 0
HC210702

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113798 0
Prof Lynne Bilston
Address 113798 0
NeuRA,
Margarete Ainsworth Building, Barker Street
Randwick NSW 2031
Country 113798 0
Australia
Phone 113798 0
+612 9399 1673
Fax 113798 0
Email 113798 0
[email protected]
Contact person for public queries
Name 113799 0
Lynne Bilston
Address 113799 0
NeuRA,
Margarete Ainsworth Building, Barker Street
Randwick NSW 2031
Country 113799 0
Australia
Phone 113799 0
+612 9399 1673
Fax 113799 0
Email 113799 0
[email protected]
Contact person for scientific queries
Name 113800 0
Lynne Bilston
Address 113800 0
NeuRA,
Margarete Ainsworth Building, Barker Street
Randwick NSW 2031
Country 113800 0
Australia
Phone 113800 0
+612 9399 1673
Fax 113800 0
Email 113800 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The necessity for a clinical trial in the case of this study stems from the usage of a low-risk investigational medical device - the gravitational magnetic resonance (MR) elastography transducer. The role of the device in question is simply to produce a low level vibration in the target tissue of participants undergoing MR scanning. This is not a study of the efficacy or safety of the device, it is to be used only as a tool to achieve one of the aims of the project, which is to characterise the mechanical properties of a target tissue using MR elastography.
As the study does not involve a target group, intervention or control group, the IPD for the study is of little benefit to anyone beyond its usage in generating the group means and standard deviations which will be reported in our publications.


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Results publications and other study-related documents

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