iPhone Targeted Content
iPad Targeted Content
Android Targeted Content
Blackberry Targeted Content
Desktop and all none targeted content
iPhone Targeted Content
THE CLINICAL CLARITY BLOG
Knees, Spines and the Bayesian Brain
Part 1
October 16, 2021 by DR MATTHEW D. LONG
iPad Targeted Content
Android Targeted Content
THE CLINICAL CLARITY BLOG
Knees, Spines and the Bayesian Brain
Part 1
October 16, 2021 by DR MATTHEW D. LONG
Blackberry Targeted Content
Desktop and all none targeted content
THE CLINICAL CLARITY BLOG
October 16, 2021 by DR MATTHEW D. LONG
You really can't get a problem that's more 'mechanical' than a knee complaint. Whether it is a meniscal tear, patellofemoral pain, or just plain osteoarthritis, most clinicians would agree that such problems are largely the result of deranged anatomy, and therefore should be treated as such. But any doctor with a modicum of experience would admit that there are some patients who will fail to respond, even to the most sophisticated forms of surgical treatment. The anatomy is repaired, but the pain persists.
Conversely, we often come across patients who have significant degeneration, yet little (or no) pain (1). So what is the difference?
Is the problem of chronic pain simply one of stubborn inflammation in a worn-out joint? Or does the answer lie somewhere completely outside of the structural components themselves? According to Louw and colleagues (18), the problem lies within the brain's perception of our body, even in cases where surgery seems to be successful. They wrote,
Conversely, we often come across patients who have significant degeneration, yet little (or no) pain (1). So what is the difference?
Is the problem of chronic pain simply one of stubborn inflammation in a worn-out joint? Or does the answer lie somewhere completely outside of the structural components themselves? According to Louw and colleagues (18), the problem lies within the brain's perception of our body, even in cases where surgery seems to be successful. They wrote,
"Pain is complex and recent research highlights the finding that pain is more likely be a measure of potential threat, than of true tissue health. The greater the perceived threat, the higher the pain experienced. Most patients view pain as an indicator of tissue health and if they believe that activity may further damage their tissue and thus increase pain, they may decrease physical movements as a logical protective mechanism. The surgical experience may likely be interpreted by the patient’s brain as the process of correcting faulty tissue. Once completed, the perception of a painful, movement limiting degenerative disc, vertebral fracture, arthritic knee or chronically inflamed elbow is re-evaluated by the brain, resulting in decreased pain and increased function."
The important distinction here is that pain is 'more likely be a measure of potential threat'. The average person defines pain as a 'signal from the body to the brain that something is wrong'. But science now tells us that this is too simplistic. We experience pain when the brain thinks that something is wrong - and this is not always the case.
Jonas et al (19) have written further about the role of surgery in the treatment of chronic musculoskeletal pain,
Jonas et al (19) have written further about the role of surgery in the treatment of chronic musculoskeletal pain,
"There is little evidence for the specific efficacy beyond sham for invasive procedures in chronic pain. A moderate amount of evidence does not support the use of invasive procedures as compared with sham procedures for patients with chronic back or knee pain. Given their high cost and safety concerns, more rigorous studies are required before invasive procedures are routinely used for patients with chronic pain."
Could it be that surgery, when successful, is simply due to a change in the brain's understanding of the body under its charge?
This notion that surgery might influence a patient's perception of pain is gaining much greater attention in the biomedical literature. It is further placing the spotlight on which surgical procedures are truly effective as a result of improving the anatomy, and which might be an elaborate form of medical theatre. For example, in recent years there has been a groundswell of concern about the appropriateness of arthroscopy for degenerative meniscal tears (2,3,4). This has come about as the evidence has repeatedly shown that structural pathologies within the knee are not related to chronic pain and symptoms (5), and that "The small inconsequential benefit seen from interventions that include arthroscopy for the degenerative knee is limited in time and absent at one to two years after surgery" (4). And it's not just knee surgery that has drawn such criticism. Harris et al (17) looked at the supporting evidence for surgery to address many common musculoskeletal problems and wrote,
This notion that surgery might influence a patient's perception of pain is gaining much greater attention in the biomedical literature. It is further placing the spotlight on which surgical procedures are truly effective as a result of improving the anatomy, and which might be an elaborate form of medical theatre. For example, in recent years there has been a groundswell of concern about the appropriateness of arthroscopy for degenerative meniscal tears (2,3,4). This has come about as the evidence has repeatedly shown that structural pathologies within the knee are not related to chronic pain and symptoms (5), and that "The small inconsequential benefit seen from interventions that include arthroscopy for the degenerative knee is limited in time and absent at one to two years after surgery" (4). And it's not just knee surgery that has drawn such criticism. Harris et al (17) looked at the supporting evidence for surgery to address many common musculoskeletal problems and wrote,
"We conclude that many common surgical procedures performed for musculoskeletal conditions causing chronic pain have not been subjected to randomised trials comparing them to not performing the procedure. Based on the observation that when such studies have been performed, only 14% (on average) showed a statistically significant and clinically important benefit to surgery; there is a need to produce such high quality evidence to determine the effectiveness of many common surgical procedures."
Of course, our natural reluctance to accept new ideas that challenge the status quo (and our livelihoods) means that many such procedures remain hugely popular. However, questions are now being asked about arthroscopy for degenerative knees, and it serves as a convenient vehicle to challenge our models of musculoskeletal pain. If anatomical 'damage' is not the driver of chronic knee or back pain, then where is the evidence that it is truly an artefact of perception?
Fortunately, the research provides us with many clues. For example, young women who suffer long-standing or recurrent patellofemoral pain show impaired conditioned pain modulation, increased temporal summation of pain, and widespread hyperalgesia (6,7). In other words, their propensity to pain is not simply due to mechanical factors. According to Holden et al (6), who published a study examining the characteristics of sufferers,
Fortunately, the research provides us with many clues. For example, young women who suffer long-standing or recurrent patellofemoral pain show impaired conditioned pain modulation, increased temporal summation of pain, and widespread hyperalgesia (6,7). In other words, their propensity to pain is not simply due to mechanical factors. According to Holden et al (6), who published a study examining the characteristics of sufferers,
"This study is the first to demonstrate altered pain mechanisms in those with a previous history of adolescent patellofemoral pain (PFP) who are currently pain-free, providing the first potential mechanism for explaining their recurrent knee-pain episodes. The increased pain sensitivity and facilitated pronociceptive mechanisms in the recovered-PFP group means that minimal/reduced nociceptive input would be required for subsequent pain episodes to occur in this group. Dynamic processes influenced by past pain inputs or “somatosensory pain memories” may play a role."
Te and colleagues (8) found that the primary motor cortex (M1) is altered in those suffering from persistent patellofemoral pain, specifically the area relating to the quadriceps muscle. These changes cause a down-regulation of the normal intermuscular co-ordination seen in healthy states and lead to the adoption of 'simplified movement patterns'. As we shall see later within the context of lumbar complaints, this loss of movement diversity is maladaptive and frequently associated with pain. Indeed, the literature has made much of the changes in movement patterns that occur in musculoskeletal pain patients (9). While some of this clearly involves the traditional areas of central motor control, other research has implicated the limbic system, and a patient's beliefs about their pain, as primary drivers of their ongoing disability (10,11,12). A fascinating paper by Robertson et al (10) examined the correlation between an individual's beliefs about the meaning of crepitus in patellofemoral pain, and the impact of those beliefs upon their subsequent behaviour. Simply put, "Participants frequently voiced concern that their knee was prematurely ageing, and many linked this with their belief that the noise represented bone-on bone, or wear." As a consequence, they slowed their movements, became more vigilant, ceased performing certain activities and adopted the behaviours that they felt were appropriate for someone with an old, arthritic joint. However, it is important to appreciate that there is no evidence to suggest any relevant link between between joint noise and pathology (9), and that crepitus is often present in the complete absence of any joint damage (13).
The role of the limbic system, and a patient's beliefs about their condition, has also been studied extensively within the context of knee replacement surgery. Ever since the procedure began widespread adoption it has been noted that "patients who preoperatively have psychological distress (pain catastrophizing and high mental distress) and psychological disorders (somatization dysfunction and anxiety and/or depression) are more likely to have a poor outcome after total knee arthroplasty (TKA) compared with patients without psychological distress" (14). This is important, as the proportion of patients who are unsatisfied with the long‐term pain outcome ranges from 10% to 34% (15). Indeed, 15% of individuals have severe and ongoing postsurgical pain. According to Escobar and colleagues (15), "We have found 2 modifiable baseline factors, expectations and mental health, that should be properly managed by different specialists. Indication of total knee replacement (TKR) should take into account these modifiable factors for improving outcomes after TKR."
Why might this be so? Why do psychological factors rank higher than physical variables when predicting the ultimate success of knee replacement surgery?
The role of the limbic system, and a patient's beliefs about their condition, has also been studied extensively within the context of knee replacement surgery. Ever since the procedure began widespread adoption it has been noted that "patients who preoperatively have psychological distress (pain catastrophizing and high mental distress) and psychological disorders (somatization dysfunction and anxiety and/or depression) are more likely to have a poor outcome after total knee arthroplasty (TKA) compared with patients without psychological distress" (14). This is important, as the proportion of patients who are unsatisfied with the long‐term pain outcome ranges from 10% to 34% (15). Indeed, 15% of individuals have severe and ongoing postsurgical pain. According to Escobar and colleagues (15), "We have found 2 modifiable baseline factors, expectations and mental health, that should be properly managed by different specialists. Indication of total knee replacement (TKR) should take into account these modifiable factors for improving outcomes after TKR."
Why might this be so? Why do psychological factors rank higher than physical variables when predicting the ultimate success of knee replacement surgery?
IS IT ALL IN THE HEAD?
At this point it is important to pause and reflect for a moment upon what exactly is meant by terms like 'psychological'. When used colloquially this is often interpreted pejoratively - such as "It's all in your head". However, once we truly understand the way that pain works we'd quickly realise that all pain is always in all of our heads. Unlike nociception, the experience of pain is a creation of the brain itself, not the body (we'll come back to this idea later). This gives rise to the oft-quoted saying that "All pain is real", which means that we should believe the patient who is in pain and try not to judge some forms of pain experience as less valid than others. Weisman et al (20) stated it nicely when they wrote,
"First, the human body does not possess a pain system responsible for the processing of pain signals. This epistemological error appears to arise from a conflation of pain (an experience) with nociception (a neurobiological process). Experiences cannot travel via nerves nor can they ever be reduced to an electrical signal."
To put this another way, 'nociception' travels along the nerves to the brain and 'pain' is the response (once the brain has interpreted the input and decided what it means). This is similar to the process of hearing a joke (the sensory input) and deciding whether it is funny, or offends you (the response). In this case the amusement or anger responses are the equivalent of pain. Pain comes after an evaluation, and therefore it depends upon many preconceived ideas about what the sensory inputs might mean.
To illustrate the overlap between the anatomical and the psychological domains we can learn from an interesting study by Lewis et al (16), entitled 'Structural Brain Alterations Before and After Total Knee Arthroplasty: A Longitudinal Assessment'. The authors were particularly interested in why some patients fail to recover after seemingly successful knee replacement surgery. Specifically, they looked at an area of pain processing called the nucleus accumbens (NAc), which plays a role in the expectation of noxious stimuli and anticipation of pain relief. As we shall see later in this article, expectation is key when it comes to pain. In Lewis' study they found an alteration in the volume of the NAc in those with knee OA. They wrote,
To illustrate the overlap between the anatomical and the psychological domains we can learn from an interesting study by Lewis et al (16), entitled 'Structural Brain Alterations Before and After Total Knee Arthroplasty: A Longitudinal Assessment'. The authors were particularly interested in why some patients fail to recover after seemingly successful knee replacement surgery. Specifically, they looked at an area of pain processing called the nucleus accumbens (NAc), which plays a role in the expectation of noxious stimuli and anticipation of pain relief. As we shall see later in this article, expectation is key when it comes to pain. In Lewis' study they found an alteration in the volume of the NAc in those with knee OA. They wrote,
"There was decreased gray matter volume bilaterally in the amygdala and nucleus accumbens (NAc), as well as the ipsilateral S1 in the preoperative (PREOP) group compared with the controls. Both the NAc and the amygdala are subcortical components of the limbic system, with the latter implicated in conveying emotional significance to sensory input and initiating behavioral and affective responses, particularly in relation to fear. It may have a pronociceptive role in persistent pain conditions due to its high connectivity with the brainstem centers that mediate descending pain modulation. Furthermore, the amygdala appears to play a prominent role in OA-related pain, with its activation associated with OA pain intensity, daily variation in symptoms, and analgesic use. In agreement with previous findings in a hip OA population, we observed decreased amygdala volume in people with knee OA compared with controls with a subsequent reversal (increase) in volume following joint arthroplasty."
WHAT ABOUT THE SPINE?
Of course, such brain changes are not limited to disorders of the knee. The spine is also an area that has been extensively studied, and its complexity makes it even more susceptible to maladaption within the brain.
Investigators have documented numerous alterations to brain function in long-term spinal pain sufferers. Many clinicians are aware of the current interest in brain changes with back pain, but often pool these together under a singular concept like 'central sensitisation' (21), which describes enhanced activity within the pain pathways. However, this does not fully encapsulate the real dimensions of the problem. Chronic lower back pain patients show many irregularities which are thought to perpetuate their suffering, irrespective of the state of their tissues. Indeed, while tissue damage is often the initiator of pain, it is not necessary for its continuation. I wrote about this previously in the article "Yes chiropractic is 'neurological', but what does that actually mean?" (here), which is worth reviewing. Goosens et al (22) summarised this as follows,
Investigators have documented numerous alterations to brain function in long-term spinal pain sufferers. Many clinicians are aware of the current interest in brain changes with back pain, but often pool these together under a singular concept like 'central sensitisation' (21), which describes enhanced activity within the pain pathways. However, this does not fully encapsulate the real dimensions of the problem. Chronic lower back pain patients show many irregularities which are thought to perpetuate their suffering, irrespective of the state of their tissues. Indeed, while tissue damage is often the initiator of pain, it is not necessary for its continuation. I wrote about this previously in the article "Yes chiropractic is 'neurological', but what does that actually mean?" (here), which is worth reviewing. Goosens et al (22) summarised this as follows,
"Sensorimotor impairments have been identified as possible key factors in the development and recurrence of nonspecific LBP. For example, patients with LBP show a disrupted body schema of the trunk and a decreased tactile and proprioceptive acuity at the lumbar spine compared with healthy controls. To compensate for the less accurate lumbosacral proprioceptive signals, patients with LBP predominantly use ankle muscle proprioception during postural control. This altered use of proprioception in patients with LBP resulted in increased postural sways during challenging postural conditions and was related to a worse sit-to-stand-to-sit performance compared with healthy subjects. Altogether, this vast body of behavioral work indicates that patients with LBP show sensorimotor impairments, which can be present before the emergence of pain."
Stanton and colleagues (23) said the following,
"There is consistent evidence of perceptual abnormalities in people with LBP: alterations in perceived shape of the back; reduced tactile acuity at the back; impaired motor imagery of the back; and impaired trunk voluntary motor control. Our work suggests that this dysfunction extends to the perception of force applied to the back. Changes in the perception of touch have been linked to changes of receptive fields and response profiles of primary sensory cortex (S1) neurons – so-called cortical reorganisation, – raising the possibility that alterations in force perception might also represent cortical changes related to the back. That people with back pain are less accurate than healthy controls on a task requiring intact cortical proprioceptive representation supports this possibility."
We could summarise this by suggesting that there is a reduction in sensory acuity, associated with a 'distortion' of the brain's internal representation of the spine (it's 'schema'). In other words, the brain doesn't accurately know where the spine is, and has lost the ability to move it with precision and stability. As a result, the brain often resorts to its default strategy for protection - the production of pain and/or stiffness. But things get even stranger when researchers attempt to objectively measure parameters such as stiffness. Again, it seems that the brain may distort reality. Stanton et al (23) showed that patients with lower back pain may indeed feel 'stiff', but this is not always supported by evidence. They suggest that subjective feelings of spinal stiffness may simply serve as a 'perceptual mechanism' to reduce movement and limit the potential for injury or nociception. In other words, the brain makes us feel stiff, so as to avoid potential harm, although nothing has actually changed to produce objective stiffness of the spinal tissues. They further question whether a patient's description of stiffness may actually represent a 'lack of movement velocity', intertwined with a fear of movement (kinesiophobia).
As we can see, the ongoing experience of musculoskeletal pain is complex, involving a number of central mechanisms. Interestingly, there is a theme emerging in the neuroscience literature that sits atop all of these processes - an idea that shall be the focus of part II of this article - the idea of prediction.
As we can see, the ongoing experience of musculoskeletal pain is complex, involving a number of central mechanisms. Interestingly, there is a theme emerging in the neuroscience literature that sits atop all of these processes - an idea that shall be the focus of part II of this article - the idea of prediction.
Something to think about...
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq), FIANM (au)
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq), FIANM (au)
References:
1. Son, K. M., Hong, J. I., Kim, D. H., Jang, D.-G., Crema, M. D., & Kim, H. A. (2020). Absence of pain in subjects with advanced radiographic knee osteoarthritis. BMC Musculoskelet Disord, 21(1), 640. http://doi.org/10.1186/s12891-020-03647-x
2. Abram, S. G. F., Hopewell, S., Monk, A. P., Bayliss, L. E., Beard, D. J., & Price, A. J. (2019). Arthroscopic partial meniscectomy for meniscal tears of the knee: a systematic review and meta-analysis. British Journal of Sports Medicine, bjsports–2018–100223–13. http://doi.org/10.1136/bjsports-2018-100223
3. Roos, E. M., & Thorlund, J. B. (2017). It is time to stop meniscectomy. British Journal of Sports Medicine, 51(6), 490–491. http://doi.org/10.1136/bjsports-2016-097273
4. Thorlund, J. B., Juhl, C. B., Roos, E. M., & Lohmander, L. S. (2015). Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ (Clinical Research Ed), 350, h2747. http://doi.org/10.1136/bmj.h2747)
5. Tornbjerg, S. M., Nissen, N., Englund, M., Jørgensen, U., Schjerning, J., Lohmander, L. S., & Thorlund, J. B. (2017). Structural pathology is not related to patient-reported pain and function in patients undergoing meniscal surgery. British Journal of Sports Medicine, 51(6), 525–530. http://doi.org/10.1136/bjsports-2016-096456
6. Holden, S., Straszek, C. L., Rathleff, M. S., Petersen, K. K., Roos, E. M., & Graven-Nielsen, T. (2018). Young females with long-standing patellofemoral pain display impaired conditioned pain modulation, increased temporal summation of pain, and widespread hyperalgesia. Pain, 159(12), 2530–2537. http://doi.org/10.1097/j.pain.0000000000001356
7. van der Heijden, R. A., Rijndertse, M. M., Bierma-Zeinstra, S. M. A., & van Middelkoop, M. (2018). Lower Pressure Pain Thresholds in Patellofemoral Pain Patients, Especially in Female Patients: A Cross-Sectional Case-Control Study. Pain Medicine (Malden, Mass), 19(1), 184–192. http://doi.org/10.1093/pm/pnx059
8. Te, M., Baptista, A. F., Chipchase, L. S., & Schabrun, S. M. (2017). Primary Motor Cortex Organization Is Altered in Persistent Patellofemoral Pain. Pain Medicine (Malden, Mass), 18(11), 2224–2234. http://doi.org/10.1093/pm/pnx036
9. Silfies, S. P., Vendemia, J. M. C., Beattie, P. F., Stewart, J. C., & Jordon, M. (2017). Changes in Brain Structure and Activation May Augment Abnormal Movement Patterns: An Emerging Challenge in Musculoskeletal Rehabilitation. Pain Medicine (Malden, Mass), 18(11), 2051–2054. http://doi.org/10.1093/pm/pnx190
10. Robertson, C. J., Hurley, M., & Jones, F. (2017). People's beliefs about the meaning of crepitus in patellofemoral pain and the impact of these beliefs on their behaviour: A qualitative study. Musculoskeletal Science & Practice, 28, 59–64. http://doi.org/10.1016/j.msksp.2017.01.012
11. Maclachlan, L. R., Collins, N. J., Matthews, M. L. G., Hodges, P. W., & Vicenzino, B. (2017). The psychological features of patellofemoral pain: a systematic review. British Journal of Sports Medicine, 51(9), 732–742. http://doi.org/10.1136/bjsports-2016-096705
12. Pan, F., Tian, J., Cicuttini, F., Jones, G., & Aitken, D. (2018). Differentiating knee pain phenotypes in older adults: a prospective cohort study. Rheumatology (Oxford, England), 31, 79–10. http://doi.org/10.1093/rheumatology/key299
13. Robertson, C. J. (2010). Joint crepitus - are we failing our patients? Physiotherapy Research International, 15(4), 185–188. http://doi.org/10.1002/pri.492
14. Sorel, J. C., Veltman, E. S., Honig, A., & Poolman, R. W. (2019). The influence of preoperative psychological distress on pain and function after total knee arthroplasty. The Bone & Joint Journal, 101-B(1), 7–14. http://doi.org/10.1302/0301-620X.101B1.BJJ-2018-0672.R1
15. Escobar, A., García Pérez, L., Herrera-Espiñeira, C., Aizpuru, F., Sarasqueta, C., Gonzalez Sáenz de Tejada, M., et al. (2017). Total knee replacement: Are there any baseline factors that have influence in patient reported outcomes? Journal of Evaluation in Clinical Practice, 2(1), 566–8. http://doi.org/10.1111/jep.12765
16. Lewis, G. N., Parker, R. S., Sharma, S., Rice, D. A., & McNair, P. J. (2018). Structural Brain Alterations Before and After Total Knee Arthroplasty: A Longitudinal Assessment. Pain Medicine (Malden, Mass), 19(11), 2166–2176. http://doi.org/10.1093/pm/pny108
17. Harris, I. A., Sidhu, V., Mittal, R., & Adie, S. (2020). Surgery for chronic musculoskeletal pain: the question of evidence. Pain, 161(1), S95–S103. http://doi.org/10.1097/j.pain.0000000000001881
18. Louw, A., Diener, I., Fernández-de-las-Peñas, C., & Puentedura, E. J. (2017). Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Medicine (Malden, Mass), 18(4), 736–750. http://doi.org/10.1093/pm/pnw164
19. Jonas, W. B., Crawford, C., Colloca, L., Kriston, L., Linde, K., Moseley, B., & Meissner, K. (2018). Are Invasive Procedures Effective for Chronic Pain? A Systematic Review. Pain Medicine (Malden, Mass). http://doi.org/10.1093/pm/pny154
20. Weisman, A., Quintner, J., & Masharawi, Y. (2021). Amplified Pain Syndrome - An Insupportable Assumption. JAMA Pediatrics. http://doi.org/10.1001/jamapediatrics.2021.0111
21. Pelletier, R., Higgins, J., & Bourbonnais, D. (2015). Is neuroplasticity in the central nervous system the missing link to our understanding of chronic musculoskeletal disorders? BMC Musculoskelet Disord, 16, 25. http://doi.org/10.1186/s12891-015-0480-y
22. Goossens, N., Rummens, S., Janssens, L., Caeyenberghs, K. & Brumagne, S. Association Between Sensorimotor Impairments and Functional Brain Changes in Patients With Low Back Pain. Am J Phys Med Rehab 97, 200–211 (2018).
23. Stanton, T. R., Moseley, G. L., Wong, A. Y. L., & Kawchuk, G. N. (2017). Feeling stiffness in the back: a protective perceptual inference in chronic back pain. Scientific Reports, 7(1), 9681. http://doi.org/10.1038/s41598-017-09429-1
1. Son, K. M., Hong, J. I., Kim, D. H., Jang, D.-G., Crema, M. D., & Kim, H. A. (2020). Absence of pain in subjects with advanced radiographic knee osteoarthritis. BMC Musculoskelet Disord, 21(1), 640. http://doi.org/10.1186/s12891-020-03647-x
2. Abram, S. G. F., Hopewell, S., Monk, A. P., Bayliss, L. E., Beard, D. J., & Price, A. J. (2019). Arthroscopic partial meniscectomy for meniscal tears of the knee: a systematic review and meta-analysis. British Journal of Sports Medicine, bjsports–2018–100223–13. http://doi.org/10.1136/bjsports-2018-100223
3. Roos, E. M., & Thorlund, J. B. (2017). It is time to stop meniscectomy. British Journal of Sports Medicine, 51(6), 490–491. http://doi.org/10.1136/bjsports-2016-097273
4. Thorlund, J. B., Juhl, C. B., Roos, E. M., & Lohmander, L. S. (2015). Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ (Clinical Research Ed), 350, h2747. http://doi.org/10.1136/bmj.h2747)
5. Tornbjerg, S. M., Nissen, N., Englund, M., Jørgensen, U., Schjerning, J., Lohmander, L. S., & Thorlund, J. B. (2017). Structural pathology is not related to patient-reported pain and function in patients undergoing meniscal surgery. British Journal of Sports Medicine, 51(6), 525–530. http://doi.org/10.1136/bjsports-2016-096456
6. Holden, S., Straszek, C. L., Rathleff, M. S., Petersen, K. K., Roos, E. M., & Graven-Nielsen, T. (2018). Young females with long-standing patellofemoral pain display impaired conditioned pain modulation, increased temporal summation of pain, and widespread hyperalgesia. Pain, 159(12), 2530–2537. http://doi.org/10.1097/j.pain.0000000000001356
7. van der Heijden, R. A., Rijndertse, M. M., Bierma-Zeinstra, S. M. A., & van Middelkoop, M. (2018). Lower Pressure Pain Thresholds in Patellofemoral Pain Patients, Especially in Female Patients: A Cross-Sectional Case-Control Study. Pain Medicine (Malden, Mass), 19(1), 184–192. http://doi.org/10.1093/pm/pnx059
8. Te, M., Baptista, A. F., Chipchase, L. S., & Schabrun, S. M. (2017). Primary Motor Cortex Organization Is Altered in Persistent Patellofemoral Pain. Pain Medicine (Malden, Mass), 18(11), 2224–2234. http://doi.org/10.1093/pm/pnx036
9. Silfies, S. P., Vendemia, J. M. C., Beattie, P. F., Stewart, J. C., & Jordon, M. (2017). Changes in Brain Structure and Activation May Augment Abnormal Movement Patterns: An Emerging Challenge in Musculoskeletal Rehabilitation. Pain Medicine (Malden, Mass), 18(11), 2051–2054. http://doi.org/10.1093/pm/pnx190
10. Robertson, C. J., Hurley, M., & Jones, F. (2017). People's beliefs about the meaning of crepitus in patellofemoral pain and the impact of these beliefs on their behaviour: A qualitative study. Musculoskeletal Science & Practice, 28, 59–64. http://doi.org/10.1016/j.msksp.2017.01.012
11. Maclachlan, L. R., Collins, N. J., Matthews, M. L. G., Hodges, P. W., & Vicenzino, B. (2017). The psychological features of patellofemoral pain: a systematic review. British Journal of Sports Medicine, 51(9), 732–742. http://doi.org/10.1136/bjsports-2016-096705
12. Pan, F., Tian, J., Cicuttini, F., Jones, G., & Aitken, D. (2018). Differentiating knee pain phenotypes in older adults: a prospective cohort study. Rheumatology (Oxford, England), 31, 79–10. http://doi.org/10.1093/rheumatology/key299
13. Robertson, C. J. (2010). Joint crepitus - are we failing our patients? Physiotherapy Research International, 15(4), 185–188. http://doi.org/10.1002/pri.492
14. Sorel, J. C., Veltman, E. S., Honig, A., & Poolman, R. W. (2019). The influence of preoperative psychological distress on pain and function after total knee arthroplasty. The Bone & Joint Journal, 101-B(1), 7–14. http://doi.org/10.1302/0301-620X.101B1.BJJ-2018-0672.R1
15. Escobar, A., García Pérez, L., Herrera-Espiñeira, C., Aizpuru, F., Sarasqueta, C., Gonzalez Sáenz de Tejada, M., et al. (2017). Total knee replacement: Are there any baseline factors that have influence in patient reported outcomes? Journal of Evaluation in Clinical Practice, 2(1), 566–8. http://doi.org/10.1111/jep.12765
16. Lewis, G. N., Parker, R. S., Sharma, S., Rice, D. A., & McNair, P. J. (2018). Structural Brain Alterations Before and After Total Knee Arthroplasty: A Longitudinal Assessment. Pain Medicine (Malden, Mass), 19(11), 2166–2176. http://doi.org/10.1093/pm/pny108
17. Harris, I. A., Sidhu, V., Mittal, R., & Adie, S. (2020). Surgery for chronic musculoskeletal pain: the question of evidence. Pain, 161(1), S95–S103. http://doi.org/10.1097/j.pain.0000000000001881
18. Louw, A., Diener, I., Fernández-de-las-Peñas, C., & Puentedura, E. J. (2017). Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Medicine (Malden, Mass), 18(4), 736–750. http://doi.org/10.1093/pm/pnw164
19. Jonas, W. B., Crawford, C., Colloca, L., Kriston, L., Linde, K., Moseley, B., & Meissner, K. (2018). Are Invasive Procedures Effective for Chronic Pain? A Systematic Review. Pain Medicine (Malden, Mass). http://doi.org/10.1093/pm/pny154
20. Weisman, A., Quintner, J., & Masharawi, Y. (2021). Amplified Pain Syndrome - An Insupportable Assumption. JAMA Pediatrics. http://doi.org/10.1001/jamapediatrics.2021.0111
21. Pelletier, R., Higgins, J., & Bourbonnais, D. (2015). Is neuroplasticity in the central nervous system the missing link to our understanding of chronic musculoskeletal disorders? BMC Musculoskelet Disord, 16, 25. http://doi.org/10.1186/s12891-015-0480-y
22. Goossens, N., Rummens, S., Janssens, L., Caeyenberghs, K. & Brumagne, S. Association Between Sensorimotor Impairments and Functional Brain Changes in Patients With Low Back Pain. Am J Phys Med Rehab 97, 200–211 (2018).
23. Stanton, T. R., Moseley, G. L., Wong, A. Y. L., & Kawchuk, G. N. (2017). Feeling stiffness in the back: a protective perceptual inference in chronic back pain. Scientific Reports, 7(1), 9681. http://doi.org/10.1038/s41598-017-09429-1