Imaging Biomarkers in Chronic Neuropathic Pain Management: Comparison
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Chronic neuropathic pain is a very important public health issue with profound negative implications in many aspects of patients’ individual lives, as well as society, health systems, productivity, and macroeconomics. The development of imaging, especially molecular and functional imaging, provides objectivity and makes the connection between structural changes, receptors involved in the mechanisms of action, and potentially therapeutic or diagnostic molecules by highlighting the place of action and the involved systems. The approval of composite biomarkers, including serological, genetic, clinical, and imaging markers, with high sensitivity and specificity will accelerate and improve diagnosis, staging, predictive and prognostic evaluation, stratification (phenotyping) and inclusion in trials, and the development of therapeutic options (pharmacological, biomedical) through preclinical, translational, clinical studies. 

  • neuropathic pain
  • imaging biomarkers
  • MRI
  • PET
  • MRS

1. Chronic Neuropathic Pain and the Pain Matrix

CNP is a complex syndrome that manifests as a cluster of signs and symptoms. Neuropathic pain is often confused with nociceptive pain, both in the clinical and in the preclinical setting. While nociception occurs when non-neuronal tissues are injured, neuropathic pain necessarily involves damage to the components of the somatosensory nervous system [33][1]. The irritation of the sensory nerves triggers a cascade of events, transmitting painful signals at different levels that ultimately leads to the production of a painful sensation. The normal circuits of pain sensation begin at the skin, muscle, or visceral level, where specific receptors respond to the painful stimulus by creating a depolarization wave from the activation of Na/K pumps. The electrical impulse is transmitted to the spinal cord (dorsal horn), where the synapse with the first-order neuron takes place. At this level, more specifically, in the presynaptic cleft, the dependent voltage-gated Ca channels are activated, and the Ca influx allows the release, into the synaptic space, of excitatory neurotransmitters (glutamate). These neurotransmitters bind with specific receptors, located at the level of the second neuron, thus triggering its depolarization. The nerve fibers rise upwards, intersect, and reach the third synapse in the thalamus, so that later the dendritic extensions reach the limbic system and the cerebral cortex, where the information contributes to the sensation of pain [34][2].
Therefore, facing a real public health issue and a therapeutic challenge, there is a need to develop new reliable, objective, and quantifiable methods of diagnosing chronic neuropathic pain. This could be achieved by taking advantage of technological advances in medicine, such as the use of combined imaging techniques to detect biomarkers of disease and speed up pharmacological safety and efficacy testing of new compounds in assessing effects and bioavailability through molecular imaging [31,32][3][4]. The aim of this paper is to provide both preclinical and clinical researchers and physicians with an overview of the current imaging techniques that offer biomarkers for the diagnosis, prognosis, and efficient management of chronic neuropathic pain.

1.1. Classification and Etiology

Currently, there are several classifications used for chronic neuropathic pain. In the clinical setting, physicians most often discriminate between different neuropathies based on etiology, pain characteristics, and the anatomic location of the lesion. Although useful for the differential diagnosis, these classifications do not necessarily reflect a different management course or distinct response to treatment. Woolf and Mannion suggested classifying neuropathic pain according to the presence/absence of the painful stimulus, i.e., stimulus-independent pain and stimulus-evoked pain. Stimulus-independent pain can further be divided into continuous and paroxysmal pain [35][5]. In stimulus-evoked pain, two key features must be taken into account: hyperalgesia and allodynia. Hyperalgesia is an exaggerated response to a stimulus that would normally cause pain, being an abnormal processing of a nociceptor stimulus. It can be caused by mechanical, thermal, or chemical inputs. Mechanical hyperalgesias are further classified as brush-evoked (dynamic), pressure-evoked (static), and punctate hyperalgesias. On the other hand, allodynia appears when a normally innocuous stimulus triggers pain, having two known mechanisms: by the action of low-threshold myelinated A fibers on an altered central nervous system, or by a reduction in the threshold of nociceptor terminals in the periphery [35][5]. Chronic neuropathic pain can be a symptom of several conditions, which is why it is commonly divided into categories: peripheral, central, or mixed. Whereas central neuropathic pain is a consequence of injuring sensory fibers belonging to the central nervous system (brain and spinal cord), peripheral neuropathic pain results from damage to the peripheral nerve fibers and originates in small non-myelinated C and F-type myelinated fibers (Aβ and Aδ). The injury of these nerve fibers leads to changes in the expression of neurotransmitters, neuromodulators, growth factors, receptors, neuroactive molecules, and inflammatory mediators, thus leading to hypersensitivity in reaction to stimuli [36][6]. Chronic neuropathic pain with peripheral etiology can be further divided into generalized (polyneuropathies) and focal or multifocal neuropathies.

1.2. Structural and Functional Changes in CNP

In the case of neuropathic pain, the mechanisms are not fully known and the relationship between etiology, mechanisms, and symptoms is extremely complex [37][7]. A single mechanism may be responsible for producing several symptoms, and the same symptom may be caused by different mechanisms from one patient to another. No pain mechanism is an inevitable consequence of a particular disease process, and there are no consistent predictors to indicate which patient will develop neuropathic pain [35][5]. Several studies have shown that at the cortical and subcortical levels, there is a complex network involved in various aspects of the perception of painful sensations produced by thermal, mechanical, or chemical stimuli: the so-called “pain matrix” [39,40][8][9] (Figure 1). By means of functional imaging techniques, the following structures have been identified as playing a key role in the pain matrix: the thalamus, the primary and secondary somatosensory cortex (S1, S2), the insular cortex, the anterior cingulated cortex (ACC), and the prefrontal cortex (PFC). The sensory–discriminative aspect of pain is associated with the S1, S2, thalamic nuclei, and the posterior insula, known as the lateral pain system. The affective–motivational processing of pain, which makes up the median pain system, has been associated with ACC, anterior insular cortex, PFC, and thalamic nuclei. Finally, the cognitive aspects of pain are considered to be closely related to PFC [41][10].
/media/item_content/202301/63b7769b18359ijms-23-13038-g001.png
Figure 1. Illustrative pain matrix (created with BioRender.com, accessed on 15 March 2022). ACC = Anterior Cingulate Cortex; AMG = Amygdala; BS = Brainstem; HPC = Hippocampus; INS = Insula; PAG = Periaqueductal gray; PFC = Prefrontal Cortex; PPC = Posterior Parietal Cortex; S1 = Primary Somatosensory Cortex; S2 = Secundary Somatosensory Cortex; SMA = Supplementary Motor Area; TLM = Thalamus; CRB = Cerebellum.
Changes in brain regions outside of the pain matrix as a response to chronic neuropathic pain, commonly referred to as a “pain signature”, can involve cortical areas normally responsible for attention, affection, and mood. These changes are unique to each patient, and most commonly affect the dorsolateral frontal cortex, areas of parietal association, and some of the brainstem nuclei embedded in pain modulatory systems [46][11].
Although brain reorganization and maladaptive neuroplasticity are noted in several conditions that lead to CNP, phantom pain syndrome is probably the best researched. This type of neuropathic pain occurs after amputation of a limb, and is characterized by a variety of sensations, including the feeling of the presence of the amputated extremity and paresthesia inside the phantom member. Magnetoencephalography (MEG) imaging was performed in patients with this condition, and it was observed that the distribution area of the mouth in the somesthetic area was found to be shifted into that of the former limb. The extent of the shift was directly proportional to the intensity of the perceived neuropathic pain [47][12]. The pathophysiological basis of neuroplasticity in neuropathic pain could be based on the fact that the stimulation of nociceptors on the limb, before it is amputated, produces some changes in the brain, thus creating a memory area of this type of pain. Thus, maladaptive plasticity is a very likely explanation for the perception of pain in the phantom limb [48][13]. The default mode network is a system of connected brain areas that show increased activity when the person is not focused on what is happening around them [50][14]. In the case of chronic neuropathic pain, some connections in this network appear to be altered, a feature objectified by fMRI in a group of patients suffering from chronic back pain. While performing a visual task, these patients experienced reduced deactivation in several key default mode network regions, compared to the control group, suggesting that network damage could be the cause of the behavioral and cognitive changes that accompany chronic pain [51][15]. In the pathophysiology of chronic neuropathic pain, peripheral sensitization plays a key role, and is generated by the appearance of perilesional inflammatory changes. The secretion of mediators (e.g., neurotrophic growth factor, PGE2, bradykinin, cytokines, and chemokines) leads to the stimulation of the axons of peripheral neurons, and thus the activation and migration of macrophages in the nerves and dorsal root ganglion. Inflammatory mediators interact with cellular receptors and ion channels, leading to a series of intracellular changes, ultimately decreasing activation thresholds and increasing membrane excitability, which consequently results in a painful sensory effect [52][16]. Another consequence of neurochemical changes secondary to nerve injury is the activation of other neural cells located in the vicinity. These cells can release immune modulators that paradoxically promote nociception by altering neuronal function. 

1.3. Biochemical Changes in CNP

Understanding the long-term modifications of the peripheral and central nervous system after chronic pain has greatly increased in the past few years due to emerging preclinical research techniques, mostly performed in vitro. Such approaches are useful in understanding sensory neuron functions, based on their sensory and nociceptor-specific molecular profiles [54][17], i.e., ion channels and neuropeptides. The best-known ion channels involved in CNP are the voltage-activated sodium channels (Nav) [55][18], the voltage-gated calcium channels (Cav/VGCC), the calcium-activated potassium channels (KCa), the purinergic receptor (P2X), the transient receptor potential vanilloid family ion channel 1 (TRPV1), and the transient receptor potential cation channel ankyrin 1 (TRPA1) [56][19]. Of the neuropeptides, calcitonin-gene-related peptide (CGRP), substance P (SP), galanin, somatostatin and its receptors, endothelin-1 (ET1), angiotensin II and its receptors, isolectin B4 (IB4), neurotrophins, nitric oxide synthase (NOS), gamma amino butyric acid (GABA), and phospholipase β3 are known as molecules characteristic of nociceptors [57][20].

2. Current Imaging Techniques Used in CNP

Several imaging technologies are currently used for providing objective structural and functional measurements of different brain regions involved in the perception of pain. The best-known imaging tools are magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), electroencephalography (EEG), and magnetoencephalography (MEG) [74][21].

MRI is a versatile technique that produces cross-sectional high-resolution images using a strong magnet and radio waves. From an anatomical point of view, gray matter can be assessed by MRI scanning with voxel-based morphology (VBM) or cortical thickness analysis (CTA). On the other hand, the changes caused by neuropathic pain in white matter are visible by means of MR-based diffusion tensor imaging (DTI) [75][22]. MRI has been used for several years in patients with chronic neuropathic pain, especially in cases that could benefit from surgery.

PET and SPECT are molecular imaging techniques with high sensitivity and good spatial resolution and penetration depth that have made a significant contribution in the evaluation of the physiological function and biochemical changes of molecular targets. Both techniques are based on the quantification of radionuclide decay, during which a positron or a γ-ray is detected. One of the main advantages that makes these imaging technologies vital, both for preclinical and clinical studies, is their capability of using highly specialized radiopharmaceutical probes tailored for specific indications, without changes in the chemical structure of the ligand [85][23]. 

EEG and MEG are electrophysiological imaging techniques that create electrical brain wave maps of various areas with high temporal resolution, but low spatial resolution and specificity. EEG collects the impulse of neural electric activity of a specific region with the aid of scalp electrodes, and MEG maps the brain activity by recording magnetic fields produced by electrical currents spontaneously occurring in the brain, using highly sensitive magnetometers [88][24].

3. Emerging Techniques for Diagnosing CNP

All of the imaging investigations so far offer low specificity and sensitivity for the etiologic diagnosis of neuropathic pain. It is also important to note that the diagnosis of chronic neuropathic pain is primarily based on patient symptoms, and will probably remain so in the near future. Structural and functional changes in the CNS or the peripheral nervous system do not always correlate with the presence or absence of neuropathic pain, and there is no link between the severity of the alterations and the intensity of perception. Moreover, there is still not enough data to clearly state positive and negative predictive values for any of the imaging tests discussed in this article, most likely due to several factors: heterogeneity of clinical trial inclusion criteria, interobserver variability, technical performance of the device, different chronic pain models, and various CNP etiologies in clinical practice [41][10]. These important hindrances could have a significant impact on patients’ lives and lead to unnecessary exposure to expensive and potentially irradiating imaging tests [155][25]. As such, improving specificity and sensibility for any CNP imaging assessment considered for clinical use should be a priority, especially since some of the available imaging techniques can often link CNP to changes in the nervous system, thus aiding the diagnostic process. Of note, improvements in nerve structure or function can sometimes be an indicator that the treatment is, or will be, effective [155][25]. Moreover, imaging biomarkers will probably be used more and more for predicting which patients will develop CNP after a nerve lesion, and for identifying those at risk of CNP, which is particularly useful when choosing a neurotoxic treatment (as is the case with cancer patients and chemotherapy). In this sense, the use of molecular biomarkers, specific to pain-generating pathology, can identify the presence of pathological biological processes, even in the apparent absence of anatomical changes. Functional molecular and cellular imaging techniques are currently being investigated, taking advantage of heightened metabolic, hemodynamic, mediator, and cellular changes that are associated with increased nociceptive activity, in order to identify abnormal activity anywhere along the nociceptive pathways in the CNS and peripheral nervous system.

Chronic neuropathic pain is associated with a state of hyperexcitability, resulting from alteration of the excitation threshold, which leads to an increase in action potential. These changes occur due to the increase in the number and activity of voltage pumps dependent on Na and Ca, allowing increased activity of the nerves, as identified by PET studies [156][26]. The voltage-gated sodium channels Nav1.7 and Nav1.8 are highly expressed in sensory neurons, and have been identified as promising targets for the development of new analgesics [157][27]. Immunofluorescence assays and in vitro co-culture models using DRG and dorsal horn (DH) neurons in a three-compartment microfluidic platform showed that while blocking presynaptic Nav1.7 and Nav1.8 channels is effective in reducing synaptic transmission in uninjured cultures, the same blockers are ineffective in cultures where the DRG axons in the periphery compartment had been axotomized [55][18]. Live cell imaging and surface channel labelling in primary rat DRG neuron cultures showed that treatment with paclitaxel (PTX), which causes dose-limiting chemotherapy-induced peripheral neuropathy (CIPN), is associated with increased levels of endogenous Nav1.7 channels in DRG and long-distance axonal vesicular transport in sensory axons [158][28]. An immunofluorescence assay with immortalized DRG neuronal cell line (differentiated F11 cell line) identified several potential neuroprotective drugs, such as α-lipoic acid, pregabalin, and melatonin, and confirmed the same effect of felodipine and nitrendipine [159][29].

Glial activation is a key process in chronic pain states. A study based on immunofluorescence staining that assessed the efficacy of gabapentin in CNP showed that the development and maintenance of hypersensitivity after spinal/peripheral nerve injury is correlated with activation of microglia and astrocytes that present large cell bodies and thick processes. Additionally, glial activation is accompanied by an increase in ionized calcium-binding adapter molecule 1 (Iba-1), as a microglial biomarker; GFAP, as an astrocytic biomarker; the VGCC α2/δ-1 subunit in primary afferent fiber terminals and dorsal horn neurons; and fractalkine/CX3CL1, a putative activator of microglia in the spinal dorsal horn, and its receptor CX3CR1/GPR13, mainly expressed in the spinal microglia [160][30]. In chronic neuropathic pain, activated microglia and other macrophages express, on the cell surface, a specific protein (TSPO). Imaging techniques can identify and locate activated microglia using radioligands that connect to TSPO, and thus identify the areas with increased neuroinflammation and sensitization [161][31]. Upregulation of sigma-1 receptors (S1R) occurs in Schwann cells and macrophages at the site of inflammation. Using the 18F-FTC-146, as specific PET radiotracer sigma-1 receptor ligand it was shown that increased uptake in the case of a neuroma caused by nerve injury was correlated with increased receptor expression [162][32]. The endocannabinoid system, which plays an important part in pain perception, has also been investigated by means of imaging studies in preclinical research. Expressed by peripheral immune cells, neurons, and glia [163][33], such as microglia and astrocytes, the cannabinoid type 2 receptor (CB2R) was identified as a promising therapeutic target for immunological modulation [164[34][35],165], its activation decreasing inflammation [166,167][36][37]. CB2 receptors are also upregulated in the CNS and DRG by pathological pain condition [168][38]. The dorsal spinal cord microglia is known as an important site involved in CB2-receptor-mediated analgesia, while the overexpression of P2Y12 and P2Y13 purinoceptors in spinal dorsal horn microglia is involved in neuropathic pain [169][39]. Endocannabinoid anandamide-treated primary cultures of microglial cells showed an alleviation of E. coli lipopolysaccharide (LPS)-induced neuroinflammation, an effect primarily controlled by the CB2 receptors [170][40]. Molecular biology has promoted the development of new molecularly targeted diagnostic and therapeutic methods. However, in vitro discoveries cannot always be replicated in vivo. Obviously, the best method of in vivo study of pathophysiological mechanisms would be direct research on human subjects, but this is often impossible due to ethical limitations. Therefore, small animal study models are an important bridge between molecular findings and the implementation of clinically relevant diagnostic techniques or therapies. Studies on small animal models have previously been based on ex vivo tissue sectioning and microscopy. These methods require the existence of a histopathological laboratory, and do not allow the longitudinal study of a single animal. In this sense, out of the need for simplification and modernization, imaging-based methods have become important non-invasive techniques for in vivo investigation of animal research models. Imaging offers the possibility of serial, uniform, automated, non-invasive, and comparable studies on subjects, with advantages and reduction in the number of animals and experimental costs. [174][41]. As each imaging method has its own advantages and disadvantages, the effective choice of the most appropriate imaging technique or techniques should be made according to the hypotheses and questions whose answers are to be discovered in the published research (Table 31) [175,176][42][43].
Table 31. Approaches to key questions on drug development using appropriate preclinical imaging methods for translational research (adapted after [176][43]).
Issue Question Preclinical Imaging Approach
Validation Does the therapeutic target play a key role in the pathophysiological mechanism? MRI whole-body scan
Biodistribution Does the molecule reach the targeted tissue? Can pharmacologically active concentrations be reached for the compound being studied? Radiolabeling of the compound to study the distribution or interactions in the target area (use of PET, SPECT, or MRS)
Interactions Does the studied molecule interact with the target receptor? What is the relationship between dose and effect? Saturation studies (plasma concentration–occupancy–time) using PET or SPECT radiolabeling
Pharmacodynamics What is the effect and duration of the compound? Dynamic biochemical studies, structural or functional studies (non-ionizing radiation imaging techniques are recommended for long-term effects follow-up)
Toxicology Does the compound have acute or chronic toxic effects? Dynamic biochemical studies, structural or functional studies of at risk organs (MRI, CT, US)
MRI, magnetic resonance imaging; PET, positron emission tomography; H-MRS, proton magnetic resonance spectroscopy; SPECT, single-photon emission computed tomography; CT, computed tomography; US, ultrasonography.
One of the most promising applications of imaging studies in chronic pain comes from the ability to screen for the effectiveness of a new analgesic drug. Imagistic screening of drugs represents a predictive tool that allows the selection of new compounds that act on limbic structures and sensorimotor system, important areas for neuropathic pain pathways. For example, using pharmacological MRI (phMRI), Hooker et al. (2014) [180][44] showed that gabapentin significantly altered the brain’s functional circuits when administered in the treatment of neuropathic pain. Variations of receptors expression, also identifiable using PET analysis, can explain the differences in responses to treatment between patients and also the depression-like behavior/emotional disturbances associated with neuropathic pain [179][45]. Of note, by means of fMRI studies, we now know that drugs exhibit specificity regarding the activation of different brain areas [179][45].

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