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Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumPain in Motion International Research GroupDepartment of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumPain in Motion International Research GroupDepartments of Human Physiology and Physiotherapy, Free University of Brussels, Faculty of Physical Education and Physiotherapy, Medical Campus Jette, Brussels, Belgium
Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumSchool of Psychology, Faculty of Health Sciences, Australian Catholic University, Sydney, Australia
Magnetic resonance imaging has shown brain alterations in chronic musculoskeletal pain patients.
Brain changes are related to clinical pain measures in chronic musculoskeletal pain.
Structural and functional brain alterations are related to clinical pain measures.
This systematic review reports preliminary to moderate evidence for these relations.
Inconclusive results exist regarding the direction of these relations.
Compelling evidence has shown chronic widespread and exaggerated pain experience in chronic musculoskeletal pain (MSKP) conditions. In addition, neuroimaging research has revealed morphological and functional brain alterations in these patients. It is hypothesized that brain alterations play a role in the persistent pain complaints of patients with chronic MSKP. Nevertheless, lack of overview exists regarding the relations between brain alterations and clinical measures of pain. The present systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, to investigate the relations between structural or functional brain alterations, using magnetic resonance imaging scans, and clinical pain measures in patients with chronic MSKP. PubMed, Web of Science, Cinahl, and Cochrane databases were searched. First, the obtained articles were screened according to title and abstract. Second, the screening was on the basis of full-text. Risk of bias in included studies was investigated according to the modified Newcastle-Ottawa Scale. Twenty studies met the inclusion criteria. Moderate evidence shows that higher pain intensity and pressure pain sensitivity are related to decreased regional gray matter (GM) volume in brain regions encompassing the cingulate cortex, the insula, and the superior frontal and temporal gyrus. Further, some evidence exists that longer disease duration in fibromyalgia is correlated with decreased total GM volume. Yet, inconclusive evidence exists regarding the association of longer disease duration with decreased or increased regional GM volume in other chronic MSKP conditions. Inconclusive evidence was found regarding the direction of the relation of pain intensity and pressure pain sensitivity with microstructural white matter and functional connectivity alterations. In conclusion, preliminary to moderate evidence demonstrates relations between clinical pain measures, and structural and functional connectivity alterations within brain regions involved in somatosensory, affective, and cognitive processing of pain in chronic MSKP. Nevertheless, inconclusive results exist regarding the direction of these relations. Further research is warranted to unravel whether these brain alterations are positively or negatively correlated to clinical pain measures.
Structural and functional brain alterations within regions involved in somatosensory, affective, and cognitive pain processing play a crucial role in the persistent pain of chronic MSKP patients. Accordingly, these brain alterations have to be taken into account when assessing and treating patients with chronic MSKP.
Additionally, this condition is frequently characterized by disproportional pain, meaning that pain severity and dysfunction are disproportionate to the nature and extent of the musculoskeletal damage/deficit.
Central sensitization can be defined as an augmented responsiveness of the central nervous system to nociceptive as well as non-nociceptive stimuli (eg, pain, electrical stimuli, pressure, and temperature).
This exaggerated responsiveness can cause allodynia, hyperalgesia, hypersensitivity of senses unrelated to the musculoskeletal system, and referred pain across multiple spinal segments, leading to chronic widespread pain.
This advent provided the opportunity to examine brain structure and function in clinical chronic pain states. During the past decade, the role of the brain in chronic pain conditions has been gradually elucidated.
Brain MRI techniques can be roughly divided into structural and functional MRI (fMRI).
Structural MRI has the ability to measure gray matter (GM) and white matter (WM) morphology in vivo. High-resolution T1-weighted images can be used to assess global measures, such as whole brain volume, GM volume,
Diffusion imaging data are used to map the 3-dimensional diffusion of water molecules in the brain. Currently, diffusion tensor imaging (DTI) is the most widely used method for assessing WM orientation and integrity. The diffusion tensor characterizes the degree, the magnitude of anisotropy, and the orientation of directional diffusion.
Compelling structural MRI research has shown alterations in GM morphology and WM properties in various chronic MSKP conditions, including patients with fibromyalgia, chronic low back pain, and chronic temporomandibular disorders,
within brain regions involved in somatosensory, affective, and cognitive modulation of pain, such as the somatosensory cortex (S1, S2), medial and dorsolateral prefrontal cortex, anterior (ACC) and posterior cingulate cortex (PCC), insula, amygdala, hippocampus, and periaqueductal gray.
Resting-state fMRI and FC analyses have improved our knowledge on how brain regions work together as networks to modulate pain and how these networks may be modified in the presence of persistent pain.
fMRI research has shown alterations in (resting-state) functional activity and connectivity within various brain regions involved in somatosensory, affective, and cognitive modulation of pain in patients with various chronic MSKP.
Scientific evidence for underlying central mechanisms of pain processing has become increasingly necessary. Imaging studies investigating the relation between brain alterations and clinical behavioral measures in chronic MSKP patients have been published during the past years.
In particular, accumulating research investigating the relationship between clinical measures of pain such as pain duration, pain intensity, pressure pain sensitivity, and brain alterations has been published.
Evaluation of clinical pain measures is highly important and is often used in clinical assessment, therapy, and research in patients with chronic MSKP to evaluate the nature and extent of symptoms as well as the evolution of pain.
In particular, various dimensions of pain, different types of scales/questionnaires and descriptors, and varying reporting periods of pain (eg, current pain intensity, mean pain intensity during past week or past month) are examined in chronic MSKP research. Overall, clinical pain measures can be subdivided into self-reported pain measures such as pain intensity and pain duration, and more objective experimental pain measures such as pressure pain sensitivity and hypersensitivity for various stimuli.
Unfortunately, currently no clear overview exists on how brain alterations are related to clinical correlates of pain in various chronic MSKP conditions. However, knowledge on this relationship is important to integrate neuroimaging findings into clinical practice and to further unravel the underlying mechanisms of persistent pain. Therefore, the aim of the present systematic review was to investigate the relations between structural and functional brain alterations and clinical pain measures in chronic MSKP patients, examined with structural and functional brain MRI techniques.
This systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines.
The Patient, measurement Instrument, Comparison, Outcome (PICO) approach was applied to formulate the following research questions: 1) ‘What are the relations between structural brain alterations (O = outcome) and clinical pain measures (O) in chronic MSKP patients (P = patient), examined with structural brain MRI techniques (I = measurement instrument)? 2) ‘What are the relations between functional brain alterations (O) and clinical pain measures (O) in chronic MSKP patients (P), examined with functional brain MRI techniques (I)?
Eligibility assessment was performed by screening the obtained articles on the basis of the inclusion and exclusion criteria (Table 1). To be included, articles had to investigate a relation or association between structural or functional brain alterations and clinical measures/correlates of pain (ie, pain duration, pain intensity, pain perception, pressure sensitivity, hyperalgesia, hypersensitivity, allodynia, referred pain) (O) by using brain MRI techniques (I) in patients with chronic MSKP (P).
Eligibility assessment of the obtained articles was performed by 2 independent researchers (I.C. and B.C.), who have published systematic reviews and were trained in conducting a systematic review by the second author (M.M.). After deduplication, a first screening was performed on the basis of the title and abstract of the remaining articles. If any of the inclusion criteria were not met, the article was excluded. In the second phase, publications were screened on the basis of the full-text and fulfilment of the inclusion criteria was ensured.
Methodological quality of all included studies was assessed by 2 independent reviewers (I.C. and J.K.), both PhD candidates working with chronic MSKP patients in the research field of brain MRI. Both reviewers were trained by M.M., a PhD experienced in conducting systematic reviews. Risk of bias was evaluated using the Newcastle-Ottawa Scale (NOS) for case control studies (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp).
The NOS applies a star rating system to judge methodological quality on the basis of 3 subcategories: selection of groups, comparability, and ascertainment of exposure. This checklist is recommended for case-control studies
and has frequently been used by the Cochrane Collaboration (www.cochrane.org). The criterion on response rate could not be scored because this item was not applicable for the articles on the current research topic. Therefore, item 9 was replaced by a self-constructed additional subcategory, ‘MRI data quality and preprocessing’ that includes 2 items, which was chosen specifically for the current systematic review. Item 9 scores whether the researchers performed visual inspection of the MRI data quality (eg, head motion). Item 10 scores whether manual exclusion in case of low data quality and/or data adjustment was included in the preprocessing pipeline. Subsequently, each study could reach a maximum score of 10 on the modified NOS, representing the highest methodological quality. A study earned 1 point when controlling for sex or age in the ‘comparability’ section and an additional point when controlling for another factor (eg, medication use, collecting cardiorespiratory data).
On the basis of study design and methodological quality, each individual study received a level of evidence, according to the 2005 classification system of the Dutch Institute for Healthcare Improvement (CBO) (Supplementary Table 1). Subsequently, strength of conclusion was determined after clustering studies with comparable experimental methods and research aims, accounting for the study design and the risk of bias (Supplementary Table 2). Strength of conclusion 2 was assigned when there were at least 2 independently conducted studies of evidence level B. Strength of conclusion 3 was assigned when there was at least 1 study of evidence level B. Strength of conclusion 4 was given in case of inconclusive or inconsistent results between various studies.
Data Extraction Process
The following information was extracted from each included study and is shown in the evidence table (Supplementary Table 3): 1) patients, 2) control group, 3) brain MRI technique, 4) clinical pain measures, 5) correlations, relations, associations, 6) main results, and 7) correlation coefficients, t-scores, Z-scores. The data were obtained by the first author (I.C.) and a second reviewer (R.D.P.) checked the extracted data. Noteworthy, the evidence table only includes the MRI techniques and clinical pain measures, which were used to evaluate possible relations. In addition, the main results regarding relations between clinical pain measures and brain alterations in chronic MSKP patients are summarized whereas the results among the healthy control group are not shown.
The selection process of relevant articles is presented in Figure 1. The initial search resulted in 137 articles. After removing the duplicates, 91 articles remained. Two articles
were found by manual search: these articles were found in the reference list of included studies. The entire selection process resulted in 20 eligible articles.
All included studies (n = 20) applied a case-control design, comparing chronic MSKP patients with healthy pain-free individuals. The characteristics of each study were extracted and presented in the evidence table (Supplementary Table 3). Articles were divided on the basis of the applied MRI technique. Six articles compared clinical pain measures with GM alterations,
The risk of bias and level of evidence is shown in Table 3. All studies scored a level of evidence B. Methodological quality was moderate to good, varying between 5 of 10 (50%) and 9 of 10 (90%). Most studies lost points on ‘representativeness of the cases’ (80%), ‘selection of controls’ (85%), and ‘definition of controls’ (60%), either because authors did not mention the required information or the information was not adequate. Nevertheless, most studies were awarded for taking into account confounding factors (eg, matching for age and sex), ascertainment of exposure, and for using the same method of ascertainment for cases and controls. All studies were awarded for manual exclusion in case of low data quality and/or inclusion of automated data adjustment in the preprocessing pipeline.
Table 3Methodological Quality for Case-Control Studies
Abbreviations: LOE, level of evidence; −, score not fulfilled; +, score fulfilled; /, answer is unclear.
NOTE. Newcastle-Ottawa Quality Assessment Scale: case-control studies: 1 = Is the case definition adequate?; 2 = Representativeness of the cases; 3 = Selection of controls; 4 = Definition of controls; 5 = Study controls for age or sex; 6 = Study controls for any additional factor; 7 = Ascertainment of exposure; 8 = Same method of ascertainment for cases and controls; 9 = Visual inspection of the MRI data quality; 10 = Manual exclusion in case of low data quality and/or automated data adjustment included in preprocessing pipeline.
In most cases (90.5% or 181 of the 200 items), the 2 reviewers (I.C. and J.K.) agreed. After a second review and a comparison of the 19 differences, the reviewers reached a consensus for 197 items. For the 3 remaining items, a third investigator was consulted (R.D.P.). The final score of each study is presented in Table 3.
Syntheses of Results
Structural Brain MRI
Overall, 10 studies investigated the relationship between structural brain alterations and clinical pain measures in chronic MSKP patients.
reported a significant relation between pain intensity and regional GM volume. Increased pain intensity in patients with chronic temporomandibular disorders was associated with decreased GM volume in the right rostral ACC, right PCC, precuneus, and superior frontal and superior temporal gyrus.
reported a negative correlation between pain intensity in temporomandibular disorders patients and GM thickness in the anterior midcingulate cortex and the ventrolateral aspect of the primary motor cortex. Furthermore, they reported that increased pain unpleasantness was associated with decreased GM thickness in the lateral orbitofrontal cortex.
In conclusion, there is some evidence that increased pain intensity and pain unpleasantness in chronic temporomandibular disorders patients is correlated with decreased GM thickness in pain, motor, and cognitive processing regions of the brain (strength of conclusion 3).
Pressure Pain Sensitivity
Two studies reported an association between pressure pain sensitivity and regional GM volume alterations.
observed significant relations between increased pressure pain sensitivity and decreased GM volume in the left anterior insula and PCC in fibromyalgia patients.
In conclusion, there is moderate evidence that increased pressure pain sensitivity in chronic MSKP patients is associated with decreased GM volume in somatosensory, pain, and affect-cognitive processing brain regions (strength of conclusion 2).
described a positive relation between duration of temporomandibular disorders and regional GM volume. Increased GM volume was found in the PCC and midbrain bilaterally, in the right hippocampus and in the right middle cerebellar peduncle.
In conclusion, there is moderate evidence that regional GM volume alterations are correlated with chronic MSKP duration (strength of conclusion 2). However, inconclusive evidence exists regarding the relation between longer disease duration and decreased or increased regional GM volume (strength of conclusion 4).
Additionally, there is some evidence that longer disease duration in fibromyalgia patients is correlated with decreased total GM volume (strength of conclusion 3).
In conclusion, there is moderate evidence that higher pain intensity is correlated with FA alterations in regional WM tracts involved in transmission of somatosensory, pain, and affective and cognitive information (strength of conclusion 2). However, there is inconclusive evidence as to whether greater pain intensity is related to decreased or increased FA values in these WM tracts (strength of conclusion 4).
reported positive correlations in chronic MSKP patients between higher total pain experience scores and increased AD in the left anterior and posterior limb of the internal capsule. Additionally, increased typical pain scores on the McGill pain questionnaire were positively correlated with increased AD in the left anterior limb.
In conclusion, there is some evidence that increased subjective pain scores in chronic MSKP patients are correlated with increased AD in WM tracts involved in transmission of information through the anterior and posterior limb of the internal capsule (strength of conclusion 3).
Functional Brain MRI
Overall, 11 articles described interrelations between clinical pain correlates and functional brain alterations using fMRI and/or resting-state fMRI in chronic MSKP patients.
reported in fibromyalgia patients a positive association between higher current pain intensity and increased FC between the DMN and right middle and anterior insula, cerebellum, dorsolateral prefrontal cortex, and subgenual ACC. Further, a positive covariation was reported between higher current pain intensity and increased FC between the right executive attention network and right anterior, left middle, and posterior insula and putamen.
reported higher current pain intensity to be related to decreased FC between the right executive attention network and the hippocampus, periaqueductal gray, nucleus cuneiformis, and the pontine raphe. A negative relation was shown in temporomandibular disorders patients between pain intensity and FC between the left anterior insula and rostral ACC during resting-state fMRI by Ichesco et al.
reported a correlation between higher pain intensity and increased changes (from the pain phase through the rest phase) in S1 leg connectivity to the anterior insula in fibromyalgia patients. Additionally, increased temporal summation of pain was correlated with increased changes in S1 leg connectivity to the right anterior/middle insula in fibromyalgia patients. In contrast, higher clinical pain intensity was related to decreased resting-state FC within S1.
examined associations between pain rating index scores and FC in fibromyalgia patients. Higher FC, between insula and superior temporal gyrus, was associated with higher affective scores. Higher sensory scores were correlated with greater FC between the right middle insula and bilateral precuneus. In contrast, Yu et al
observed in chronic low back pain patients a negative relationship between increased low back pain ratings and FC between periaqueductal gray and left ventromedial prefrontal cortex/rostral ACC after a pain-inducing maneuver.
In conclusion, there is moderate evidence that greater clinical pain intensity is related to alterations in FC in chronic MSKP patients (strength of conclusion 2). However, inconclusive evidence exists regarding the direction of the relation within somatosensory, pain, and affect-cognitive processing regions/networks in chronic MSKP patients. Positive
reported that increased pressure pain sensitivity in fibromyalgia was correlated with decreased FC between the right inferior orbitofrontal regions and right associative visual cortex. In contrast, they also reported a relation between increased pressure pain sensitivity and increased FC between pain-related regions (ie, the left insula and dorsal PCC, the left Rolandic operculum, left parahippocampal gyrus, and thalamus and prefrontal cortex).
investigated correlations between FC and pressure pain thresholds at different intensities. In fibromyalgia patients, a negative correlation was detected between lower pressure pain thresholds, hence increased pressure pain sensitivity and higher FC. Higher FC was reported between the right posterior insula and PCC during a faint, mild, and slightly intense stimulus. A slightly intense stimulus correlated with FC between the left middle insula and left middle cingulate cortex. When a faint stimulus was given, higher FC was reported between the left middle insula and right middle cingulate cortex and between the right posterior insula and left middle ACC. Ichesco et al
reported that increased pressure pain sensitivity was related to decreased FC between the left anterior insula and the right ACC and medial frontal gyrus in chronic temporomandibular disorders patients.
In conclusion, there is moderate evidence that pressure pain sensitivity is related to alterations in FC within somatosensory, pain, and affect-cognitive processing brain regions/networks in chronic MSKP patients (strength of conclusion 2). However, inconclusive evidence exists regarding the direction of the relation between increased pressure pain sensitivity and FC alterations in chronic MSKP patients. Positive
observed negative correlations between pain intensity in fibromyalgia patients and activation in primary and secondary visual cortical areas. Furthermore, hypersensitivity to tactile stimulation (ie, allodynia) was related to decreased activation in the superior middle temporal gyri.
In conclusion, there is some evidence that higher pain intensity and allodynia are associated with decreased functional brain activation in fibromyalgia patients (strength of conclusion 3). Further, there is some evidence that greater pain intensity is related to increased functional activity in the anterior insula in men with chronic pelvic pain (strength of conclusion 3).
The purpose of this systematic review was to summarize the evidence regarding relations between structural and functional brain alterations and clinical pain measures in chronic MSKP patients, examined with brain MRI techniques. Most studies reported significant relations between structural and functional alterations in the brain and various clinical pain correlates such as pain intensity, pain duration, and pressure pain sensitivity. Overall, the included studies examined a wide range of brain regions involved in somatosensory, cognitive, and affective processing of pain. Remarkably, the direction of the relations (eg, increased or decreased GM volume related to higher pain measures) often differed between and within various studies. This might be due to a variety of conditions that are classified as chronic MSKP, together with the multiple MRI acquisition and analytical techniques that have been applied to measure alterations in the brain. Furthermore, the different standardized scales and questionnaires that have been used to measure clinical features of pain could have influenced the direction and nature of the observed relations as well as the specific brain regions that were investigated. Nevertheless, several conclusions can be made and are summarized in Table 4. In addition, a glossary of important terms regarding MRI analysis of brain alterations is presented in Table 5.
Table 4Summary of Evidence Regarding Interrelations Between Brain Alterations and Clinical Pain Measures
Brain Structural and Functional Alterations, Clinical Pain Measures
Strength of Conclusion
Interrelations between GM alterations and clinical pain measures in chronic MSKP
FA is a measure of the degree of diffusion anisotropy. The FA is normalized so that it ranges from 0 (diffusion is isotropic) to 1 (diffusion is constrained along 1 axis only). FA is typically much higher in WM structures than in CSF and GM, because of the highly organized and tightly packed myelinated axons in WM. Because of this, FA is often used as a surrogate marker for WM ‘integrity.’
As such, AD leads to a more specific interpretation of the concept of WM ‘integrity’ associated with FA.
A Z-score is a way of standardizing the scale of 2 distributions. When the scales have been standardized, it is easier to compare scores on one distribution with scores on the other distribution. The mean of a distribution of Z-scores is always 0. The SD of a distribution of Z-scores is always 1.
The t-score is a measure not of the strength of the association but the confidence with which we can assert that there is an association. A t-score is a standard score Z-shifted and scaled to have a mean of 50 and an SD of 10.
Twenty case-control studies met the inclusion criteria. All studies scored a level of evidence B. Methodological quality was moderate to good, varying between 5 of 10 (50%) and 9 of 10 (90%). Moderate evidence shows that higher pain intensity and pressure pain sensitivity are related to decreased regional GM volume in brain regions encompassing the cingulate cortex, the insula, and the superior frontal and temporal gyrus.
Further, some evidence exists that longer disease duration in fibromyalgia patients is correlated with decreased total GM volume. Yet, inconclusive evidence exists regarding the association of longer disease duration with decreased or increased regional GM volume in other chronic MSKP conditions.
It can be summarized that different chronic MSKP syndromes, which seem to be a heterogeneous group, expose unique (specific for each chronic MSKP condition) anatomical ‘brain signatures’ and functional reorganization. However, among all included chronic MSKP conditions it seems that brain regions involved in the limbic-affective and cognitive component of pain processing are involved in the observed neuroplastic brain remodeling. On the basis of this compelling evidence it can be stated that chronic MSKP is not only involved with somatosensory processing but also critically involves cognitive and affective-limbic processing in regions such as the ACC, insula, prefrontal cortex, and amygdala.
Important to discuss is that the observed relations (eg, extent and direction) between clinical pain characteristics and brain alterations can be influenced by multiple factors. Research has shown in chronic MSKP and non-MSKP patients the influence on pain and neuroplasticity of sex, age, genetics, environment, preexisting vulnerabilities, previous experiences, medication, culture, and psychosocial factors.
Accordingly, all of these variables could interfere with the observed relations between brain alterations and clinical pain measures and therefore may explain the incongruence found in this systematic review.
Various hypotheses can be made to explain the relation between clinical pain measures and GM decreases. It has been suggested that GM decrease is associated with long-term nociceptive input and neuroplastic changes.
The frontal pole may process the cognitive dimension of pain, which suggests that pain has a cognitive load and this may require continuous engagement of regions in the frontal cortex and subsequently may lead to cortical thickness. The same theories could be hypothesized for alterations in limbic-affective brain regions.
To put the results of the current systematic review into a broader perspective, scientific studies regarding the relations between brain alterations and clinical pain measures in chronic non-MSKP patients should be reported. Research in other chronic pain syndromes such as irritable bowel syndrome and complex regional pain syndrome has also investigated the relationship between structural and functional brain alterations, and clinical pain measures such as pain intensity, pain inhibition, and pain duration.
Thicker posterior insula is associated with disease duration in women with irritable bowel syndrome (IBS) whereas thicker orbitofrontal cortex predicts reduced pain inhibition in both IBS patients and controls.
Positive and negative correlations between clinical pain measures and GM morphology alterations have been reported in chronic non-MSKP patients in similar regions involved in somatosensory, affective, and cognitive components of pain processing, as reported in chronic MSKP patients.
Thicker posterior insula is associated with disease duration in women with irritable bowel syndrome (IBS) whereas thicker orbitofrontal cortex predicts reduced pain inhibition in both IBS patients and controls.
The observed relations between brain alterations and clinical pain measures in chronic non-MSKP patients are in accordance with the results of our systematic review, but the direction of the relation was often conflicting.
Clinical Relevance and Implications
To our knowledge, this is the first systematic review summarizing the current evidence regarding relations between brain alterations explored with MRI, and clinical pain correlates (ie, pain duration, pain intensity, pain perception, pressure sensitivity, hyperalgesia, hypersensitivity, allodynia, and referred pain) in patients with chronic MSKP. Regarding the results, it can be stated that structural and functional brain alterations are closely related to clinical aspects of pain perception, modulation, and duration. Increased pain intensity and pressure pain sensitivity seem to be related to decreased GM volume in regions involved in somatosensory, affective, and cognitive processing of pain. In contrast, inconclusive evidence was found regarding the direction of the relation between WM and FC alterations, and increased pain intensity or pressure pain sensitivity.
On the basis of the summarized evidence, we can presume that central pain