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Contextual processing is implicated in the pathophysiology of addictive disorders, but the nature of putative deficiencies remains unclear. We assessed some aspects of contextual processing across multimodal experimental procedures with detoxified subjects who were dependent on opioids (n = 18), alcohol- (n = 20), both opioids and alcohol (n = 22) and healthy controls (n = 24) using a) facial- and b) emotionally laden images; c) gambling task and d) sucrose solutions. Healthy subjects displayed consistent response pattern throughout all categories of the presented stimuli. As a group, dependent subjects rated (i.e., valuated) attractive and average faces respectively more and less attractive in comparison to controls. Dependent subjects' motivational effort, measured in the units of computer keypress to determine the attractive faces' viewing time, accorded the valuational context but was diminished relatively to the average faces’ valuation. Dependent subjects’ motivational effort for pleasant and aversive images respectively mirrored the attractive and average faces; their neutral images’ motivational effort was incongruent with the valuational context framed by the intermixed images. Also, dependent subjects’ emotional responses to counterfactual comparisons of gambling outcomes were unmatched by the riskiness context. Moreover, dependent subjects failed to show greater liking of sweet solutions that normally accompanies low sweetness perceptual context indicative of higher sucrose concentration needed for maximal hedonic experience. Consistent differences among the dependent groups (opioid vs. alcohol vs. comorbid) on the above procedures were not observed. The present findings suggest that opioid and/or alcohol dependence may be associated with amplified hedonic and motivational valuation of pleasant stimuli and with a disrupted link between behavioral/emotional responsivity and contextual variations. Further research is warranted to unravel the distinctive features of contextual processing in opioid- vis-à-vis alcohol addiction and how these features may interrelate in comorbid conditions.

Brain-related plasticity can occur at a significant rate varying on the developmental period. Adolescence in particular has been identified as a period of growth and change across the structure and function of the nervous system. Notably, research has identified migraines as common in both pediatric and adult populations, but evidence suggests that the phenotype for migraines may differ in these cohorts due to the unique needs of each developmental period. Accordingly, primary aims of this study were to define hippocampal structure in females (7–27 years of age) with and without migraine, and to determine whether this differs across developmental stages (i.e., childhood, adolescence, and young adulthood). Hippocampal volume was quantified based on high-resolution structural MRI using FMRIB's Integrated Registration and Segmentation Tool. Results indicated that migraine and age may have an interactional relationship with hippocampal volume, such that, while hippocampal volumes were lower in female migraineurs (compared to age-matched controls) during childhood and adolescence, this contrast differed during young adulthood whereby hippocampal volumes were higher in migraineurs (compared to age-matched controls). Subsequent vertex analysis localized this interaction effect in hippocampal volume to displacement of the anterior hippocampus. The transition of hippocampal volume during adolescent development in migraineurs suggests that hippocampal plasticity may dynamically reflect components of migraine that change over the lifespan, exerting possible altered responsivity to stress related to migraine attacks thus having physiological expression and psychosocial impact.

Migraine is underpinned by central nervous system neuroplastic alterations thought to be caused by the repetitive peripheral afferent barrage the brain receives during the headache phase (cortical hyperexcitability). Calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAbs) are highly effective migraine preventative treatments. Their ability to alter brain morphometry in treatment-responders vs. non-responders is not well understood. Our aim was to determine the effects of the anti-CGRP-mAb galcanezumab on cortical thickness after 3-month treatment of patients with high-frequency episodic or chronic migraine. High-resolution magnetic resonance imaging was performed pre- and post-treatment in 36 migraine patients. In this group, 19 patients were classified responders (≥50 % reduction in monthly migraine days) and 17 were considered non-responders (

As our definition of pain evolves, the factors implicit in defining and predicting pain status grow. These factors each have unique data characteristics and their outcomes each have unique target attributes. The clinical characterization of pain does not, as defined in the most recent IASP definition, require any tissue pathology, suggesting that the experience of pain can be uniquely psychological in nature. Predicting a persons pain status may be optimized through integration of multiple independent observations; however, how they are integrated has direct relevance towards predicting chronic pain development, clinical application, and research investigation. The current challenge is to find clinically-mindful ways of integrating clinical pain rating scales with neuroimaging of the peripheral and central nervous system with the biopsychocial environment and improving our capacity for diagnostic flexibility and knowledge translation through data modeling. This commentary addresses how our current knowledge of pain phenotypes and risk factors interacts with statistical models and how we can proceed forward in a clinically responsible way.

Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain’s responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.

Central disinhibition (CD), as applied to pain, decreases thresholds of endogenous systems. This provokes onset of spontaneous or evoked pain in an individual beyond the ability of the nervous system to inhibit pain resulting from a disease or tissue damage. The original CD concept as proposed by Craig entails a shift from the lateral pain pathway (i.e. discriminative pain processing) towards the medial pain pathway (i.e. emotional pain processing), within an otherwise neurophysiological intact environment. In this review, the original CD concept as proposed by Craig is extended by the primary “nociceptive pathway damage – CD” concept and the secondary “central pathway set point – CD”. Thereby, the original concept may be transferred into anatomical and psychological non-functional conditions. We provide examples for either primary or secondary CD concepts within different clinical etiologies as well as present surrogate models, which directly mimic the underlying pathophysiology (A-fiber block) or modulate the CD pathway excitability (thermal grill). The thermal grill has especially shown promising advancements, which may be useful to examine CD pathway activation in the future. Therefore, within this topical review, a systematic review on the thermal grill illusion is intended to stimulate future research. Finally, the authors review different mechanism-based treatment approaches to combat CD pain.

Chronic pain in youth is common, with prevalence rates in some reports exceeding 50%. Given the plasticity of brain systems in youth and their general level of activity, the underlying processes relating to the evolution of chronic pain may be different from that observed in adults. One aspect that affects brain development is childhood stress. Preliminary research indicates that maladaptive responses to stressful events that induce biological and psychological inability to adapt may be related to pain chronicity in youth. This relationship is particularly notable given the high rates of exposure to stressful events in pediatric pain populations. A review of the literature was performed in the areas of biological, cognitive, psychological and social processes associated with chronic pain and psychological stress and trauma in youth and adult populations. The current review presents a theoretical framework, adapted from McEwen’s model (1998) on stress and allostatic load, which aims to outline the potential connection between exposure to stressful events and pediatric chronic pain. Avenues for future investigation are also identified.

Pain interventions with no active ingredient, placebo, are sometimes effective in treating chronic pain conditions. Prior studies on the neurobiological underpinnings of placebo analgesia indicate endogenous opioid release and changes in brain responses and functional connectivity during pain anticipation and pain experience in healthy subjects. Here, we investigated placebo analgesia in healthy subjects and in interictal migraine patients (n=9) and matched healthy controls (n=9) using 11C-diprenoprhine Positron Emission Tomography (PET) and simultaneous functional Magnetic Resonance Imaging (fMRI). Intravenous saline injections (the placebo) led to lower pain ratings, but we did not find evidence for an altered placebo response in interictal migraine subjects as compared to healthy subjects.

Numerous pathologies can contribute to photophobia. When considering light transduction alone, photophobia may be triggered through melanopsin pathways (non-image forming), rod and cone pathways (image-forming), or some combination of the two. We evaluated a 39 year old female patient with longstanding idiopathic photophobia that was exacerbated by blue light, and tested her by presenting visual stimuli in an event-related fMRI experiment. Analysis showed significantly greater activation in bilateral pulvinar nuclei, associated with the melanopsin intrinsically photosensitive retinal ganglion cell (ipRGC) visual pathway, and their activation is consistent with the patient's report that blue light differentially evoked photophobia. This appears to be the first demonstration of functional activation of the ipRGC pathway during photophobia in a patient. Keywords: Melanopsin, Photo-oculodynia, Photalgia, Photoallodynia, Pain, ipRGCs

Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis.

Pediatric complex regional pain syndrome (P-CRPS) offers a unique model of chronic neuropathic pain as it either resolves spontaneously or through therapeutic interventions in most patients. Here we evaluated brain changes in well-characterized children and adolescents with P-CRPS by measuring resting state networks before and following a brief (median = 3 weeks) but intensive physical and psychological treatment program, and compared them to matched healthy controls. Differences in intrinsic brain networks were observed in P-CRPS compared to controls before treatment (disease state) with the most prominent differences in the fronto-parietal, salience, default mode, central executive, and sensorimotor networks. Following treatment, behavioral measures demonstrated a reduction of symptoms and improvement of physical state (pain levels and motor functioning). Correlation of network connectivities with spontaneous pain measures pre- and post-treatment indicated concomitant reductions in connectivity in salience, central executive, default mode and sensorimotor networks (treatment effects). These results suggest a rapid alteration in global brain networks with treatment and provide a venue to assess brain changes in CRPS pre- and post-treatment, and to evaluate therapeutic effects.