In the Spine Or in the Brain? Recent Advances in Pain Neuroscience Applied in the Intervention for Low Back Pain J

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In the spine or in the brain? Recent advances in pain neuroscience applied in the intervention for low back pain J. Nijs1-3, J. Clark1,2,4,5, A. Malfliet1-3,7, K. Ickmans1-3, L. Voogt1,2,6, S. Don1,2,6, H. den Bandt1,2,6, D. Goubert1,2,7, J. Kregel1,2,7, I. Coppieters1,2,7, W. Dankaerts8

1Pain in Motion International Research ABSTRACT social, economic, and public health Group, www.paininmotion.be; Conservative, surgical and pharmaco- problem of all chronic pain disorders 2 Dept. of Physiotherapy, Human Physiology logical strategies for chronic low back across the world (1). It is a complex and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije pain (CLBP) management offer at best disorder which is difficult to treat (2- Universiteit Brussel, Belgium; modest effect sizes in reducing pain and 5). The global point prevalence of LBP 3Department of Physical Medicine and related disability, indicating a need for was estimated at 9.4% in 2010, with the Physiotherapy, University Hospital improvement. Such improvement may highest prevalence of 15% in Western Brussels, Belgium; be derived from applying contemporary Europe (3), a significant proportion of 4 Faculty of Health, Psychology and Social pain neuroscience to the management of whom develop CLBP. The prevelance Care, Manchester Metropolitan University, CLBP. Current interventions for people of CLBP has been shown to be increas- UK; 5The Physio Shed, private practice for with CLBP are often based entirely on a ing in the United States of America, Physiotherapy, Omokoroa, New Zealand; “biomedical” or “psychological” mod- e.g., from 3.2% in 1992 to 10.2% in 6Dept. of Physiotherapy, University of Ap- el without consideration of information 2006 in North Carolina (6). Conserva- plied Sciences Rotterdam, The Netherlands; concerning underlying pain mecha- tive and pharmacological strategies for 7 Dept. of Rehabilitation Sciences and nisms and contemporary pain neuro- CLBP management offer at best mod- Physiotherapy, Faculty of Medicine and science. Here we update readers with est effect sizes in reducing pain and Health Sciences, Ghent University, Belgium; 8Musculoskeletal Rehabilitation Research our current understanding of pain in related disability (7-9), suggesting the Unit, Dept. of Rehabilitation Sciences, people with CLBP, showing that CLBP need for improvement. Faculty of Kinesiology and Rehabilitation is not limited to spinal impairments, but Improvement in management of CLBP Sciences, University of Leuven, Belgium. is also characterised by brain changes, may emerge from applying contem- Jo Nijs, PT, MT including functional connectivity reor- porary pain neuroscience. Current in- Jacqui Clark, PT, MT ganisation in several brain regions and tervention strategies for people with Anneleen Malfliet, MSc, MT increased activation in brain regions CLBP are often based on a biomedical Kelly Ickmans, PhD, MT of the so-called ‘pain matrix’ (or ‘pain (e.g., neuromuscular training, myofas- Lennard Voogt, PhD, MT Sanneke Don, MSc, PT connectome’). Indeed, in a subgroup cial treatment) or cognitive behaviour- Hester den Bandt, MSc, PT of the CLBP population brain changes al model (i.e., graded exposure, graded Dorien Goubert, PhD, MT associated with the presence of central activity) without accounting for the Jeroen Kregel, MSc, PE sensitisation are seen. Understanding underlying pain mechanisms and our Iris Coppieters, PhD, MT the role of these brain changes in CLBP present understanding of contemporary Wim Dankaerts, PhD, PT, MT improves our understanding not only pain neuroscience (10). Interventions Please address correspondence to: of pain symptoms, but also of prevalent often focus either on input (treating Dr Jo Nijs, CLBP associated comorbidities such as muscles and joints) or output mecha- Vrije Universiteit Brussel, Building F-Kima, Laarbeeklaan 103, sleep disturbances and fear avoidance nisms (motor control), while there is BE-1090 Brussels, Belgium. behaviour. Applying contemporary pain less attention paid to the well docu- E-mail: [email protected] neuroscience to improve care for people mented impairments in central nocic- Received and accepted on September 1, with CLBP includes identifying relevant eptive processing mechanisms (11-15). 2017. pain mechanisms to steer intervention, Here we update readers with our cur- Clin Exp Rheumatol 2017; 35 (Suppl. 107): addressing sleep problems and optimis- rent knowledge of pain in people with S108-S115. ing exercise and activity interventions. CLBP, including recent advances in © Copyright Clinical and This approach includes cognitively pre- understanding impairments in central Experimental Rheumatology 2017. paring patients for exercise therapy us- nociceptive processing mechanisms ing (therapeutic) pain neuroscience ed- (11-15). First, we will show that CLBP Key words: ucation, followed by cognition-targeted is also characterised by differences in Pain, low back pain, neuroplasticity, functional exercise therapy. the morphology and functionality of clinical reasoning, exercise therapy the brain. Understanding these brain Introduction changes in CLBP improves our under- Funding information on page S-113. Chronic low back pain (CLBP) is the standing not only of pain symptoms, Competing interests: none declared. most common and important clinical, but also of prevalent CLBP comor-

S-108 Clinical and Experimental Rheumatology 2017 Recent advances in pain neuroscience for chronic low back pain / J. Nijs et al. bidities like sleep disturbances and fear increased activation in brain regions of pain-induced activations from more avoidance behaviour. The second part involved in somatosensory-discrimina- affective brain regions towards sensory- of the paper explains how clinicians tive, affective, and cognitive process- discriminative regions, including the can apply our current understanding of ing of pain (the so-called “pain matrix”) posterior insula and primary somatosen- contemporary pain neuroscience to im- (25), including the primary/secondary sory cortex, following behavioural ex- prove care for people with CLBP. This somatosensory cortex, anterior and pos- tinction training (28). approach includes identifying relevant terior cingulate, insula, prefrontal cor- pain mechanisms to steer intervention, tices, and the thalamus (14). On a side The amygdala as a key target optimising exercise and activity and note, the term ‘pain matrix’ should be for exercise therapy in people with addressing sleep problems in people used with caution (26), as it remains un- chronic low back pain with CLBP. clear whether such a ‘limited network’ One key brain area involved in the pain represents the full perception of pain. (neuro)matrix is the amygdala, often Understanding brain changes in Pain perception possibly arises from a referred to as the fear-memory centre chronic low back pain spatiotemporal signature of brain net- of the brain. The amygdala has an im- Central sensitisation in people with work communication that represents the portant role in negative emotions, and chronic low back pain integration of all cognitive, affective, takes part of the central fear network Modern pain neuroscience has ad- and sensorimotor aspects of pain, re- in the brain, together with the anterior vanced our understanding about pain, ferred to as the ‘pain connectome’ (27). cingulate cortex (30). The amygdala’s including the role of central sensiti- Prospective cohort studies are needed to role includes negative emotions (e.g. sation (or central hyperexcitability) examine whether such brain alterations anger), pain-related memories (31) and in the presence and amplification of were not present before the onset of represents – together with the anterior (persistent) pain experiences. Central back pain, and whether they are specific cingulate cortex – the central fear net- sensitisation is defined as “an ampli- for CLBP only. work in the brain (30). Moreover, the fication of neural signaling within the amygdala has been identified as a fa- central nervous system (CNS) that Functional brain changes can be cilitator of chronic pain development, elicits pain hypersensitivity” (16) and treated in people with chronic low including sensitisation of CNS pain as “an increased responsiveness of no- back pain pathways (30-35). On the other hand, ciceptive neurons in the CNS to their Increasing evidence supports the idea the amygdala, together with the soma- normal or subthreshold afferent input” that the functional brain changes found tosensory cortex and insula, show less (17). Many people with CLBP lack a in people with CLBP are not permanent, activity during pain delivery in case of clear origin of nociceptive input, or this and can be reversed by effective inter- positive treatment expectations (36). input is not severe enough to explain ventions (28). For instance, one study Another crucial aspect of the amyg- the experienced pain severity, related found changes in the anterior default dala entails its role in the development disability and other symptoms. In such mode network functional connectivity of pain memories as a result of oper- patients (estimated at 25% of the CLBP with the amygdala and periaqueductal ant learning processes (37), including population), central sensitisation often gray and increased functional connec- memories of painful movements, for dominates the clinical picture. It is tivity of the basal ganglia with the right which the amygdala closely collabo- now well-established that sensitisation somatosensory cortex following cogni- rates with the hippocampus and the of the CNS is an important feature in tive behavioural therapy, compared with anterior cingulate cortex. The develop- many people with chronic pain, includ- an educational materials intervention ment of such a pain memory applies to ing those with CLBP (15). in people with chronic musculoskel- all movements that once provoked pain, Central sensitisation encompasses etal pain (29). The available evidence and results in protective behaviours various related dysfunctions within the provides low level evidence favouring (e.g., antalgic postures, antalgic move- CNS, including altered sensory pro- both functional and structural changes ment patterns, including altered lumbo- cessing in the brain (13). Functional in prefrontal areas following cogni- pelvic motor control, and/or avoidance magnetic resonance studies revealed tive behavioural therapy, including of particular movements like forward that people with CLBP have functional increased pain-evoked activation and bending) in people with CLBP (38). connectivity reorganisation in several increased grey matter volume in people Preparing for such ‘dangerous’ move- brain regions: increased activation in with chronic musculoskeletal pain (28). ments is enough to evoke an activation the medial prefrontal cortex (11, 18-21), The respective structural brain changes of the fear-memory centre in the brain cingulate cortex (19, 20, 22), amygdala were associated with intervention-relat- and hence to produce pain (without (19, 20), and insula (22, 23), and a dis- ed improvements of coping with pain peripheral nociceptive input), and em- rupted default mode network connectiv- symptoms, pain management, anxiety, ploy an altered (protective) motor con- ity (19, 22-24). When reviewing stud- catastrophising, and cognitive speed trol strategy (39). Even visualisation of ies that explored the brain responses to (28), which underscores the clinical such ‘dangerous’ movements can trig- noxious stimuli in people with CLBP, it importance of these brain changes. Pre- ger feelings of discomfort and pain, to- was concluded that most studies found liminary evidence was found for a shift gether with increased activation of pain

Clinical and Experimental Rheumatology 2017 S-109 Recent advances in pain neuroscience for chronic low back pain / J. Nijs et al. and memory related areas of the brain (40, 41). Exercise therapy can address this by applying the ‘exposure without danger’ principle (37), which is further explained below.

Glial overactivity as an underlying mechanism of central sensitisation in people with chronic low back pain Despite our increased understanding of the mechanisms explaining (hypersensitivity) symptoms in people with CLBP, there is much to learn about the development of (chronic) LBP, including the aetiological mechanisms underlying central sensitisation as a facilita- Fig. 1. Multimodal features of people with chronic low back pain. tor of chronicity and severe disability (42) in this population. The question is, why do some pain people with LBP de- TNF-α availability, which in turn in- in Figure 1). The application of con- velop central sensitisation while others duces long-term potentiation (52) and temporary pain neuroscience to clini- do not? Or is central sensitisation in- consequent enhanced synaptic efficacy cal practice for a better management of nate? Recent studies indicate that glial (53) and pain sensitisation (52). Long- people with CLBP requires three im- cells, to a greater extent than neurons, term potentiation and enhanced synap- portant considerations, discussed here. might play a key role in answering this tic efficacy are possibly coordinated by Firstly, identification of relevant pain question (43). glial overactivity and are (partly over- mechanisms in people with CLBP is Glia are non-neuronal cells that reside lapping) key mechanisms underlying explained; secondly issues relating to within the nervous system. An increas- increased excitability of the CNS (54- the retraining of pain memories using ing number of studies suggest that ab- 56) and the formation of (maladaptive) cognition-targeted functional exercise errant glial activation might explain the pain memories (38, 57) in people with therapy for people with CLBP will be establishment and/or maintenance of chronic pain and central sensitisation. discussed; thirdly, interventions that central sensitisation, and persistent pain target sleep disturbances in people who (44-48). In the acute or subacute phases Poor sleep, glial overactivity have CLBP and comorbid insomnia. of injury and pain, glial activation like- and central sensitisation in people ly plays an adaptive role, as it favours with chronic low back pain Identifying relevant pain mechanisms tissue healing and restoring homeosta- Poor sleep is one possible trigger for in chronic low back pain sis. Glial activation produces inflam- glial overactivity. Sleep deprivation Available evidence indicates that cen- matory mediators and when glial acti- results in low-grade inflammatory re- tral sensitisation is present in a sub- vation does not resolve, and becomes sponses (58-60), including increased group of the CLBP population (42, chronic, it can become pathogenic lead- levels of IL-6, prostaglandin E2 (59, 64, 65). This potentially impacts upon ing to collateral damage of nearby neu- 60) and nitric oxide (61) possibly me- clinical practice, as CLBP patients with rons and other glia (49) (i.e., gliopathy). diated by cerebral microglia (61). This a predominant central sensitisation pain Such increased glial activation has been may in part explain why a single night type require intervention targeted at the found in people with CLBP (47). Pro- of total sleep deprivation in healthy CNS rather than the lower back region spective cohort studies are needed to people can induce generalised hyper- (15, 66, 67). Therefore awareness is examine whether such glial activation algesia and increase state anxiety (62, growing that people with CLBP should is genetic, innate or specific for CLBP. 63). Taken together, poor sleep sustains be stratified clinically as experiencing Aberrant glial activity has the potential the underlying mechanisms of central either predominantly nociceptive, neu- to initiate central sensitisation through sensitisation in people with CLBP, a ropathic or central sensitisation pain several mechanisms. Activated micro- notion that may require addressing dur- (42, 68) in order to target intervention glia have been identified as a major ing intervention (43). strategies appropriately. A practical source for the synthesis and release guide is available elsewhere (69), and of brain-derived neurotrophic factor, Applying modern pain neuroscience is summarised below. which is responsible for increasing for a better management of chronic Following identification of red flags, neuronal excitability by causing dis- low back pain excluding the possibility of a back dis- inhibition in dorsal horn neurons in From what is presented above, it be- order with neuropathic pain is often the the spinal cord (50, 51). Aberrant glial comes clear the CLBP entails much first step (70, 71) that can be taken by activity is accompanied by increased more than spinal changes (summarised applying international guidelines for

S-110 Clinical and Experimental Rheumatology 2017 Recent advances in pain neuroscience for chronic low back pain / J. Nijs et al. the stratification of neuropathic pain (72, 73). Examples of a back disorder with neuropathic pain include radicu- lar pain with several patho-anatomical dysfunctions in case of compression of the dorsal root ganglion (direct) or the spinal nerve (indirect) (17). Possible dysfunctions that could induce such compression include foraminal steno- sis (e.g., due to osteophytes), prolapsed intervertebral disk, radiculitis (e.g., caused by a viral infection like herpes zoster), etc. Although the presence of neuropathic pain does not exclude a predominant central sensitisation underlying mechanism, if neuropathic pain is excluded two options remain: predominantly either nociceptive or central sensitisation LBP. To differen- tiate between predominant nociceptive and central sensitisation LBP, clini- Fig. 2. Algorithm for the differential diagnosis of predominant nociceptive versus central sensitisation cians are advised to use the algorithm low back disorder (modified from Nijs et al. (77)). presented in Figure 2. This algorithm guides the clinician through the screening patients for exercise therapy using (82-85), although at present effect sizes ing of three major stratification criteria (therapeutic) pain neuroscience educa- are often small and it remains to be ex- (69): tion. Pain neuroscience has taught us amined whether effects are independ- 1) the severity of LBP must be dispro- that pain is often present without tissue ent from socioeconomic status and cul- portionate to the nature and extent of damage, is often disproportionate to tural background. the injury or pathology (i.e., tissue tissue damage, and that tissue damage The pain neuroscience education pre- damage or structural impairments (and nociception) does not per se result pares the CLBP patient for cognition- which might cause nociceptive LBP); in the feeling of pain. Pain neurosci- targeted exercise therapy (10) that aims 2) the pain pattern lacks a neuroana- ence education intends to transfer that at systematic desensitisation. This in- tomically distribution, e.g., one that knowledge to patients, allowing them cludes graded and repeated exposure to is not neuroanatomically plausible to understand their pain and hence to fearful movements in order to generate for the presumed sources of (lumbar) cope effectively with their pain. The a new memory of safety in the brain, and nociception; main goal of pain neuroscience edu- to replace or bypass the old and mala- 3) a score of 40 or higher on part A of cation is to improve the patient’s pain daptive movement-related pain memo- the Central Sensitisation Inventory beliefs and decrease the threatening ries (38). Hence, such an approach (CSI) (74), which assesses symptoms nature of pain, including possible acute directly targets the brain circuitries common to central sensitisation, with pain flares following exercises or daily orchestrated by the amygdala detailed the total score ranging from 0 to 100 physical activity. Guidelines for ena- above. The mechanism of long-term and a recommended and validated bling clinicians to apply pain neurosci- potentiation of brain synapses is crucial cutoff score of 40 (75, 76). ence education in clinical practice are for (re)learning and developing new In addition to the above guide for strat- available (79, 80), and imply the use of (pain/movement-related) memories, ification of LBP patients according to an information leaflet, an explanatory and hence for altering pain memories in the dominant pain mechanism, thor- handbook [e.g., Explain Pain (81)] and the brain (38). Part of these intervention ough clinical examination including websites (retrainpain.org) designed principles are in line with graded expo- the use of screening questionnaires is specifically for explaining pain to pa- sure in vivo (86), a cognitive behaviour required (78), but is beyond the scope tients with persistent pain. Preceding intervention that has yielded good out- of the present paper. therapeutic exercise interventions with comes in people with CLBP (87, 88). a preparatory phase using pain neuro- Whether such a combined approach Optimising exercise and activity science education enhances deep learn- of pain neuroscience education with interventions for people with chronic ing and reconceptualisation of pain(10, cognition-targeted exercise therapy is low back pain 38) with the intention of improving superior over standard evidence based Applying contemporary pain neuro- exercise outcomes. Mounting evidence care in people with CLBP is currently science to exercise interventions for supports the use of pain neuroscience under investigation (89), but prelimi- people with CLBP includes prepar- education for the intervention of CLBP nary results are promising.

Clinical and Experimental Rheumatology 2017 S-111 Recent advances in pain neuroscience for chronic low back pain / J. Nijs et al.

‘Cognition-targeted’ implies a time- addressed comorbidity within current The results from 2 small scale pilot tri- contingent (“Perform this exercise 10 interventions for CLBP. Indeed, people als supports combining CBT-I with a times regardless the symptoms it might suffering from CLBP are eighteen times more pain management-focused (cog- induce”) rather than pain-contingent more likely to experience clinically de- nition-targeted) intervention for chronic (“Stop or adapt the exercise as soon as fined insomnia (91). If present, insom- pain: the combined approach was feasi- symptoms occur”) approach to exercise nia contributes substantially to CLBP ble to deliver and produced significant interventions (10), and should account severity and related disability (91). improvements in sleep, disability from for the individual (pain) cognitions and Whether insomnia or the back pain is pain, pain interference, depression and apply the reconceptualisation of pain to the chicken or the egg (cause and ef- fatigue (92, 97). Importantly, the com- exercises and daily physical activities fect) probably varies from patient to pa- bined intervention appeared to have a (e.g., walking, cycling, gardening and tient, but regardless of that, if insomnia strong advantage over more pain man- lifting heavy objects) (38). Thorough is left untreated, it represents a barrier agement-focused (cognition-targeted) questioning and discussion of the pa- for effective CLBP management (92). intervention alone and modest advan- tient’s perceptions about the exercise Cognitive behavioural therapy for in- tage over CBT-I alone in reducing in- (before, during and following the exer- somnia (CBT-I) is the standard evi- somnia severity in chronic pain patients cise) is required (38), including discus- dence-based care for treating chronic (92). The gains in insomnia severity and sion of the anticipated consequences of primary insomnia (93), but evidence pain interference were maintained at the exercises. supporting the use of CBT-I in people one- and six-months follow-up (97). Therapists should try to decrease the an- with CLBP is scarce. A proof of con- Taken together, increasing evidence ticipated danger (threat level) of the ex- cept study found that CBT-I was suc- supports the application of CBT-I for ercises/physical activities by challeng- cessful in improving sleep and the ex- people with CLBP with comorbid in- ing the nature of, and reasoning behind tent to which pain interfered with daily somnia as a way of applying our cur- the patients’ fears, assuring the safety functioning in people with CLBP, with rent understanding of pain neurosci- of the exercises, and increasing confi- moderate to large effect sizes and clini- ence, including the role of insomnia dence in a successful accomplishment cally important improvements (94). in sustaining central sensitisation, to of the exercise (38). This can be done CBT-I typically includes changing clinical practice. Still, larger multicen- by applying graded exposure in vivo negative thoughts about sleep, sleep tre trials and collecting outcome data in experiments (87). After performing the hygiene, sleep restriction therapy, and usual care are required to confirm these exercise/physical activity, the therapist teaching relaxation skills (94-96). Im- promising findings. discusses the patient’s experience with proving thoughts about sleep includes the exercises, including the threatening “decatastrophisation” to address the Conclusions nature of the exercise/physical activity. perception of dire consequences of It is now well established that CLBP The experienced difference between the sleep loss (94). Sleep hygiene implies is not limited to spinal impairments, anticipated (pre-exercise) pain increase promoting good sleep habits and may but can also be characterised brain and the actual experience most often include stimulus control to establish changes. The latter include functional decreases the threat value of the exer- a strong association between the bed- connectivity reorganisation in several cise/physical activity. room and sleep by allowing for sleep to brain regions and increased activation In addition, within cognitive functional occur uniquely in association with the in brain regions of the so-called “pain therapy control over maladaptive pro- bedroom (94). Some authors propose matrix”. Increasing evidence supports vocative patterns of maladaptive pain sleep restriction therapy in which the the idea that these functional brain dif- behaviour is also included (90). Cog- amount of time spent in bed is limited to ferences found in people with CLBP nitive functional therapy represents an an amount equal to their average sleep are not permanent, and can be reversed individually targeted behaviourally- time for a week (92). This has been by effective interventions (28). Under- orientated intervention for people with shown to enhance homeostatic sleep standing these brain changes in CLBP CLBP, which directs at the identifica- drive (93) in which the mechanisms improves our understanding not only tion of the modifiable and no-modifia- which induce sleep are made more ef- of pain symptoms, but also of prevalent ble factors associated with the disorders ficient. Once sleep becomes more ef- CLBP comorbidities like sleep distur- (90). CFT provides a personalised bio- ficient, total sleep time is incremen- bances. Poor sleep sustains the underly- psycho-social understanding of pain, tally increased on a week-to-week basis ing mechanisms of central sensitisation enhances pain controllability, targets (92). Relaxation skills can be applied to in people with CLBP, which can be ad- behavioural and lifestyle change and improve falling asleep and learn people dressed by including CBT-I in a com- positive adaptation (90). to adequately cope with high levels of prehensive intervention programme. arousal before falling asleep (96). The brain changes seen in people with Addressing sleep problems for CBT-I cannot be a standalone inter- CLBP are in line with the presence of a comprehensive management vention for CLBP, but instead should central sensitisation in a subgroup of of chronic low back pain provide an added value to available the CLBP population. Identifying rel- Insomnia is an important yet seldom evidence-based intervention for CLBP. evant pain mechanisms in people with

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CLBP is required to steer intervention. Flanders (FWO), Belgium. K. Ickmans with cognition-targeted motor control train- In addition to addressing comorbidi- and D. Goubert are post-doctoral re- ing. Phys Ther 2014; 94: 730-8. 11. BALIKI MN, PETRE B, TORBEY S et al.: ties like insomnia, applying our current searchers funded by the Applied Bio- Corticostriatal functional connectivity pre- understanding of pain neuroscience to medical Research Programme, Institute dicts transition to chronic back pain. Nat the management of people with CLBP for the Agency for Innovation by Sci- Neurosci 2012; 15: 1117-9. includes optimising exercise interven- ence and Technology, Belgium (IWT- 12. FLOR H, BRAUN C, ELBERT T, BIRBAUMER N: Extensive reorganization of primary so- tions. This includes preparing patients TBM project no. 150180). I. Coppiet- matosensory cortex in chronic back pain pa- for exercise therapy using (therapeutic) ers is a postdoctoral researcher funded tients. Neurosci Lett 1997; 224: 5-8. pain neuroscience education, followed by the Research Foundation Flanders 13. GIESECKE T, GRACELY RH, GRANT MA et al.: Evidence of augmented central pain pro- by cognition-targeted exercise therapy (FWO), Belgium (FWO project no. cessing in idiopathic chronic low back pain. (10) that aims at systematic desensi- G007217). J. Kregel is a PhD research Arthritis Rheum 2004; 50: 613-23. tisation, or graded, repeated exposure fellow funded by the Applied Biomedi- 14. KREGEL J, MEEUS M, MALFLIET A et al.: to generate a new memory of safety in cal Research Programme, Institute for Structural and functional brain abnormalities in chronic low back pain: A systematic review. the brain, replacing or bypassing the the Agency for Innovation by Science Semin Arthritis Rheum 2015; 45: 229-37. old and maladaptive movement-related and Technology, Belgium (IWT-TBM 15. ROUSSEL NA, NIJS J, MEEUS M, MYLIUS V, pain memories (38). project no. 130246). J. 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