Brain biomarkers of chronic pain likely will involve the dynamic pain connectome because it is a system for pain sensing, attention, and modulation.39 In addition, biomarkers based on an individual's inherent characteristics (sex, gender, age, personality, traits, etc.) should be considered for their modulating impact on the brain and behaviour.
2. Individual variability and behavioural biomarkers
Sex, gender, genetics, race, environmental and cultural factors, behavioural states, and traits could potentially contribute to the constellation of biomarkers used to predict chronic pain treatment outcomes. Individuals can vary tremendously in terms of their individual make-up of these factors, which may impact how they sense and respond to noxious stimuli, and their ability to cope with pain. For example, my laboratory has identified intersubject variability (including some sex differences) in many aspects of pain sensitivity (such as threshold, habituation, and adaptation) and resilience.10,28,29 We have also introduced 2 types of behavioural phenotypes related to pain-attention interactions: The A/P phenotype spectrum is based on the disruptive effect of pain on concurrent cognitive task performance; P-type individuals lie at one end of the spectrum (pain dominates and task performance diminished during concurrent pain) and A-type individuals (attention dominates and task performance maintained) lie at the other end.21,52 Another phenotype is based on an individual's intrinsic attention to pain (IAP) score, which is calculated from the degree to which an individual attends to pain vs mind wanders away from pain.41 Both the A/P and IAP phenotypes potentially could be used as biomarkers of treatment outcome, but this has yet to be tested.
Additional behavioural attributes that are potential biomarkers of pain and pain treatment outcomes include individual characteristics measured using standardized questionnaires (eg, for pain catastrophizing, resilience, anxiety, etc.), and threshold and suprathreshold psychophysical measures of pain sensitivity and modulation (eg, quantitative sensory testing). In particular, 2 well-known behavioural measures of pain sensitivity and modulation—temporal summation of pain (TSP) and conditioned pain modulation (CPM) hold promise for predicting chronic pain treatment outcome. Conditioned pain modulation (a type of counterirritation paradigm) is used as a proxy measure for antinociceptive brain attributes such as descending antinociceptive activity within the dynamic pain connectome and pain modulation.57 By contrast, TSP can serve as a proxy measure for pronociceptive brain attributes such as activity in the dynamic pain connectome (in particular, the ascending sensing pathway), pain facilitation, and central sensitization.
3. Imaging biomarkers and brain-behaviour relationships
There are many types of brain attributes that can potentially be used to develop biomarkers of pain treatment outcomes. These indicators can be acquired using structural and/or functional brain imaging with magnetic resonance imaging (MRI), electroencephalograph (EEG), magnetoencephalography (MEG), or positron emission tomography. For a general description of these approaches, see Refs. 6, 14, 18, 39, 40, and 46. Here, I will focus on MRI and MEG.
Structural MRI scans and diffusion tensor imaging can be used to measure structural metrics that provide insight into the cellular and scaffolding aspects of the brain. Thus, one can measure aspects of gray matter (volume, density, cortical thickness, etc.) and of white matter. There are 2 types of white matter assessments that can be used to measure integrity and connectivity. Measures such as fractional anisotropy, as well as mean diffusivity, radial diffusivity, and axial diffusivity can provide information pertaining to the health of the white matter, and abnormalities of these metrics have been associated with a variety of conditions such as edema, inflammation, and demyelination.18 Tractography can be used to assess the strength of structural connectivity between brain areas, typically mapped using fractional anisotropy values.
Functional imaging measures include evoked responses, functional connectivity (FC), and regional activity. Most relevant to chronic pain conditions is that FC (also known as functional coupling in MEG studies) and regional activity can be assessed during “resting state” conditions using functional MRI (fMRI), arterial spin labeling, positron emission tomography, EEG, and MEG. These are useful to examine the “chronic pain” brain associated with ongoing pain because no additional stimulus needs to be applied. There are 2 main types of FC assessments—those that measure how brain areas show general synchrony over time (static FC [sFC]) and those that measure how a pair or network of brain areas exhibit dynamic (flexible) synchrony over time (dynamic FC [dFC]). Dynamics in the activity within a region of the brain can also be examined by measuring regional BOLD variability or fractional amplitude of low-frequency fluctuations during a resting state fMRI scan, or through spectral analyses of MEG or EEG data.
My laboratory and others has linked many attributes of individual variability in acute pain sensitivity measures, pain-attention phenotypes (A/P and IAP), and personality described above with brain measures of structure, connectivity, and function of the dynamic pain connectome.9,10,20–22,30,41,48,50–52,55 For example, we found that there is a strong link between TSP and FC. Individuals who exhibited high TSP had strong FC in the ascending nociceptive pathway and weak FC in the descending antinociceptive pathway, whereas individuals with low TSP had the opposite connectivity pattern10 (Fig. 5). These findings indicate that individuals not only lie on a behavioural spectrum of pronociception to antinociception as described by Yarnitsky's group25,57 but also a brain connectivity spectrum of pronociception to antinociception.
4. The dynamic pain connectome dictates how we feel pain
Unlike static models of pain, the dynamic pain connectome concept emphasizes temporal dynamics across brain networks of attention, default mode, salience, ascending nociceptive, and descending modulation systems. This concept provides new thinking about brain mechanisms underlying pain and fluctuations across time and conditions. The fine temporal features within regions of the dynamic pain connectome are largely unknown because previous human studies of pain used fMRI whose signals arise from slow hemodynamics. But a deep understanding of pain requires a technique that can measure signals on a timescale that directly relates to neuronal activity. One such technique is MEG that measures fast brain signals with millisecond precision. Magnetoencephalography also has several advantages over EEG, although it is less sensitive to radial dipoles and debates continue regarding deep source localization.4 Nonetheless, MEG provides more accurate source localization than EEG, deep sources are possible,4 and it is more tolerable for patients with chronic pain because the scalp electrode placement is less onerous.4 Furthermore, unlike fMRI, the presence of ferromagnetic implants such as spinal cord stimulator systems is not a contraindication for using MEG.
5. What could go wrong? Coding and communication in the brain, and how to model it all
The brain uses temporal codes to represent perception. Neurons in the brain exhibit spontaneous (ongoing) activity in the absence of a particular task or stimulus. This activity provides a baseline (ie, a type of prior) from which a response to a given stimulus or situation can arise and shape the subsequent stimulus response and behavior. Thus, this prior contributes to behavioral responsivity and sensitivity.
At the population level, synchronous activity of large numbers of neurons produces oscillatory patterns of activity. It has been proposed that an oscillatory form of activity at rest is an efficient way for neuronal assemblies to be kept close to their firing thresholds.8 Brain oscillations are categorized into different frequency bands (delta, theta, alpha, beta, and gamma),8 and different brain areas have characteristic power spectra.36 Each frequency band is associated with several purported functions including roles in excitatory and inhibitory processes within localized regions or long range communications.35 The assessment of firing patterns from populations of neurons within these frequency bands requires a technique that can measure signals on millisecond timescales such as MEG or EEG.
Brain areas that are connected structurally might not be functionally communicating with each other effectively. Magnetoencephalography can be used to evaluate the communication functionality between brain areas. As noted above, FC is a measure of the synchrony of activity between 2 brain areas. Magnetoencephalography can characterize this type of brain communication by measuring different metrics of functional coupling based on the phase and amplitude of oscillations.19 There are several ways in which ineffectual communication between brain areas or networks can arise (Fig. 6); abnormal communication can arise if (1) regional activity of 2 normally functionally connected brain areas exhibit abnormal coupling or (2) if there is abnormal oscillatory activity within one or both of 2 connected brain areas.
Over the last decade, functional and structural abnormalities within areas, networks, and connections of the dynamic pain connectome have been identified in patients with a variety of chronic pain conditions (for reviews see Refs. 6, 14, 15, 18, and 39), mostly using MRI-based brain imaging technologies. Many imaging studies have also linked these abnormalities to levels of pain and the impact of pain on activities of daily living.7,30,31,37,49 In addition to brain abnormalities, we and others have used diffusion tensor imaging–MRI studies to identify structural abnormalities in the trigeminal nerve of patients with orofacial pains such as trigeminal neuralgia and temporomandibular disorders.14,17,18,46 These brain and peripheral nerve studies provide insight into neural dysfunction that have been reversed in some cases after effective treatment14,16,24 (see next section).
It is not clear yet how best to construct a model of chronic pain. Most imaging studies of chronic pain abnormalities have used conventional, univariate statistical approaches. However, given the complexities of brain mechanisms underlying pain and the limitations of fMRI, many groups have developed more sophisticated, multivariate, and machine learning approaches to understand and predict acute pain,54 the transition to chronic pain,1,27 and chronic pain conditions.43–45,53 Despite some promising results, previous, there remain many challenges to establish models of chronic pain that will be applicable to predict treatment outcome in an individual. One area for future development is to explore what type of brain imaging metric (function, structure, sFC/dFC, oscillations, spectral patterns, etc.), should be used from what type of imaging modality (MRI, MEG, etc.) and what individual attributes (for a discussion see Ref. 13) to include in the model such as (1) pain attributes (intensity and quality), (2) pain state (current pain) vs pain trait (average pain over time), (3) pain etiology (neuropathic, inflammatory, etc.), and (4) impact on activities of daily living, mood, behaviour, etc. For example, my laboratory recently used a machine learning approach to construct models of chronic pain based on FC data for patients with a form of arthritis, ankylosing spondylitis.11 We found that the models for state and trait pains were similar but had distinct features. These models were driven by pain severity, patients with neuropathic pain (rather than inflammatory pain), and had features of predominantly dFC (rather than sFC).
6. Predicting chronic pain treatment outcomes
Much of the effort to predict chronic pain treatment outcome is being directed at assessing the brain (see below). However, we have reported that structural abnormalities in the trigeminal nerve are reversed in patients with significant pain relief after microvascular decompression or gamma knife surgery (but not in patients with no clinical benefit of surgery).16 Furthermore, our group has shown that there are a constellation of pretreatment abnormalities in the trigeminal nerve and brain white matter that are predictors of treatment outcome.33,59
In the central nervous system, the analgesic effect of a treatment may depend not only on the ability to resolve a dysfunction (eg, an overactive ascending nociceptive pathway) but also on the presence of a healthy or modifiable pain modulation system. That is, an effective treatment may work through 2 mechanisms: (1) enhancement of the descending pain modulation system and/or (2) removal of an abnormality that is suppressing or overriding a potentially strong endogenous pain modulation system.
Evidence for the first scenario (ie, boosting inefficient descending modulation) comes from studies by Yarnitsky's group56,58 that found duloxetine to be more efficacious to treat diabetic neuropathy pain in people exhibiting deficient pain modulation and/or enhanced pain facilitation. The interpretation was that the drug was more effective in those with less-efficient CPM because the drug is boosting the descending modulation system, whereas patients whose CPM is operating efficiently do not benefit from this drug because the system cannot be further boosted. Furthermore, because CPM is opiate-mediated, it can be potentiated by opioids2,38 but remains unchanged by drugs with a nonopioid mechanism of action.42,47 The TSP response reflects the magnitude of central neuronal sensitization and can be attenuated by N-methyl-D-aspartate antagonists,3 and calcium and sodium channel blockers but not by serotonin–norepinephrine reuptake inhibitors.26 Furthermore, enhanced TSP but not less-efficient CPM was a successful predictor for response to pregabalin in pain patients.47 Thus, accumulating evidence indicates that simple tests of pain modulation (CPM) and pain magnification (TSP) can indicate whether a certain family of drugs is likely or unlikely to benefit an individual patient. Also, our work showing individual and sex differences in the dynamic pain connectome9,10,12,21,28,48,55 suggests that some patients may benefit from boosting or blocking activity in specific brain areas or networks with techniques such as deep brain stimulation, transcranial magnetic stimulation, or spinal cord stimulation based on identifying brain areas in these patients that are operating suboptimally or with weak functional connections to other brain areas.
We recently provided evidence for the second scenario (ie, reducing an overactive ascending nociceptive system that is suppressing a strong descending modulation system)5 (Fig. 7): We showed that the patients who achieved good pain relief from a treatment of intravenous ketamine exhibited 2 pretreatment features that distinguished them from patients who did not benefit from treatment and healthy controls: unusually high TSP and a strong and flexible connectivity within the descending modulation pathway. Although both the brain and TSP were predictive of pain relief, the functional connectivity was a stronger predictor of pain relief than TSP. Ketamine is an N-methyl-D-aspartate inhibitor that acts to reduce spinal cord windup3,32 and thus can attenuate abnormally high activity in the ascending sensing pathway associated with TSP.10 Thus, the ketamine treatment response may have occurred because the drug blocked an overactive ascending sensing pathway, which released and allowed a strong and flexible descending modulation system to work effectively (Fig. 7).
There are promising developments in the use of both imaging-based metrics of brain function and structure, as well as measures of pain sensitivity and related individual attributes to predict pain treatment outcome. In the future, the choice of which or how many predictive biomarkers to use most effectively may depend on the type of pain, treatment modality, and practical and cost issues.
Conflict of interest statement
The author has no conflict of interest to declare.
Funding for studies discussed in this review include grants to K.D. Davis from the Canadian Institutes of Health Research (including funding from the CHIR SPOR program to the Chronic Pain Network), the Mayday Fund, and the MS Society of Canada. The author thanks all her trainees and collaborators for their contributions to the findings and ideas included in this article.
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Keywords:© 2019 International Association for the Study of Pain
Biomarker; Imaging, fMRI; Functional connectivity; Temporal summation of pain; Dynamic pain connectome; Modulation; Default mode network; Ketamine; Prediction