Anterior Cruciate Ligament InjuriesAQUARIUSNCT04837417
Deficit in Quadriceps Voluntary Activation After Anterior Cruciate Ligament Reconstruction: Roles of the "Learned Non-use" Paradigm and the Interhemispheric Inhibition
An observational study of Anterior Cruciate Ligament Injuries, run by Istituto Auxologico Italiano at 2 sites in Italy.
Trial summary
Anterior cruciate ligament (ACL) tear is mainly caused by sport injuries. 40% of injuries are attributed to noncontact mechanisms involving pivoting. Regaining quadriceps strength is a primary focus of patients pursuing a rehabilitation program after ACL reconstruction (ACLR). Read more about this study
- Who is it for?
- Ages 18 to 35 years, men only
- Conditions the study is for
- Anterior Cruciate Ligament Injuries
- What is being tested?
- Pathologic group
- How many people
- 10 participants
- Where
- 2 sitesItaly
- Study dates
- 14 Jul 2021to 31 Dec 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
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 35 years
- Men only
- No healthy volunteers
- Adult
Study population: The participants will be recruited by ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Presidio Ospedaliero Gaetano Pini, among those who underwent the surgical interventions in the Centre.
Who may be able to join
- anterior cruciate ligament tear with arthroscopic reconstruction, between 6 and 18 months before the tests;
- Tegner activity level > 5;
- Body Mass Index between 18 and 25;
- voluntary knee extension of at least 70°;
- ability to understand the instructions;
- ability to wittingly sign the informed consent form.
Who cannot join
- other previous knee injuries or surgical interventions;
- major procedures associated with the anterior cruciate ligament reconstruction: osteotomy, other ligaments reconstruction;
- meniscectomy, with surgical removal of more than 30% of the meniscal volume or removal of the meniscal root;
- comorbidities, such as: rheumatic diseases; other congenital or acquired neuromuscular pathologies; diabetes mellitus; osteoporosis; cancer; heart disease; history of epilepsy, endocranial hypertension;
- first degree relatives affected by epilepsy;
- current treatment with oral anticoagulant or antiplatelet therapy;
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- drug therapy, which could induce epileptic crisis;
- history of high alcohol consumption;
- implanted electro-sensitive devices;
- implanted intracranial or intraocular metallic devices;
- history of retinal detachment;
- presence of cochlear implant.
Trial locations and contacts
2 sites in 1 country.
Italy2 sites
Istituto Auxologico Italiano
Milan, MI, 20121
ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Presidio Ospedaliero Gaetano Pini
Milan
About this study
Anterior cruciate ligament (ACL) tear is mainly caused by sport injuries. 40% of injuries are attributed to noncontact mechanisms involving pivoting. Regaining quadriceps strength is a primary focus of patients pursuing a rehabilitation program after ACL reconstruction (ACLR). Unfortunately, despite rehabilitation programs aimed at reversing this muscle weakness, quadriceps strength deficits may persist for years. Moreover, this deficit leads to increased risk of sustaining another knee injury, and increased risk for developing posttraumatic osteoarthritis. At present, neither the optimal rehabilitative program nor the clinical and instrumental parameters to take into account at the time of return to activity have reached a consensus among clinicians.
The investigators hypothesize that:
Read more
- a persistent deficit in voluntary activation, that is an inability to achieve complete activation of a muscle, is present after ACLR.
- this deficit in voluntary activation is associated with a phenomenon of "learned/acquired non-use" both in balance and during gait. This phenomenon will be demonstrated by investigating asymmetries in the recruitment of the injured lower limb in balance tests and during gait.
- the "learned/acquired non-use" paradigm is associated to asymmetries in the hemispheric cortical activity. This phenomenon will be investigated through transcranial magnetic stimulation.
The primary endpoint is the demonstration that the quadriceps muscle weakness after ACLR may represent a case of "learned non-use". This behaviour looks automatic and unconscious, so that the adjective "acquired" seems preferable to "learned". It consists of the under recruitment of the impaired side, once healed, as a form of unconscious protection, which is adopted when the contralateral side may carry out the function.
The secondary outcome is the investigation of the correlation among the deficits in voluntary activation, in balance tests, during gait, and in the neurophysiologic trials, with the clinical conditions of the patients.
It is expected that the injured lower limb show a deficit in the activation of the quadriceps muscle with respect to the contralateral one and with respect to normative data. The impaired limb will present lower recruitment in balance tests and a deficit in power production during gait.
The contralesional hemisphere will demonstrate higher interhemispheric inhibition, lower short-interval intracortical inhibition (SICI) and higher short-interval intracortical facilitation (SICF) with respect to the ipsilesional hemisphere.
The evidence for an asymmetry between the two lower limbs would support the hypothesis that the "acquired non-use" paradigm has a role in the deficits following ACL lesions and that it is unspecific across asymmetric impairments, and independent of the underlying disease.
Results from the present study will allow:
- the identification of clinical and instrumental criteria to guide the return-to-sport decision following ACLR.
- the estimate of the sample size for future experimental protocols and new rehabilitative programs.
- Conditions
- Anterior Cruciate Ligament Injuries
- Being tested
- Pathologic group
- Keywords
- Anterior cruciate ligament reconstruction, acquired non-use, voluntary activation, quadriceps femoris, rehabilitation
- Medical subject headings
- Anterior Cruciate Ligament Injuries
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pathologic groupDiagnostic test
Voluntary Activation level will be determined with the interpolate twitch technique (ITT), both during isometric contractions (knee at 40° flexion) and during isokinetic contraction at angular velocity equal to 100°/s.
Vastus Medialis and Soleous H-reflex will be measured. Cortical excitability and interhemispheric connectivity will be measured through transcranial magnetic stimulation (TMS).
Tests of balance in standing will be performed using the EquiTest platform. Individuals will be requested to perform three different tasks: Sensory Organization test, Adaptation Test upward/downward, Motor Control test backward/forward. Surface electromyography from lower limbs will be recorded.
Through TMS driven by neuronavigation, the cortical representation of the Quadriceps muscle will be studied.
Gait analysis will be performed on a treadmill mounted on force sensors. Participants will walk at increasing velocities from 0.4 m/s to 1.6 m/s. Speed will be increased of 0.2 m/s every 30 s.
| Study group | Role | What they receive |
|---|---|---|
| Pathologic group | At least 10 male participants who underwent anterior cruciate ligament arthroscopic reconstruction using semitendinosus and gracilis tendons graft, between 6 and 18 months before the tests Receives: Diagnostic Test: Pathologic group |
What is being measured
The primary outcome is the main question the study is designed to answer.
Voluntary Activation
Voluntary Activation = [1 - (Interpolated Twitch/Resting Twitch)] percent, where Interpolated Twitch and Resting Twitch are the peak torques caused by the electric shock during the voluntary contraction and at rest, respectively.
Measured: Day 1
Secondary outcomes (9)
H-reflex minimal latency
H-reflex latency is defined as the time it takes for the H-reflex to appear on the EMG relative to the introduction of the stimulus. H-reflex minimal latency represents the minimal latency among the H-reflex amplitudes recorded at the different stimulus intensities.
Measured: Day 1
H/M ratio
H/M ratio is the ratio between H-reflex amplitude and M-wave amplitude.
Measured: Day 1
iSP (Ipsilateral Silent Period) durations
Eight stimuli are applied over the hotspot at an intensity of 140 percent of the stimulator output while subjects are performing a voluntary maximal contraction of the ipsilateral hand, with a figure-of-eight coil for transcranial magnetic stimulation (TMS). Both hemispheres are tested.
ISP durations are determined by rectifying the EMG traces and averaging them among the 8 stimuli. Baseline EMG is defined as the average value of EMG in the 100 ms before the TMS stimulus. ISP onset is defined as the latency at which the averaged EMG activity became constantly (for at least 10 ms) smaller than the average baseline EMG. ISP offset is set at the first point after ISP onset at which the EMG activity regained the baseline activity for at least 10 ms. ISP duration is defined as: ISPduration = ISPoffset - ISPonset.
Measured: Day 1
iSP (Ipsilateral Silent Period) area
Eight stimuli are applied over the hotspot at an intensity of 140 percent of the stimulator output while subjects are performing a voluntary maximal contraction of the ipsilateral hand, with a figure-of-eight coil for transcranial magnetic stimulation (TMS). Both hemispheres are tested.
ISParea is computed as the product between baseline EMG and iSP duration.
Measured: Day 1
SICI (Short interval IntraCortical Inhibition)
A paired pulse will be applied over the hand area of the motor cortex to evoke EMG responses in the contralateral muscle. The conditioning stimuli will be given at an intensity of 75 percent of the resting Motor Threshold (rMT) and the test stimuli will be given at an intensity of 120 percent of the rMT. The interstimulus intervals will be 3 and 5 ms. For each interstimulus interval, 8 stimuli will be applied in a random order.
Measured: Day 1
SICF (Short interval IntraCortical Facilitation)
A paired pulse will be applied over the hand area of the motor cortex to evoke EMG responses in the contralateral muscle. The conditioning stimuli will be given at an intensity of 75 percent of the resting Motor Threshold (rMT) and the test stimuli will be given at an intensity of 120 percent of the rMT. The interstimulus intervals will be 15 and 20 ms. For each interstimulus interval, 8 stimuli will be applied in a random order.
Measured: Day 1
SOT score
The patient's task is to maintain an upright stance during 3 20 s trials under six different conditions, including platform and visual surround 'tuned' with individual's sagittal oscillation. The SOT score will be calculated by comparing the sagittal oscillation of the body's centre of mass (COM) to the maximal sagittal oscillation. Score is averaged across the six conditions (range 0 - 100 the higher the score, the lower the oscillation, in each condition).
Measured: Day 1
Map area of quadriceps muscle
Transcranial magnetic stimulation (TMS) will be used to map cortical representation of quadriceps muscle. An optoelectronic neuronavigation system will be used to digitize the scalp stimulation coordinates, to guide the TMS coil to focus on a stimulation site, and to ensure spatial precision during the procedure. Two or three TMS stimuli will be delivered at each of the stimulated scalp sites. The largest peak-to-peak MEP amplitude (mean of three MEPs) across the positions making up the motor map was measured. The map area was defined as the number of scalp positions associated with the mean MEP amplitude larger than 100 μV.
Measured: Day 1
Ankle joint power
Joint kinematics will be recorded through an optoelectronic method as per the Davis anthropometric model. The 3D displacement of the markers will be captured using 10 near-infrared stroboscopic cameras. Joint power will be computed through the spatiotemporal synchronization of ground reaction force vectors and the joint centers of rotation. Only the sagittal plane will be considered for the analysis. Joint power will be computed as the product of joint torque and joint rotation speed. Power will be defined as positive or generated when the joint moment and rotation speed shared the same directions (i. e., when agonist muscles are contracting while shortening), as negative or absorbed otherwise. Positive work will be computed as the integral of the generated (positive) power over time.
Measured: Day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Apr 2021
- Study start14 Jul 2021
- Primary completion31 Dec 2024
- Study completion31 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Anterior Cruciate Ligament InjuriesStudies of the same condition, open and under way.
- More trials run by Istituto Auxologico ItalianoThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Istituto Auxologico Italiano
- Sponsor type
- University, hospital or other
- Collaborators
- ASST Gaetano Pini-CTO
- Responsible party
- Sponsor
- Investigators
- Luigi Tesio, MD, Full professor, Principal investigator, Istituto Auxologico Italiano
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04837417
- Sponsor's protocol ID
- 24C021_2020
- Acronym
- AQUARIUS
- Status last verified
- Nov 2025
- First submitted
- 31 Mar 2021
- Last updated
- 18 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
Scarano S, Caronni A, Menon A, Rota V, Amadei M, Perucca L, Brevi E, Maione A, Ferrua P, Tesio L, Randelli PS. Anterior cruciate ligament reconstruction is associated with increased corticospinal excitability and rate of force development. BMC Sports Sci Med Rehabil. 2026 Feb 9;18(1):123. doi: 10.1186/s13102-026-01577-0.
PubMed 41656237
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Deficit in Quadriceps Voluntary Activation After Anterior Cruciate Ligament Reconstruction: Roles of the "Learned Non-use" Paradigm and the Interhemispheric Inhibition
- ClinicalTrials.gov ID
- NCT04837417
- Acronym / sponsor ID
- AQUARIUS / 24C021_2020
- Conditions
- Anterior Cruciate Ligament Injuries
- Keywords
- Anterior cruciate ligament reconstruction, acquired non-use, voluntary activation, quadriceps femoris, rehabilitation
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Istituto Auxologico ItalianoUniversity, hospital or other
- Collaborators
- ASST Gaetano Pini-CTO
- Study start
- 14 Jul 2021 (actual)
- Primary completion
- 31 Dec 2024 (actual)
- Study completion
- 31 Dec 2024 (actual)
- First posted
- 8 Apr 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.
Anterior cruciate ligament (ACL) tear is mainly caused by sport injuries. 40% of injuries are attributed to noncontact mechanisms involving pivoting. Regaining quadriceps strength is a primary focus of patients pursuing a rehabilitation program after ACL reconstruction (ACLR). Unfortunately, despite rehabilitation programs aimed at reversing this muscle weakness, quadriceps strength deficits may persist for years. Moreover, this deficit leads to increased risk of sustaining another knee injury, and increased risk for developing posttraumatic osteoarthritis. At present, neither the optimal rehabilitative program nor the clinical and instrumental parameters to take into account at the time of return to activity have reached a consensus among clinicians.
The investigators hypothesize that:
- a persistent deficit in voluntary activation, that is an inability to achieve complete activation of a muscle, is present after ACLR.
- this deficit in voluntary activation is associated with a phenomenon of "learned/acquired non-use" both in balance and during gait. This phenomenon will be demonstrated by investigating asymmetries in the recruitment of the injured lower limb in balance tests and during gait.
- the "learned/acquired non-use" paradigm is associated to asymmetries in the hemispheric cortical activity. This phenomenon will be investigated through transcranial magnetic stimulation.
The primary endpoint is the demonstration that the quadriceps muscle weakness after ACLR may represent a case of "learned non-use". This behaviour looks automatic and unconscious, so that the adjective "acquired" seems preferable to "learned". It consists of the under recruitment of the impaired side, once healed, as a form of unconscious protection, which is adopted when the contralateral side may carry out the function.
The secondary outcome is the investigation of the correlation among the deficits in voluntary activation, in balance tests, during gait, and in the neurophysiologic trials, with the clinical conditions of the patients.
It is expected that the injured lower limb show a deficit in the activation of the quadriceps muscle with respect to the contralateral one and with respect to normative data. The impaired limb will present lower recruitment in balance tests and a deficit in power production during gait.
The contralesional hemisphere will demonstrate higher interhemispheric inhibition, lower short-interval intracortical inhibition (SICI) and higher short-interval intracortical facilitation (SICF) with respect to the ipsilesional hemisphere.
The evidence for an asymmetry between the two lower limbs would support the hypothesis that the "acquired non-use" paradigm has a role in the deficits following ACL lesions and that it is unspecific across asymmetric impairments, and independent of the underlying disease.
Results from the present study will allow:
- the identification of clinical and instrumental criteria to guide the return-to-sport decision following ACLR.
- the estimate of the sample size for future experimental protocols and new rehabilitative programs.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pathologic group | – | Diagnostic Test: Pathologic groupAt least 10 male participants who underwent anterior cruciate ligament arthroscopic reconstruction using semitendinosus and gracilis tendons graft, between 6 and 18 months before the tests |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- Study population
- The participants will be recruited by ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Presidio Ospedaliero Gaetano Pini, among those who underwent the surgical interventions in the Centre.
Key inclusion criteria (6 listed)
- anterior cruciate ligament tear with arthroscopic reconstruction, between 6 and 18 months before the tests;
- Tegner activity level > 5;
- Body Mass Index between 18 and 25;
- voluntary knee extension of at least 70°;
- ability to understand the instructions;
Key exclusion criteria (12 listed)
- other previous knee injuries or surgical interventions;
- major procedures associated with the anterior cruciate ligament reconstruction: osteotomy, other ligaments reconstruction;
- meniscectomy, with surgical removal of more than 30% of the meniscal volume or removal of the meniscal root;
- comorbidities, such as: rheumatic diseases; other congenital or acquired neuromuscular pathologies; diabetes mellitus; osteoporosis; cancer; heart disease; history of epilepsy, endocranial hypertension;
- first degree relatives affected by epilepsy;
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 |
|---|---|---|
| Pathologic groupVoluntary Activation level will be determined with the interpolate twitch technique (ITT), both during isometric contractions (knee at 40° flexion) and during isokinetic contraction at angular velocity equal to 100°/s. Vastus Medialis and Soleous H-reflex will be measured. Cortical excitability and interhemispheric connectivity will be measured through transcranial magnetic stimulation (TMS). Tests of balance in standing will be performed using the EquiTest platform. Individuals will be requested to perform three different tasks: Sensory Organization test, Adaptation Test upward/downward, Motor Control test backward/forward. Surface electromyography from lower limbs will be recorded. Through TMS driven by neuronavigation, the cortical representation of the Quadriceps muscle will be studied. Gait analysis will be performed on a treadmill mounted on force sensors. Participants will walk at increasing velocities from 0.4 m/s to 1.6 m/s. Speed will be increased of 0.2 m/s every 30 s. | Diagnostic test | Pathologic group |
Primary outcome
Voluntary Activation
Time frame: Day 1
Voluntary Activation = [1 - (Interpolated Twitch/Resting Twitch)] percent, where Interpolated Twitch and Resting Twitch are the peak torques caused by the electric shock during the voluntary contraction and at rest, respectively.
9 secondary outcomes
H-reflex minimal latency
Time frame: Day 1
H/M ratio
Time frame: Day 1
iSP (Ipsilateral Silent Period) durations
Time frame: Day 1
iSP (Ipsilateral Silent Period) area
Time frame: Day 1
SICI (Short interval IntraCortical Inhibition)
Time frame: Day 1
SICF (Short interval IntraCortical Facilitation)
Time frame: Day 1
SOT score
Time frame: Day 1
Map area of quadriceps muscle
Time frame: Day 1
Ankle joint power
Time frame: Day 1
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2025.
- Derived from this study: PubMed 41656237Scarano S, Caronni A, Menon A, Rota V, Amadei M, Perucca L, Brevi E, Maione A, Ferrua P, Tesio L, Randelli PS. Anterior cruciate ligament reconstruction is associated with increased corticospinal excitability and rate of force development. BMC Sports Sci Med Rehabil. 2026 Feb 9;18(1):123. doi: 10.1186/s13102-026-01577-0.
- Individual participant dataSharing planned: Yes
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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.
Luigi Tesio, MD, Full professor principal investigator
Istituto Auxologico Italiano
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Anterior Cruciate Ligament Injuries, run by Istituto Auxologico Italiano at 2 sites in Italy.
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 6 inclusion and 12 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: finished, as of the sponsor's last update on 18 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. 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.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Voluntary Activation (time frame: Day 1). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04837417, which also lists 1 linked publication.
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 18 Nov 2025.