Primary dysmenorrhea (PDM) is the most prevalent gynecological disorder for women in the reproductive age. PDM patients suffer from lower abdominal pain that starts with the onset of the menstrual flow. Prolonged nociceptive input to the central nervous system can induce functional and structural alterations throughout the nervous system. In PDM, a chronic viscero-nociceptive drive of cyclic nature, indications of central sensitization and altered brain metabolism suggest a substantial central reorganization. Previously, we hypothesized that disinhibition of orbitofrontal networks could be responsible for increased pain and negative affect in PDM. Here, we further tested this hypothesis. We used an optimized voxel-based morphometry (VBM) approach to compare total and regional gray matter (GM) increases and decreases in 32 PDM patients with 32 healthy age and menstrual cycle matched (peri-ovulatory phase) controls. Abnormal decreases were found in regions involved in pain transmission, higher level sensory processing, and affected regulation while increases were found in regions involved in pain modulation and in regulation of endocrine function. Moreover, GM changes in regions involved in top-down pain modulation and in generation of negative affect were related to the severity of the experienced PDM pain. Our results demonstrate that abnormal GM volume changes are present in PDM patients even in the absence of pain. These changes may underpin a combination of impaired pain inhibition, increased pain facilitation and increased affect. Our findings highlight that longer lasting central changes may occur not only in sustained chronic pain conditions but also in cyclic occurring pain conditions.

Menstrual pain is the most prevalent gynecological complaint, and is usually without organic cause (termed primary dysmenorrhea, PDM). The high comorbidity in the later life of PDM with many functional pain disorders (associated with central dysfunction of pain inhibition, eg, fibromyalgia) suggests possible maladaptive functionality of pain modulatory systems already occurred in young PDM women, making them vulnerable to functional pain disorders. Periaqueductal gray (PAG) matter functions as a critical hub in the neuraxis of pain modulatory systems; therefore, we investigated the functional connectivity of PAG in PDM. Forty-six PDM subjects and 49 controls received resting-state functional magnetic resonance imaging during menstruation and periovulatory phases. The PAG of PDM subjects exhibited adaptive/reactive hyperconnectivity with the sensorimotor cortex during painful menstruation, whereas it exhibited maladaptive hypoconnectivity with the dorsolateral prefrontal cortex and default mode network (involving the ventromedial prefrontal cortex, posterior cingulate cortex, or posterior parietal cortex) during menstruation or periovulatory phase. We propose that the maladaptive descending pain modulatory systems in PDM may underpin the central susceptibility to subsequent development of various functional disorders later in life. This hypothesis is corroborated by the growing body of evidence that hypoconnectivity between PAG and default mode network is a coterminal to many functional pain disorders.

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Dysmenorrhea is the most prevalent gynecological disorder in women of child-bearing age. Dysmenorrhea is associated with central sensitization and functional and structural changes in the brain. Our recent brain morphometry study disclosed that dysmenorrhea is associated with trait-related abnormal gray matter (GM) changes, even in the absence of menstrual pain, indicating that the adolescent brain is vulnerable to menstrual pain. Here we report rapid state-related brain morphological changes, ie, between pain and pain-free states, in dysmenorrhea. We used T1-weighted anatomic magnetic resonance imaging to investigate regional GM volume changes between menstruation and periovulatory phases in 32 dysmenorrhea subjects and 32 age- and menstrual cycle-matched asymptomatic controls. An optimized voxel-based morphometry analysis was conducted to disclose the possible state-related regional GM volume changes across different menstrual phases. A correlation analysis was also conducted between GM differences and the current menstrual pain experience in the dysmenorrhea group. Compared with the periovulatory phase, the dysmenorrhea subjects revealed greater hypertrophic GM changes than controls during the menstruation phase in regions involved in pain modulation, generation of the affective experience, and regulation of endocrine function, whereas atrophic GM changes were found in regions associated with pain transmission. Volume changes in regions involved in the regulation of endocrine function and pain transmission correlated with the menstrual pain experience scores. Our results demonstrated that short-lasting cyclic menstrual pain is associated not only with trait-related but also rapid state-related structural alterations in the brain. Considering the high prevalence rate of menstrual pain, these findings mandate a great demand to revisit dysmenorrhea with regard to its impact on the brain and other clinical pain conditions.

Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsychological mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion-/conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal distension-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients.

Primary dysmenorrhea (PDM) is the most prevalent gynecological problem. Many key brain systems are engaged in pain processing. In light of dynamic communication within and between systems (or networks) in shaping pain experience and behavior, the intra-regional functional connectivity (FC) in the hub regions of the systems may be altered and the functional interactions in terms of inter-regional FCs among the networks may be reorganized to cope with the repeated stress of menstrual pain in PDM. Forty-six otherwise healthy PDM subjects and 49 age-matched, healthy female control subjects were enrolled. Intra- and inter-regional FC were assessed using regional homogeneity (ReHo) and ReHo-seeded FC analyses, respectively. PDM women exhibited a trait-related ReHo reduction in the ventromedial prefrontal cortex, part of the default mode network (DMN), during the periovulatory phase. The trait-related hypoconnectivity of DMN-salience network and hyperconnectivity of DMN-executive control network across the menstrual cycle featured a dynamic transition from affective processing of pain salience to cognitive modulation. The altered DMN-sensorimotor network may be an ongoing representation of cumulative menstrual pain. The findings indicate that women with long-term PDM may develop adaptive neuroplasticity and functional reorganization with a network shift from affective processing of salience to the cognitive modulation of pain.

Primary dysmenorrhea (PDM), the most prevalent menstrual cycle-related problem in women of reproductive age, is associated with negative moods. Whether the menstrual pain and negative moods have a genetic basis remains unknown. Brain-derived neurotrophic factor (BDNF) plays a key role in the production of central sensitization and contributes to chronic pain conditions. BDNF has also been implicated in stress-related mood disorders. We screened and genotyped the BDNF Val66Met polymorphism (rs6265) in 99 Taiwanese (Asian) PDMs (20–30 years old) and 101 age-matched healthy female controls. We found that there was a significantly higher frequency of the Met allele of the BDNF Val66Met polymorphism in the PDM group. Furthermore, BDNF Met/Met homozygosity had a significantly stronger association with PDM compared with Val carrier status. Subsequent behavioral/hormonal assessments of sub-groups (PDMs = 78, controls = 81; eligible for longitudinal multimodal neuroimaging battery studies) revealed that the BDNF Met/Met homozygous PDMs exhibited a higher menstrual pain score (sensory dimension) and a more anxious mood than the Val carrier PDMs during the menstrual phase. Although preliminary, our study suggests that the BDNF Val66Met polymorphism is associated with PDM in Taiwanese (Asian) people, and BDNF Met/Met homozygosity may be associated with an increased risk of PDM. Our data also suggest the BDNF Val66Met polymorphism as a possible regulator of menstrual pain and pain-related emotions in PDM. Absence of thermal hypersensitivity may connote an ethnic attribution. The presentation of our findings calls for further genetic and neuroscientific investigations of PDM.