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Chiropractic, Chronic Back Pain and Brain Shrinkage: A better understanding of Alzheimer’s, Dementia, Schizophrenia, Depression and Cognitive Disorders and Chiropractic’s Role A Literature Review of the Mechanisms: THE BRAIN CONNECTION

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Chiropractic, Chronic Back Pain and Brain Shrinkage:

 

A better understanding of Alzheimer’s, Dementia, Schizophrenia, Depression and Cognitive Disorders and Chiropractic’s Role

 

A Review of the Mechanisms

 

A report on the scientific literature 


By: Mark Studin DC, FASBE(C), DAAPM, DAAMLP

William J. Owens DC, DAAMLP

Frank Zolli DC, EdD

 

 

Reference: Studin M., Owens W., Zolli F., (2015) Chiropractic, Chronic Back Pain and Brain Shrinkage:A better understanding of Alzheimer’s, Dementia, Schizophrenia, Depression and Cognitive Disorders and Chiropractic’s Role, A Literature Review of the Mechanisms, The American Chiropractor, 37(10) 36-38, 4042, 44-45

 

Since its inception in 1895, Chiropractic has been focused on the spine and its role in the total health and function of the human body.  Throughout its history, the profession has moved from a “bone on nerve” model to a “biomechanical/functional” model however as we evolve (through scientific findings) in our understanding of the true nature of the chiropractic principles, we now conclusively know that chiropractic results are based on the central nervous system and the detrimental role of spinal dysfuntion in the maintenance of homeostasis and “dis-ease” in the human body.  This article bridges the gap between the foundational chiropractic principles taught by the Palmers and their predecessors and today’s breakthrough findings and the correlation between unchecked spinal dysfunction AKA chronic spine pain and its effect on the brain. 

 

 

Peterson ET. AL. (2012) reported, “The … prevalence of low back pain is stated to be between 15% and 30%, the 1-year period prevalence between 15% and 45%, and a life-time prevalence of 50% to 80%” (pg. 525). While acute pain is a normal short-lived unpleasant sensation triggered in the nervous system to alert you to possible injury with a reflexive desire to avoid additional injury, chronic pain is different. Chronic pain persists and fundamentally changes the patient’s interaction with their environment. In chronic pain it is well documented that aberrant signals keep firing in the nervous system for weeks, months, even years.1 Baliki Et. AL. (2008) stated “Pain is considered chronic when it lasts longer than 6 months after the healing of the original injury. Chronic pain patients suffer from more than pain, they experience depression, anxiety, sleep disturbances and decision making abnormalities that also significantly diminish their quality of life” (pg. 1398). Chronic pain patients also have shown to have changes in brain function in sufferers with Alzheimer’ disease, depression, schizophrenia and attention deficit hyperactivity disorder giving further insight into disease states. In addition, chronic pain has a cause and effect on the morphology of the spinal cord and the brain in particular resulting in a process termed “linear shrinkage”, which has been suggested to cause ancillary negative neurological sequella.  

 

Apkarian Et. Al. (2004) reported that “Ten percent of adults suffer from severe chronic pain. Back problems constitute 25% of all disabling occupational injuries and are the fifth most common reason for visits to the clinic; in 85% of such conditions, no definitive diagnosis can be made.” (pg. 10410) Apkarian Et. AL. (2011) reported “Clinically, the most relevant conditions in which human brain imaging can have a substantial impact are chronic conditions, as they remain most poorly understood and minimally treatable by existing (author’s note: medical) therapies” (pg. S53). So in essence what these authors are stating is although many people suffer from chronic spine pain, very few of them are actually diagnosed with a “medical condition” AKA an “anatomical” lesion.  The chiropractic profession has long professed the lesion is actually functional and based on aberrant spinal biomechanics [Subluxation]. 

 

 

When we look at the human population on a larger scale and from a medical perspective, we see there is a deficit in spinal care paths with resultant negative sequella of chronic back pain.  Alkarian’s conclusion was querying allopathic doctors who have little to no training or experience in treating mechanical back pain, AKA spinal dysfunction of biomechanical origin, AKA chiropractic subluxation complex.  Raissi ET. Al. (2005) reported regarding medical providers, “(92.2%) believed that musculoskeletal education had not been sufficient in general practitioner training courses. Of the respondents, 56.8% had visited at least one disabled patient during the previous month, while 11% had visited more than 10 in the same period, but 84.3% had not studied disabilities. Musculoskeletal physical examination was the most needed educational field cited by general practitioners” (pg. 167).

 

Day Et. Al. (2007) reported that only 26% of fourth year Harvard medical students had a cognitive mastery of physical medicine (pg. 452). Schmale (2005) reported “Incoming interns at the University of Pennsylvania took an exam of musculoskeletal aptitude and competence, which was validated by a survey of more than 100 orthopaedic program chairpersons across the country. Eighty-two percent of students tested failed to show basic competency. Perhaps the poor knowledge base resulted from inadequate and disproportionately low numbers of hours devoted to musculoskeletal medicine education during the undergraduate medical school years. Less than 1⁄2 of 122 US medical schools require a preclinical course in musculoskeletal medicine, less than 1⁄4 require a clinical course, and nearly 1⁄2 have no required preclinical or clinical course. In Canadian medical schools, just more than 2% of curricular time is spent on musculoskeletal medicine, despite the fact that approximately 20% of primary care practice is devoted to the care of patients with musculoskeletal problems. Various authors have described shortcomings in medical student training in fracture care, arthritis and rheumatology, and basic physical examination of the musculoskeletal system (pg. 251).  

 

With continued evidence of lack of musculoskeletal medicine and a subsequent deficiency of training in spine care, particularly of biomechanical [Subluxation] orientation, the question becomes which profession has the educational basis, training and clinical competence to manage these cases?  Let’s take a closer look at chiropractic education as a comparison. 

 

Fundamental to the training of doctors of chiropractic according to the American Chiropractic Association is 4,820 hours (compared to 3,398 for physical therapy and 4,670 to medicine) and receive a thorough knowledge of anatomy and physiology. As a result, all accredited doctor of chiropractic degree programs focus a significant amount of time in their curricula on these basic science courses. So important to practice are these courses that the Council on Chiropractic Education, the federally recognized accrediting agency for chiropractic education requires a curriculum which enables students to be “proficient in neuromusculoskeletal evaluation, treatment and management.” In addition to multiple courses in anatomy and physiology, the typical curriculum in chiropractic education includes physical diagnosis, spinal analysis, biomechanics, orthopedics and neurology. As a result students are afforded the opportunity to practice utilizing this basic science information for many hours prior to beginning clinical services in their internship.

 

To qualify for licensure, graduates of chiropractic programs must pass a series of examinations administered by the National Board of Chiropractic Examiners (NBCE). Part one of this series consists of six subjects, general anatomy, spinal anatomy, physiology, chemistry, pathology and microbiology. It is therefore mandatory for a chiropractor to know the structure and function of the human body as the study of neuromuscular and biomechanics is weaved throughout the fabric of chiropractic education. As a result, the doctor of chiropractic is expert in the same musculoskeletal genre that medical doctors are poorly trained in their doctoral education as referenced above.

 

Now that we have a general idea of why current musculoskeletal and spine care paths are failing, let’s examine what the negative effects are with a focus on what happens to the central nervous system when a patient is suffering from chronic pain.  The following paragraphs describe what happens to the brain as a result of chronic pain and then offers solutions based upon evidenced based studies.

 

Chronic Pain Affecting Brain Activity at Rest

 

Baliki ET. Al (2008) reported “Recent studies have demonstrated that chronic pain harms cortical areas unrelated to pain, long-term pain alters the functional connectivity of cortical regions known to be active at rest, i.e., the components of the “default mode network” (DMN). This DMN is marked by balanced positive and negative correlations between activity in component brain regions. In several disorders, however this balance is disrupted. Studying with fMRI [functional MRI] a group of chronic back pain patients and healthy controls while executing a simple visual attention task, we discovered that chronic back pain patients, despite performing the task equally well as controls, displayed reduced deactivation in several key default mode network regions. These findings demonstrate that chronic pain has a widespread impact on overall brain function, and suggest that disruptions of the default mode network may underlie the cognitive and behavioral impairments accompanying chronic pain.” (pg. 1398)

 

“The existence of a resting state in which the brain remained active in an organized manner, is called the ‘default mode of brain function. The regions exhibiting a decrease in activity during task performance are the component members of the “default-mode network” (DMN), which in concerted action maintain the brain resting state. Recent studies have already demonstrated that the brain default mode network is disrupted in autism, Alzheimer’ disease, depression, schizophrenia and attention deficit hyperactivity disorder, suggesting that the study of brain resting activity can be useful to understand disease states as well as potentially provide diagnostic information.”  (pg. 1398)  This is important since for the first time we are starting to see a published correlation between spinal function, chronic pain and central nervous system changes.  This is what our founders have observed yet were unable to prove.

 

“Thus, the alterations in the patient’s brain at ‘rest’ can result in a different default mode network organization. In turn, potential changes in the default-mode network activity could be related to symptoms (other than pain) commonly exhibited by chronic pain patients, including depression and anxiety, sleep disturbances, and decision-making abnormalities, which also significantly diminish their quality of life… chronic pain patients display a dramatic alteration in several key default-mode network regions, suggesting that chronic pain has a widespread impact on overall brain function” (pg. 1398).  This information is pointing to the fact that a doctor of chiropractic should be involved in the triage and treatment of these patients and part of a long term spinal care program. 

 

Baliki ET. Al (2008) continued “Consistent with extensive earlier work examining visuospatial attention tasks, dominant activations were located in posterior parietal and lateral prefrontal cortices, whereas deactivations occurred mainly within Pre-Frontal Cortex and Posterior Cingulate/Cuneate Cortexes. Although activations in chronic back pain patients’ and controls’ brains were similar, chronic back pain patients exhibited significantly less deactivations than healthy subjects in Pre-Frontal Cortex, amygdala, and Posterior Cingulate/Cuneate Cortexes.  The focus was on identifying differences in the way chronic back pain patients’ brains process information not related to pain. This is the first study demonstrating that chronic back pain patients exhibit severe alterations in the functional connectivity between brain regions implicated in the default mode network. It seems that enduring pain for a long time affects brain function in response to even minimally demanding attention tasks completely unrelated to pain. Furthermore, the fact that the observed task performance, compared with healthy subjects, is unaffected, whereas the brain activity is dramatically different, raises the question of how other behaviors are impaired by the altered brain activity” (pg. 1399).

 

“However, the disruption of functional connectivity observed here with increased chronic back pain duration may be related to the earlier observation of brain atrophy increasing with pain duration also in chronic back pain patients. Patient’s exhibit increased pre-frontal cortex activity in relation to spontaneous pain, in addition to dorsolateral prefrontal cortex atrophy. Therefore, the decreased deactivations described here may be related to the dorsolateral pre-frontal cortex /pre-frontal cortex mutual inhibitory interactions perturbed with time. If that is the case, it will support the idea of a plastic, time-dependent, reorganization of the brain as patients continue to suffer from chronic back pain.

 

Mechanistically, the early stages of this cortical reorganization may be driven by peripheral and spinal cord events, such as those that have been documented in animal models of chronic pain, whereas later events may be related to coping strategies necessary for living with unrelenting pain. It is important to recognize that transient but repetitive functional alterations can lead to more permanent changes. Accordingly, long term interference with normal activity may eventually initiate plastic changes that could alter irreversibly the stability and subsequently the conformation of the resting state networks” (pg. 1401).

 

 

Brain Region

Function

Cingulate Cortex

Emotions, learning, motivation, memory

Insular Cortex

Consciousness, homeostasis, perception, motor control, self-awareness, cognitive function

Motor Cortex

Voluntary movements

Amygdala Cortex

Memory, decision making, emotional reactions

Somatosensory Cortex

Proprio and mechano-reception, touch, temperature, pain of the skin, epithelial, skeletal muscle, bones, joints, internal organs and cardiovascular systems

Periaqueductal Gray

Ascending and descending spinothalamtic tracts carrying pain and temperature fibers

 

 

 

 

 

 

 

 

 

 

 

 

THALAMUS

 

 

 

Chronic Pain Causing Brain “Shrinkage”

 

Apkarian ET. Al (2004) reported “Chronic back pain patients were divided into neuropathic, exhibiting pain because of sciatic nerve damage, and non-neuropathic groups. Patients with chronic back pain showed 5-11% less neocortical gray matter volume than control subjects. The magnitude of this decrease is equivalent to the gray matter volume lost in 10-20 years of normal aging. The decreased volume was related to pain duration, indicating a 1.3 cm3loss of gray matter for every year of chronic pain. Gray matter density was reduced in bilateral dorsolateral prefrontal cortex and right thalamus and was strongly related to pain characteristics in a pattern distinct for neuropathic and non-neuropathic chronic back pain. Our results imply that chronic back pain is accompanied by brain atrophy and suggest that the pathophysiology of chronic pain includes thalamocortical processes.

 

It is assumed that the cerebral cortex passively reflects spinal changes and reverts to its normal state after cessation of chronic pain. Our studies show that chronic back pain (sustained for >6 months) is accompanied by abnormal brain chemistry, mainly a reduction in theN-acetyl-aspartate-creatine ratio in the prefrontal cortex, implying neuronal loss or dysfunction in this region and reduced cognitive abilities on a task that implies abnormal prefrontal processing” (pg. 10410).

 

Apkarian ET. Al (2004) continued “At the whole-brain level, this reduction is related to pain duration, regionally depends on multiple pain-related characteristics, and is more severe in the neuropathic subtype. Therefore, these data present strong evidence that the pathophysiology of chronic pain includes cortical processes, and the observed changes likely constitute the physical substrate of the cognitive and behavioral properties of chronic pain” (pg. 10411).

 

“Thus, regional gray matter changes are strongly and specifically related to pain characteristics, and this pattern is opposite for neuropathic compared with non-neuropathic types. This dissociation is consistent with extensive clinical data showing that neuropathic pain conditions are more debilitating and have a stronger negative affect, which may be directly attributable to the larger decrease in gray matter density that we observe in the dorso-lateral pre-frontal cortex (DLPFC) of neuropathic chronic back pain patients.  Moreover, only 18% of whole-brain gray matter variance could be explained by pain duration. Therefore, a large portion of the whole-brain atrophy in chronic back pain cannot be accounted for by the measured pain characteristics, implying that there may be genetic and experiential predispositions contributing to the observed atrophy. In the DLPFC, a larger proportion of the variance could be explained by pain characteristics (40% for neuropathic chronic back pain; 80%for non- neuropathic chronic back pain), implying a tighter relationship between regional brain atrophy and perceived pain. Therefore, we suggest that the pattern of brain atrophy is directly related to the perceptual and behavioral properties of neuropathic chronic back pain.”

 

The observed regional pattern of atrophy is distinct from that seen in chronic depression or anxiety and shows a minimal relationship with anxiety and depression traits. Thus, it seems to be specific to chronic pain, especially because the regions showing atrophy, the thalamus and DLPFC, participate in pain perception. The DLPFC is activated in acute pain, with responses that do not code stimulus intensity. Recent evidence suggests that the DLPFC exerts “top-down” inhibition on orbitofrontal activity, limiting the magnitude of perceived pain. Thus, DLPFC atrophy may lead to a disruption of its control over orbitofrontal activity, which in turn is critical in the perception of negative affect in general and particularly in pain states. Thalamic atrophy in chronic back pain is important, because it is a major source of nociceptive inputs to the cortex and damage to this region may be a reason for the generalized sensory abnormalities commonly associated with chronic pain” (pg. 10413).

 

“The dorsal anterior cingulate is shown to be specifically involved in pain affect in normal subjects and exhibits decreased nociceptive signaling in various chronic pain states, which may again be caused by thalamic atrophy because the anterior thalamus is a primary input to the anterior cingulate. Therefore, we suggest that regional atrophy dictates the brain activity observed in chronic pain, and it may explain the transition from acute to chronic pain by shifting brain activity related to pain affect away from the anterior cingulate to orbitofrontal cortex.”

 

“It is possible that some of the observed decreased gray matter reflects tissue shrinkage [changes in extracellular space and microvascular volume may cause tissue shrinkage without substantially impacting neuronal properties], implying that proper treatment would reverse this portion of the decreased brain gray matter. The atrophy may be also attributable to more irreversible processes, such as neurodegeneration, which we favor because the main brain region involved (the DLPFC) also exhibits decreasedN-acetyl-aspartate, and decreasedN-acetyl-aspartate has been observed in most neurodegenerative conditions. Recent evidence also suggests that after nerve injury, some components of pain behavior are a consequence of hyperactivity of spinal cord microglia, and a histological study has shown a reduction in glial numbers in the cortex in major depressive disorder and bipolar disorder” (pg. 10414).

This article suggests that there is a reversible component in brain atrophy with the resolution of the chronic back pain, with strong evidence that there are some tissue structures that will be permanently damaged should the chronic pain go beyond the defined 6 months.  Clearly there are many different professions that handle the anatomical components of spine pain such as fracture, infection, disc herniation or tumor.  There is only one profession that has the education and training to treat the aberrant spinal biomechanics; chiropractic.  Since chiropractors are trained in treating/managing/triaging the anatomical lesions while also being the best suited to treat the biomechanical component, the evidence verifies that  the first contact for spine pain be a doctor of chiropractic who is also trained in differential diagnosis of underlying pathology. .

 

Brain Regions Effected

 

Apkarian ET. AL (2011) reported “The surprise was that the brain region best reflecting high magnitude of back pain was localized to the medial prefrontal cortex, extending into anterior cingulate cortex, a region not anticipated by acute pain studies. Additionally, brain areas observed for acute pain, like portions of the insula and mid- anterior cingulate cortex were only active transiently and only when the back pain magnitude was on the increase. These results are exciting because, for the first time, we are able to observe brain activity reflecting the subjective perception of the pain that chronic back pain patients come to the clinic to complain. We interpret the transient activity as a nociceptive signal from the periphery, which then is converted into a sustained emotional suffering signal in medial prefrontal cortex (pg. S54).

 

“Thus we can assert that, at least in this group of chronic pain patients, different brain areas encode the perceived magnitude for distinct types of pain. The prevalent expectation for brain activity in chronic pain is a sustained or enhanced activation of the brain areas already identified for acute pain. This view is partly implied by the chronic pain definition and by notions of specificity theory or labeled line theory of pain (where supraspinal organization and representation of pain is assumed to be through fixed and immutable routes). This is exactly what we donotsee. Instead these results imply that functional anatomy or physiology or some combination of both have changed in the brain of chronic back pain patients. It is also important to remember that the close relationships between fundamental properties of back pain and activity in medial prefrontal cortex and insula are correlational, and that both medial prefrontal cortex and insula respond to a long list of cognitive and emotional states (pg. S55). The morphological studies show that the brain structure undergoes changes at multiple spatial and temporal scales, which are for the most part specific to the type of chronic pain studied. That some of these changes are reversible by cessation of chronic pain speaks to the specificity of the processes and also demonstrate that chronic pain may in fact by used as a unique tool with which the dynamics of brain plasticity can be studied at multiple spatial and temporal scales” (pg. S56).

 

Chiropractic as a Solution for Chronic Back Pain

 

 

Peterson ET. AL. (2012) reported “investigate outcomes and prognostic factors in patients with acute or chronic low back pain (LBP) undergoing chiropractic treatment. In chronic LBP, recent studies indicate that significant improvement is often fairly rapid, usually by the fourth visit, and that patients initially receiving treatment 3 to 4 times a week have better outcomes. Patients with chronic and acute back pain both reported good outcomes, and most patients with radiculopathy (neurogenic) also improved” (pg. 525). “At 3 months, 69% of patients with chronic pain stated that they were either much better or better. This is unlikely to be due to the natural history of LBP because these patients have already passed the period when natural history occurs “(pg. 531).  A study by Tamcan et al (2010) was the only population based study of the so called “natural history” of lower back pain and the authors found the “natural history” of chronic lower back pain was not ending in resolution of symptoms but instead they documented patients moving “in and out” of a level of pain they could tolerate.   Based on the only population-based study of chronic lower back pain, the idea that the “natural history” of lower back pain ends with resolution of symptoms is a complete myth and one that is perpetuated by our present healthcare system.

 

 

Lawrence ET. AL (2008) reported “Existing research evidence regarding the usefulness of spinal adjusting… indicates the following, as much or more evidence exists for the use of SMT [spinal manipulation] to reduce symptoms and improve function in patients with chronic LBP as for use in acute and subacute LBP. The manual therapy group showed significantly greater improvements than did the exercise group for all outcomes. Results were consistent for both the short-term and the long-term” (pg. 670).

 

 

Dunn ET. AL. (2011) reported “The clinical outcomes achieved for this sample should be considered within the context of this veteran patient base, which is typically represented by older, white males with multiple comorbidities. A high percentage of overall service-connected disability was noted, with only a small percentage associated with the low back region. Considerable psychological comorbidity was found, with a high prevalence of PTSD (post-traumatic stress disorder) and depression diagnoses. PTSD and chronic pain tend to co-occur and may interact in a way that can negatively affect either disorder. A previous retrospective study of chiropractic management for neck and back pain demonstrated less improvement among those with PTSD. These points are significant because severe comorbidities and psychosocial factors lessen the likelihood of obtaining positive outcomes with conservative measures, including [chiropractic adjustments], for chronic low back pain. Mean percentages of clinical improvement exceeded the minimum clinically important difference, despite the levels of service-connected disability and comorbidity among this sample of veteran patients” (pg. 930). They went on to conclude that in spite of significant comorbidities that historically compromise positive results, 60.2% of patients met or exceeded the minimum clinically important difference for improvement (pg. 927).

 

Conclusion

 

Chronic pain as defined by that which has last for 6 months or longer which causes significant brain aberration in both morphology (size) and function.  The  literature suggests that this could be the precursor for many diseases as sequella of the human body’s natural reaction to prolonged pain.   Chronic back pain is one of the leading causes of chronic pain and medicine has little to no training or solutions as reported in the literature. Conversely, chiropractic has significant training and has been proven in “blinded” studies to have significant positive outcomes even in significantly adverse condition to help resolve chronic pain. As a result, the negative sequella on the brain of chronic pain, including shrinkage of the brain can be reversed through chiropractic care as the evidence has verified that once the chronic pain has resolved, the brain has the ability to return to its normal size and regain much function.

 

 

Although this evidence is strong, more research is needed and this further sets the foundation for understanding how chiropractic directly effects diseases in the human body. In addition, this also takes the chiropractic profession to the next level of understanding how and why a chiropractic adjustment works.  

 

 

References:

  1. National Institute of Neurological Disorders and Stroke, NINDS Chronic Pain Information Page (July 2015), retrieved from: http://www.ninds.nih.gov/disorders/chronic_pain/chronic_pain.htm
  2. Baliki N., Geha P., Apkarian A., Chialvo D., (2008) Beyond Feeling: Chronic Pain Hurts the Brain, disrupting the Default-Mode Network Dynamics, Journal of Neurosciences 28(6) 1398-1403
  3. Apkarian V., Sosa Y., Sonty S., Levy R., Harden N., Parrish T., Gitelman D., (2004) Chronic Back Pain Is Associated with Decreased Prefrontal and Thalamic Gray Matter Density, The Journal of Neuroscience, 24(46) 10410-10415
  4. Apkarian A., Hashmi J., Baliki M., (2011) Pain and the brain: Specificity and plasticity of the brain in clinical chronic pain, Pain 152, S49-S54
  5. Raissi G., Mansoon K., Madani P., Rayegani S., (2006) Survey of General Practitioners’ attitudes Toward Physical Medicine and Rehabilitation, International Journal of Rehabilitation Research 26: 167-170
  6. Day C., Yeh A., Franko O., Ramirez M., Krupat E. (2007) Musculoskeletal Medicine: An Assessment of the Attitudes of Medical Students at Harvard Medical School, Academic Medicine 82: 452-457
  7. Schmale G. (2005) More Evidence of Educational Inadequacies in Musculoskeletal Medicine 437, 251-259
  8. Peterson C., Bolton J., Humphreys K., (2012) Predictors of Improvement in Patients With Acute and Chronic Low Back Pain Undergoing Chiropractic Treatment, Journal of Manipulative and Physiological Therapeutics, 35(7) 525-533
  9. Lawrence, D., Meeker W., Branson R., Bronford G., Cates J., Haas M., Haneline M., Micozzi M., Updyke W., Mootz R., Triano J., Hawk C., (2008) chiropractic management of low back pain and low back-related leg complaints: a literature synthesis, Journal of Manipulative and Physiological Therapeutics, 31(9) 659-674
  10. Dunn A., Green B., Formolo L., Chicoine D. (2011) Retrospective case series of clinical outcomes associated with chiropractic management for veterans with low back pain, Journal of Rehabilitation Research & Development, 48(8) 927-934
  11. Tamcan, O., Mannion, A. F., Eisenring, C., Horisberger, B., Elfering, A., & Müller, U. (2010). The course of chronic and recurrent low back pain in the general population. Pain, 150(3), 451-457.

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