Cheng-Hao Tu

Brain morphological changes associated with cyclic menstrual pain

&NA; 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 affect 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.

Abnormal cerebral metabolism during menstrual pain in primary dysmenorrhea

Primary dysmenorrhea (PDM, menstrual pain without pelvic abnormality) is the most common gynecological disorder for women in the reproductive age. It is characterized by cramping pain and enhanced pain sensitivity during the menstruation period. PDM has been associated with peripheral and central sensitization. Abnormal brain mechanisms may further contribute to development and maintenance of the state. Using fluoro-deoxyglucose positron emission tomography, increased activity was observed in prefrontal/orbitofrontal regions and left ventral posterior thalamus while decreased activity mainly was observed in sensorimotor regions of the left hemisphere at onset compared to offset of PDM. These results were specific to menstrual pain and were not found in menstrual matched controls. Orbitofrontal activities were positively related to while somatosensory activities where negatively related to subjective pain ratings. These results show that ongoing menstrual pain in PDM is accompanied by abnormal brain metabolism. Disinhibition of thalamo-orbitofrontal-prefrontal networks may contribute to the generation of pain and hyperalgesia in PDM possibly by maintaining spinal and thalamic sensitization while increasing negative affect. Excessive excitatory input during menstrual pain may induce compensatory inhibitory mechanism in several somatic sensorimotor regions.

Menstrual pain is associated with rapid structural alterations in the brain

Summary One to 3 days of menstrual pain is associated with rapid gray matter alterations in the brain. ABSTRACT 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.

Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients.

Summary IBS patients and controls achieve comparable placebo analgesia upon experimentally induced rectal pain. The placebo analgesia during the visceral pain involves enhanced brain activities relating to affect/cognition in IBS patients. ABSTRACT 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.

Changes in functional connectivity of pain modulatory systems in women with primary dysmenorrhea.

Abstract 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.

Association of Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism with Primary Dysmenorrhea

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.

Dynamic Changes of Functional Pain Connectome in Women with Primary Dysmenorrhea.

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.

The BDNF Val66Met polymorphism is associated with the functional connectivity dynamics of pain modulatory systems in primary dysmenorrhea

Primary dysmenorrhea (PDM), menstrual pain without an organic cause, is a prevailing problem in women of reproductive age. We previously reported alterations of structure and functional connectivity (FC) in the periaqueductal gray (PAG) of PDM subjects. Given that the brain derived neurotrophic factor (BDNF) acts as a pain modulator within the PAG and the BDNF Val66Met polymorphism contributes towards susceptibility to PDM, the present study of imaging genetics set out to investigate the influence of, firstly, the BDNF Val66Met single nucleotide polymorphism and, secondly, the genotype-pain interplays on the descending pain modulatory systems in the context of PAG-seeded FC patterning. Fifty-six subjects with PDM and 60 controls participated in the current study of resting-state functional magnetic resonance imaging (fMRI) during the menstruation and peri-ovulatory phases; in parallel, blood samples were taken for genotyping. Our findings indicate that the BDNF Val66Met polymorphism is associated with the diverse functional expressions of the descending pain modulatory systems. Furthermore, PAG FC patterns in pain-free controls are altered in women with PDM in a genotype-specific manner. Such resilient brain dynamics may underpin the individual differences and shed light on the vulnerability for chronic pain disorders of PDM subjects.

Encoding of menstrual pain experience with theta oscillations in women with primary dysmenorrhea

Theta oscillation (4–7 Hz) is well documented for its association with neural processes of memory. Pronounced increase of theta activity is commonly observed in patients with chronic neurogenic pain. However, its association with encoding of pain experience in patients with chronic pain is still unclear. The goal of the present study is to investigate the theta encoding of sensory and emotional information of long-term menstrual pain in women with primary dysmenorrhea (PDM). Forty-six young women with PDM and 46 age-matched control subjects underwent resting-state magnetoencephalography study during menstrual and periovulatory phases. Our results revealed increased theta activity in brain regions of pain processing in women with PDM, including the right parahippocampal gyrus, right posterior insula, and left anterior/middle cingulate gyrus during the menstrual phase and the left anterior insula and the left middle/inferior temporal gyrus during the periovulatory phase. The correlations between theta activity and the psychological measures pertaining to pain experience (depression, state anxiety, and pain rating index) implicate the role of theta oscillations in emotional and sensory processing of pain. The present study provides evidence for the role of theta oscillations in encoding the immediate and sustained effects of pain experience in young women with PDM.

Unaltered intrinsic functional brain architecture in young women with primary dysmenorrhea

Primary dysmenorrhea (PDM), painful menstruation without organic causes, is the most prevalent gynecological problem in women of reproductive age. Dysmenorrhea later in life often co-occurs with many chronic functional pain disorders, and chronic functional pain disorders exhibit altered large-scale connectedness between distributed brain regions. It is unknown whether the young PDM females exhibit alterations in the global and local connectivity properties of brain functional networks. Fifty-seven otherwise healthy young PDM females and 62 age- and education-matched control females participated in the present resting-state functional magnetic resonance imaging study. We used graph theoretical network analysis to investigate the global and regional network metrics and modular structure of the resting-state brain functional networks in young PDM females. The functional network was constructed by the interregional functional connectivity among parcellated brain regions. The global and regional network metrics and modular structure of the resting-state brain functional networks were not altered in young PDM females at our detection threshold (medium to large effect size differences [Cohen’s d ≥ 0.52]). It is plausible that the absence of significant changes in the intrinsic functional brain architecture allows young PDM females to maintain normal psychosocial outcomes during the pain-free follicular phase.