Processing spatially distributed nociceptive information is critical for survival. The conditioned pain modulation (CPM) response has become a common psychophysical test to examine pain modulation capabilities related to spatial filtering of nociceptive information. Neuroimaging studies have been conducted to elucidate the neural mechanisms underlying the CPM response in health and chronic pain states, yet their findings have not been critically reviewed and synthesized before. This narrative review presents a simplified overview of MRI methodology in relation to CPM assessments and summarizes the findings of neuroimaging studies on the CPM response. The summary includes functional MRI studies assessing CPM responses during scanning as well as functional and structural MRI studies correlating indices with CPM responses assessed outside of the scanner. The findings are discussed in relation to the suggested mechanisms for the CPM response. A better understanding of neural mechanisms underlying spatial processing of nociceptive information could advance both pain research and clinical use of the CPM response as a marker or a treatment target.

Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

Background: Autonomic neuropathy, a relatively common complication of several chemotherapy agents, can affect the vagus nerve and its pain inhibitory capacity, thus increasing sensitivity to pain. This study aimed to evaluate the relationships between autonomic parasympathetic function and the perception of (1) spontaneous pain; (2) experimental non‐painful sensations; and (3) experimental painful sensations in chemotherapy‐induced neuropathy patients.Methods: Twenty‐seven cancer patients with chemotherapy‐induced polyneuropathy were enrolled (20 women, age 56.6 ± 7.9). Autonomic parameters of heart rate variability, deep‐breathing and Valsalva ratios, experimental non‐painful parameters of warm, cold and mechanical detection thresholds, and painful parameters of heat pain thresholds, pain rating of suprathreshold stimulus, mechanical temporal summation and conditioned pain modulation response were examined.Results: Autonomic parameters and spontaneous pain levels were not associated, yet autonomic parameters were positively correlated with non‐painful sensations – milder autonomic neuropathy was accompanied by milder sensory neuropathy as indicated by several parameters, e.g., lower Valsalva ratio was correlated with higher warmth detection threshold (r = −0.465; p = 0.033). Autonomic parameters were, however, negatively correlated with painful sensations – lower parasympathetic‐vagal activity was associated with higher pain sensitivity as indicated by several parameters, e.g., lower Valsalva ratio was correlated with higher pain rating of suprathreshold stimulus (r = −0.559; p = 0.008).Conclusions: Diminished vagal function due to neuropathy is associated with, and may possibly underlie, pain disinhibition expressed as greater levels of experimental pain.

Cognitive behavioral therapy (CBT) is a psychological intervention that involves development of coping strategies to reduce the experience of pain. Although CBT is a promising intervention to reduce headache days in patients with migraine, it may not be effective for all patients. Thus, there is a need to identify markers that could predict which patients will respond to CBT. We aimed to determine whether baseline brain function and amygdalar connectivity, assessed by functional magnetic resonance imaging, or pain modulation capacities, assessed by the conditioned pain modulation (CPM) response, can predict a reduction in headache days after CBT in adolescents with migraine. Patients with migraine (n = 20; age range 10-17 years) completed 8 weekly CBT sessions. The CPM response was examined in the trapezius and the leg. Headache days significantly decreased after CBT (P < 0.001). Greater functional connectivity before CBT between the right amygdala and frontal gyrus, anterior cingulate cortex, and precentral gyrus was related to greater headache reduction after CBT. Greater reduction in headache days after CBT was related with less efficient CPM response before CBT at the trapezius (r = −0.492, P = 0.028) but not at the leg. This study found that headache reduction after CBT was related to right amygdala connectivity with frontal and sensorimotor regions at baseline as well as baseline pain modulation capacities. These findings suggest that individual differences in brain function and pain modulation can be associated with clinical improvements and help with determination of CBT responsiveness.