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Background Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. Methods Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. Results A reduction of the total fractional power in both groups—specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex—was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). Conclusions These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M = 15.8, SD = 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR < 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS+>CS-; rp = 0.49, P = 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P < 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P < 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.

Arrhythmic fluctuations in neural activity occur at many levels of the nervous system. Such activity does not have a characteristic temporal periodicity but can exhibit statistical similarities, most commonly power-law scaling behavior, which is indicative of scale-free dynamics. The recurrence of scaling laws across many different systems and its manifestation in behavior has prompted a search for unifying principles in human brain function. With this in mind, a focused search for abnormities in scale-free dynamics is of considerable clinical relevance to migraine and other clinical pain disorders. Here, we examined the scale-free properties of the resting-state functional magnetic resonance imaging (fMRI) signal in the broadband frequency range known to be related to spontaneous neural activity (0.01-0.1 Hz). In a large cohort of episodic migraine patients (N = 40), we observed that the strength of long-range temporal correlations in the fMRI signal (captured by the scaling exponent α) was significantly higher in the sensorimotor network compared with healthy controls. Increases in the scaling exponent were positively correlated with fMRI signal variance and negatively correlated with the patient's self-reported headache intensity. These changes in the fMRI signal suggest that the temporal structure of amplitude fluctuations carries valuable information about the dynamic state of the underlying neuronal networks and ensuing sensory impairments in migraine. The demonstrated scaling laws pose a novel quantitative approach for examining clinically relevant interindividual variability in migraine and other pain disorders.

OBJECTIVES Numbness associated with neuropathic pain suggests the loss of function in myelinated, large diameter sensory neurons. The purpose of this study was to examine the relationships between pain severity and subjective (ie, severity of numbness) and objective (ie, loss of light touch sensations, vibration thresholds) measures of loss of large fiber function in adult survivors with chemotherapy-induced peripheral neuropathy (CIPN, n=426) and breast cancer patients with persistent postsurgical pain (n=80). MATERIAL AND METHODS For both samples, average pain and numbness were evaluated using a 0 to 10 numeric rating scale. Loss of light touch sensations in the hands and feet of patients with CIPN and in the upper arm of patients at 5 and 6 months following breast cancer surgery were assessed using Semmes Weinstein monofilaments. Loss of vibration in the hands and feet of patients with CIPN was assessed using a biothesiometer. Pearson Product Moment correlation coefficients were calculated between average pain and the number or percentage of sites with loss of light touch sensations, mean vibration thresholds, and the severity of numbness. RESULTS For both pain conditions, average pain scores were significantly correlated with objective measures of large fiber function (r=0.12 to 0.34; all P

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is classified as one of the most disabling symptoms that accompany an attack. Using subjective psychophysical assessments, we showed recently that migraine patients are more sensitive to all colors of light during the ictal than during the interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in the ictal and interictal phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b-wave, which was consistently larger (by 14-19% in the light-adapted and 18-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a-wave or the visual evoked potentials that differ most strikingly between the two groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that non-migraineurs feel as if they live in a cave.

It is well recognized that, despite similar pain characteristics, some people with chronic pain recover, whereas others do not. In this review, we discuss possible contributions and interactions of biological, social, and psychological perturbations that underlie the evolution of treatment-resistant chronic pain. Behavior and brain are intimately implicated in the production and maintenance of perception. Our understandings of potential mechanisms that produce or exacerbate persistent pain remain relatively unclear. We provide an overview of these interactions and how differences in relative contribution of dimensions such as stress, age, genetics, environment, and immune responsivity may produce different risk profiles for disease development, pain severity and chronicity. We propose the concept of ‘stickiness’ as a soubriquet for capturing the multiple influences on the persistence of pain and pain behavior, and their stubborn resistance to therapeutic intervention. We then focus on the neurobiology of reward and aversion to address how alterations in synaptic complexity, neural networks and systems (e.g., opioidergic and dopaminergic) may contribute to pain stickiness. Finally, we propose an integration of the neurobiological with what is known about environmental and social demands on pain behavior and explore treatment approaches based on the nature of the individual’s vulnerability to or protection from allostatic load.

Trauma-focused therapies (eg, trauma-focused cognitive-behavioral therapy, narrative exposure, and mindfulness) may be optimal for youth experiencing chronic pain to address the potential for an ongoing stress response., Nonpharmacological treatments for chronic pain in youth have been identified as first-line treatments over and above medication. Therapies such as cognitive-behavioral therapy and mindfulness-based stress reduction have shown good efficacy in reducing the psychological correlates (eg, anxiety, depression, and stress) and social or behavioral sequelae (eg, limited physical activity and lack of school engagement) associated with pediatric chronic pain. However, minimal research has examined the physiological mechanism(s) of action for these interventions. A recent review (Cunningham, et al., 2019) emphasized the need for objective (ie, physiological) assessment of treatment response in pediatric pain populations. The current review adds to this literature by identifying the physiological stress response as a particular target of interest in interventions for pediatric pain. Research indicates that youth with chronic pain report high rates of psychological stress, posttraumatic stress symptoms, and exposure to adverse childhood experiences (abuse/neglect, etc). In addition, a host of research has shown strong parallels between the neurobiology of pain processing and the neurobiology of stress exposure in both youth and adults. Interventions such as narrative or exposure therapy (eg, trauma-focused cognitive-behavioral therapy) and mindfulness-based or meditation-based therapies have shown particular promise in alleviating the neurobiological impact that stress and pain can have on the body, including reduction in allostatic load and altered connectivity in multiple brain regions. However, no study to date has specifically looked at these factors in the context of pediatric pain treatment. Future research should further explore these constructs to optimize prevention in and treatment of these vulnerable populations.

Migraine is a disease that contributes to major disability. Perhaps because migraine attacks are not immediately life-threatening per se and individuals return to a “normal” state between attacks, it is not taken seriously. However, migraine is associated with a number of comorbidities, including psychiatric disease, stroke, and other chronic pain disorders. Current acute treatments for episodic migraine are relatively effective, but preventive treatments for episodic and chronic migraine are far less so. Recent functional imaging studies have shown that the disease affects brain function and structure (either as a result of its genetic predisposition or as a result of repeated attacks). The current evidence in the pain field is that changes observed in brain function and structure may be reversible, adding credence to the notion that treating the disease aggressively and early may be beneficial to patients. Here we suggest a change in our approach to a disease that is currently not treated with the urgency that it deserves given its global prevalence, disease burden, and effects on brain function.

This review summarizes key findings of the current literature on functional neuroimaging in migraine and describes how these studies have changed our view of the disorder.Recent studies have started not only to investigate the global cerebral activation pattern during migraine attacks, but to address specific aspects of migraine attacks such as photophobia, osmophobia as well as pain perception with the aim of disentangling the underlying mechanisms. There is also more and more evidence that the migraine brain is abnormal even outside of attacks and that repeated attacks are leading to functional and structural alterations in the brain, which may in turn drive the transformation of migraine to its chronic form. Some new results are pinpointing toward a potential role of interesting new brain areas in migraine pathophysiology such as the temporal cortex or the basal ganglia.Neuroimaging studies are beginning to shed light on the mechanisms underlying the development and evolution of migraine and its specific symptoms. Future studies have the potential to also improve our understanding of established and upcoming treatment approaches and to monitor treatment effects in an objective and noninvasive way.

The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Children's Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human μ-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T-allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition.

We studied a patient after amputation of an arm and found that in less than 24 h stimuli applied on the ipsilateral face were referred in a precise, topographically organized, modality-specific manner to distinct points on the phantom. Functional magnetic resonance imaging (fMRI) performed one month later showed that brush-evoked activity in the brain demonstrates objective signal changes which correlate with perceptual changes in the phantom hand. This finding in humans corresponds to the observations of immediate plasticity in cortical pathways described in animals, including primates. The results suggest that reorganization of sensory pathways occurs very soon after amputation in humans, potentially due to the unmasking of ordinarily silent inputs rather than sprouting of new axon terminals.

Exogenous or endogenous opioids act via opioid receptors to influence the expression of opioid genes, and may alter the short- or long-term expression of both opioid and non-opioid genes. Progress has been made towards understanding the cellular control mechanisms of opioid gene expression and this has in turn formed the basis for recent developments in the understanding of the cellular mechanism of opioids in tolerance and dependence, analgesia, and responses to stress.

Plasticity in neural systems implies a process that produces an alteration in structure or function. In the pain field, neuroplasticity has been observed in response to acute and chronic pain - plasticity of function is seen with changes in neural function in the dorsal horn and alterations in more central structures such as the thalamus and cortex 22; 23; 1; 10; 18. While plasticity has been clearly observed in sensory systems with pain, the notion of how pain may affect motor systems is relatively new. In the paper by Boudreau et al., (this issue), the authors show that acute pain induced by capsaicin can affect acute plasticity of the motor cortex induced by a tongue task (tongue protrusion). Pain-induced by capsaicin impairs the changes in motor systems as evidence by a decreased response to transcranial magnetic stimulation applied over the motor cortex on motor evoked potentials (MEPS) measured in the tongue. While other reports exist on the effects of pain inhibiting motor cortex 19; 9; 7, the paper adds to this literature by evaluating changes on the effects of pain in a simple model of acute motor plasticity in a tongue ‘exercise’ (repeated protrusion) model. Specifically the paper raises number of interesting and important issues, including (1) the underlying neurobiology of pain affecting motor processing, (2) the rapidity of the effect of pain in altering the acute plasticity and (3) the effect of motor systems on pain and (4) the potential implications of this effect in patients with chronic pain. Sensory-motor integration at a reflex such as a motor withdrawal reflex in response to noxious stimuli (nocifensive response) is well understood. Persistent pain generally inhibits movement, and subjects will protect the affected area to limit movement. This inhibition may ‘act as a sort of motor ‘decerebration’ so as to allow the spinal motor system to freely develop protective responses to noxious stimulation’8. Interactions between pain systems and motor systems have long been integrated in traditional therapeutic approaches such as physical therapy or exercise or providing pain relief to enhance motor activity in conditions such as back pain or post-operative pain. However, these approaches have been devoid of neurobiological understandings of how motor systems may be affected by pain and vice-versa. The second issue that the paper reports is the rapid effect of pain on cortical motor plasticity. The rapidity of plasticity of cortical sensory systems has been well documented in animals and humans following amputations or nerve blocks 5; 21. In these cases, changes in synaptic inputs may alter cortical mapping. In the current issue, pain produces a rapid inhibition of motor cortex. Inhibition of motor cortex by pain has been considered to be via cortico-cortical circuits. The phenomenon is not limited to pain but also other sensory inputs such as acoustic simulation 13. Certainly, inhibitory and excitatory cortico-cortical circuits and known and this interaction may account for an overall inhibition by pain 20. However, more complex processes involving subcortical structures (e.g., thalamo-cortical and striato-cortical loops) cannot be excluded 12. Inputs via pain fibers (predominantly C-fibers activated by capsaicin) project to the primary somatosensory cortex and may produce inhibition of motor cortex via thalamo-cortical or cortico-cortical inhibitory inputs. With respect to these subcortical structures, the ventrolateral and anterior thalamic regions are the main relay for cerebellar and basal ganglia (globus pallidus) to the motor cortex 15. Direct pain afferents (a peptide class of nociceptors) to the globus pallidus from the spinal cord have been shown in animal tracing studies 6 and activation in the globus pallidus to pain has been reported in functional imaging studies in humans 3. While clearly complex, some evidence supports this, for example, stimulation of the anterior thalamus produces an alteration in motor cortex excitability 16. As describe in the paper, there is increasing evidence on the clinical utility of modulation of motor systems on pain. Specifically, repetitive transcranial magnetic stimulation 11; 14 or direct application of motor cortex stimulation electrodes 17 have been reported to improve a number of chronic pain conditions. This type of evidence further supports the notion of the interdependence of sensory and motor systems. The effects may be due to the same cortico-thalmic loops, producing inhibition on sensory systems. However, a mechanistic understanding is not currently known. Finally, an understanding of the rapid nature of pain effects on motor cortical plasticity may be an insight into plasticity that occur throughout the central nervous system. Such plasticity may be the underpinning of the evolution of chronic pain as a result of dysfunctional circuits, loss of neurons within circuits known to be present in chronic pain 2 and the resistance to therapeutic modulation. The paper further supports the notion that pain may be a silent predator that is manifests in changes in the nervous system. Indeed, the ‘centralization’ of pain as we better understand the nature of altered brain systems derived from recent neuroimaging studies, should make us reassess our clinical approaches to chronic pain (4; Borsook et al., in press). We need to be more aggressive with early treatments and need to find ways to understand and define whether these changes are occurring after potential chronic pain producing processes (e.g., trauma, surgery) or specific diseases (e.g., chronic arthritis). Such approaches will clearly come from an improved understanding of alterations in the plasticity of multiple central neural systems.