Introduction
Preventing the occurrence of anterior cruciate ligament (ACL) injury and rehabilitation of this ligament injury is still one of the main priorities of the sports medicine community [1]. Approximately, 35% of people with an anterior cruciate ligament injury are unable to return to their previous activity level [2, 3, 4]. Following the primary ACL injury, the occurrence of secondary injury or injury in the opposite knee in the first five years reaches more than 23%, especially in young athletes under 25 years [5, 6]. Emerging neuro-mechanical evidence suggests that altered post-injury biomechanics [7] may partially account for unresolved changes throughout the central nervous system (CNS) following an ACL injury that affects the involved and non-involved organs even after their reconstruction [8, 9, 10]. For example, in people with ACL reconstruction, brain activity related to the injured knee is seen differently in important areas related to vision, attention, and sensorimotor integration compared to uninjured people of the same age [11, 12, 13].
Regarding the significant effect of brain neuroplasticity on the occurrence of injuries in general, injuries that cause structural and functional changes in the brain, and the lack of past research directly addressing brain-related factors, the purpose of the present review was to investigate the following factors: 
1. Investigating the effects of brain neuroplasticity on the occurrence of anterior cruciate ligament injury
2. The effects of this ligament injury on the brain function and structure.
Materials and Methods
This review article was an attempt to collect the studies conducted on the role of brain function on the incidence of ACL non-collision, as well as the impact of this ligament injury on the functional and structural changes of the brain from 1980 to 2021. These articles were searched through Web of Science (WOS), Google Scholar, ScienceDirect, Scopus, PubMed, Medline, PEDro, CINAHL, Sport Discus, and Cochrane database of systematic reviews. The keywords in this search included the following items and their synonyms:
Brain AND Neuroplasticity AND ACL injury, Brain OR cortical AND (neuroplasticity OR activation) AND ACL (rupture OR deficiency), Corticomotor AND (neuroplasticity OR excitability) AND ACL (injury OR reconstruction), Brain function AND anterior cruciate ligament injury, Brains, and Sprains.
To search the Persian articles, Scientific Information Database (SID), ISC, Magiran, IranDoc, IranMedex, and Medlib databases were searched using a variety of keywords, including brain function and anterior cruciate ligament rupture, anterior cruciate ligament rupture and brain neuroplasticity, anterior cruciate ligament reconstruction and brain neuroplasticity, dysfunctional damaged anterior cruciate ligament and brain neuroplasticity. In addition, the mentioned English keywords were also used to find English articles published in national scientific journals and a manual search was also used to find the related articles. The authors evaluated the title and abstract of each study separately. The first step in selecting relevant articles was to see if the abstract or the title of the article is consistent with the research topic or not. The next stage was the selection of articles according to the following inclusion and exclusion criteria:
Inclusion criteria
1. Studies published in English and Persian
2. The full text of the article is available
3. Studies that investigated the role of the brain in the occurrence of anterior cruciate ligament injury
4. Studies that evaluated the effect of the unreconstructed anterior cruciate ligament on brain neuroplasticity
5. Studies that investigated the effect of the reconstructed anterior cruciate ligament on brain neuroplasticity
6. Studies that investigated the effect of the reconstructed anterior cruciate ligament after a rehabilitation period on brain neuroplasticity
7. Quasi-experimental studies, randomized clinical trials, cohort studies, review studies, case series studies, cross-sectional studies, case studies, and case-control studies 
Exclusion criteria
1. Studies whose score was lower than 18 (relatively good) based on the Modified Downs and Black checklist table.
2. Studies that examined the variables of the current research on people with multiple injuries (for example, anterior cruciate ligament injury with a meniscus injury, etc.) in the knee.
Results
After screening the articles based on the title, abstract, and duplicates, articles that did not meet the research criteria were excluded. Finally, 24 articles were selected and reviewed. Of a total of 24 articles, five papers investigated the effect of brain function on the incidence of ACL injury [14, 15, 16, 17, 18]. Among the five articles, two prospective articles by Dickfuss et al. [14, 15] conducted separately on 119 adolescent girls and boys showed that the functional connection of the brain of people who later suffered a cruciate ligament tear was different from people who did not suffer from this ligament injury in some parts, such as the sensorimotor area of the cerebral cortex and cerebellum. In their article, Swanik et al. [17] considered the errors occurring during movement planning by the brain to be the main cause of anterior cruciate ligament injury. The findings of Powers and Fisher [16] also emphasized that skill acquisition exercises, which have a better and long-term effect on the brain than strength exercises, were more effective in preventing anterior cruciate ligament injuries. Finally, regarding the research considering the role of the brain on the occurrence of injury highly important, Dickfus et al. [18] raised a very important question in their research: Is it possible to use the neuroplastic capacity of the CNS in young people for the so-called inoculation and prevention of anterior cruciate ligament injury?
To answer this question, they examined training programs that were designed based on the OPTIMAL PREP strategy (optimizing performance through intrinsic motivation and attention to learning in order to prevent sports injuries). They concluded that performing these exercises with focusing on this strategy created positive neuroplasticity in the brain, which created favorable biomechanical adaptations for injury prevention among both young men and women [1].
The effects of an anterior cruciate ligament injury on brain function and structure
Out of the 24 finalized articles, 19 articles investigated the impact of anterior cruciate ligament damage on brain function and structure. Of these, ten articles before reconstruction [19, 20, 21, 22, 23, 24, 25, 26, 27, 28], six articles after reconstruction [2, 3, 4, 5, 6, 7], two articles after reconstruction and rehabilitation exercises [34, 35], and one article both before and after reconstruction [36], investigated the effect of an anterior cruciate ligament injury on brain function and structure.
Kakavas et al. [22] and Neto et al. [25] reported that at least two weeks after the ACL injury, they observed changes in the level of the sensory cortex and the motor cortex of the brain, and after one year, these structural and functional changes widely increased in injured people compared to healthy people. Capreli et al. [23] concluded that a dysfunctional injured ligament causes reorganization in the CNS. Valeriani et al. [27] showed that due to the damage to mechanoreceptors, central somatosensory pathways change functionally in injured people. In the same line, Yang Wu et al. [19] also showed that one of the most important reasons for continuous functional instability in the injured knee is the change in the processing in the CNS and brain neuroplasticity.
Another important research finding was the change in the activity of motor-visual areas in injured people compared to healthy people. Grooms et al. in a prospective study pointed out [6] that the control activity of visual-motor areas increases in injured people compared to healthy people. Sowanik et al. [26] also concluded that visually impaired people had a weaker performance compared to healthy people. In another research, Grooms et al. [21] also reported that there are changes in the brain of people with ACL rupture so that the injured person will need visual feedback to control the knee more than before. Finally, Heroux and Tremblay [28] showed that in response to unilateral knee disorder resulting from anterior cruciate ligament rupture, long-term adaptation occurs in the cerebral cortex system, which moves motor strategies from a semi-automatic state to a more voluntary state.
The effects of anterior cruciate ligament reconstruction on brain function and structure out of the six studies related to this part, two studies by Zarzycki et al. [33] and Pietrosimone et al. [32] reported neuroplasticity of the brain related to the vastus medialis muscle. Two other studies by Chris et al. [29] and Gromes et al. [30] also reported changes related to vision after anterior cruciate ligament reconstruction compared to healthy subjects.
Baumeister et al. [37] indicated that after the reconstruction of the anterior cruciate ligament, sensory afferent information changed due to a decrease in peripheral proprioception, and this information did not match the expected information in long-term memory in the brain, which causes changes in the cerebral cortex related to memory processes.
Lepley et al. [31] also observed asymmetry in structural features as well as corticospinal excitability and white matter in the hemisphere associated with the reconstructed limb compared to the hemisphere associated with the healthy leg.
Valeriani et al. [36] who examined seven people before and after anterior cruciate ligament reconstruction concluded that after arthroscopy and knee reconstruction, neither knee proprioception nor central somatosensory conduction improved until two years later.
The effect of anterior cruciate ligament reconstruction and a rehabilitation exercise period on brain function and structure
The only research in this area was the prospective cohort study by Zaraycki et al. [34] showing that after 12 weeks of rehabilitation exercises, the change in corticospinal stimulation of the study subjects was not only standing but also increasing compared to healthy people.
Discussion
In anterior cruciate ligament injury, there are at least two important factors that guide us to investigate the role of the brain in the prevention, occurrence, and rehabilitation of this type of ligament injury. The first factor is the failure of the brain to accurately recognize any coordination errors, and the second factor is the high rate of anterior cruciate ligament rupture before any muscular intervention for support. Studies have shown that 40 to 70 ms are enough to tear the anterior cruciate ligament [38], while the initiation of the reflex response, as well as the accurate recognition of any coordination error and the subsequent creation of muscle tension to create stiffness, can take up to 500 ms [39, 40, 41].
Therefore, in order to increase the athlete’s speed and movement power, it is necessary to develop cognitive planning by the brain through movement control via feed-forward or predictive role. Otherwise, not only relying too much on muscle power is insufficient to create dynamic stability, but also an overreliance on reflex strategies may not be sufficient to support the anterior cruciate ligament [33]. Two prospective studies by Dickfuss et al. showed that the functional connectivity of the brain of people who later suffered anterior cruciate ligament rupture was different from people who did not suffer the injury in areas, including the motor cortex and cerebellum [14, 15]. Unlike the research related to brain function in the occurrence of anterior cruciate ligament injury, the research related to the effect of an anterior cruciate ligament injury on the function and structure of the brain has received the attention of researchers more widely. In this line, Kakavas et al. [22] and Neto et al. [25] reported that at least two weeks after an anterior cruciate ligament injury, changes were observed at the level of the sensory cortex and the motor cortex of the brain. After one year, not only these structural changes maintained but also highly increased. 
To answer the question related to the effects of these functional and structural changes on the brain after the rupture of the anterior cruciate ligament, it should be noted that we are currently at the beginning of the road to reach the answer and more extensive studies are still needed. However, one of the effects that neuroplasticity causes are the change in visual function that has been proven relatively. For example, Grooms et al. [21] showed that the control activity of visual-motor areas increased in injured people compared to healthy people. 
The ongoing debate is whether all the functional and structural changes that occur in the brain after the anterior cruciate ligament rupture will also remain in the same form after the anterior cruciate ligament reconstruction or not. It should be said that all six articles were found almost unanimous in concluding that these changes were also seen in people who had their cruciate ligament reconstructed, even months after the reconstruction. In this regard, Valeriani et al. [36] showed that the loss of knee mechanoreceptors is associated with changes in the CNS that are not compensated by other nervous structures.
In the third part of the discussion, according to the research results, we will answer the question whether rehabilitation exercises can eliminate all these negative changes in brain function and structure after rupture and reconstruction. Unfortunately, only one study was found in this area by Zaraycki et al. [34], which was conducted as a prospective cohort in 2020. They used a 12-week training protocol. Zaraycki et al. evaluated the brain changes before the rehabilitation period, i.e. two weeks after the operation, and also after a 12-week rehabilitation period. They showed that two weeks after surgery and before the start of rehabilitation exercises, the group that had reconstructed their anterior cruciate ligament had a change in corticospinal stimulation compared to healthy athletes. Also, after 12 weeks of rehabilitation exercises, the changes in the corticospinal stimulation in these people increased compared to healthy people.
Like the approaches to prevent injuries to this ligament, another very important point and question that should be mentioned at the end of the discussion is whether the currently accepted rehabilitation approaches are responsible for the proper return of athletes to activities. The high rate of re-injury as well as the inability to restore functional capacity suggests that the current standards of care for the anterior cruciate ligament, including reconstruction and rehabilitation, cannot be adequately extended to defects that existed before or after the injury [42, 43, 44, 45].
In a review article to optimize rehabilitation exercises and reduce the incidence of secondary injury of the anterior cruciate ligament in 2019, Gokeler et al. [35] proposed integrated clinical exercises using new principles of motor learning in order to support brain neuroplasticity. They proposed the following key concepts to strengthen the rehabilitation program and prepare the patient to return to sports activities after an ACL injury:
1: Performing exercises using external attention and focus, 2: performing exercises using the principles of implicit learning, 3: performing exercises using the principles of differential learning, and 4: performing exercises using the principles of self-controlled learning and contextual interference. The new principles of motor learning presented in this publication may optimize the future of rehabilitation programs and reduce the risk of secondary ACL injury, as well as the early progression of osteoarthritis in these individuals by targeting neuroplastic changes in the brain.
Possibly, the suggestion proposed by Grooms et al. with the highest number of studies in this area can be suggested at the end of this part of the discussion. They point out that the proposed rehabilitation exercise framework is best suited to bring together evidence from neuroscience, biomechanics, motor control, and psychology to support the integration of neurocognitive and visual-motor approaches with traditional neuromuscular interventions during anterior cruciate ligament injury rehabilitation [30].

Ethical Considerations
Compliance with ethical guidelines
This study was a systematic review and no experiments on animal or human samples were conducted.

Funding
This study did not receive funding from any organizations in for-profit or non-profit sectors.


Authors' contributions
Conceptualization, methodology, validation, data analysis, investigation, resources, editing & review, visualization, project administration, supervision, and funding acquisition:  All authors; initial draft preparation: Mostafa Payandeh.

Conflict of interest
The authors declare no conflict of interest.


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