Adaptive neuroplasticity in the default mode network contributing to absence of central sensitization in primary dysmenorrhea.

Introduction: Primary dysmenorrhea (PDM), the most prevalent gynecological problem among women of reproductive age, presents as a regular pattern of cyclic menstrual pain. The presence or absence of central sensitization (i.e., pain hypersensitivity) in cases of PDM is a contentious issue. Among Caucasians, the presence of dysmenorrhea is associated with pain hypersensitivity throughout the menstrual cycle, indicating pain amplification mediated by the central nervous system. We previously reported on the absence of central sensitization to thermal pain among Asian PDM females. In this study, functional magnetic resonance imaging was used to reveal mechanisms underlying pain processing with the aim of explaining the absence of central sensitization in this population. Methods: Brain responses to noxious heat applied to the left inner forearm of 31 Asian PDM females and 32 controls during their menstrual and periovulatory phases were analyzed. Results and discussion: Among PDM females experiencing acute menstrual pain, we observed a blunted evoked response and de-coupling of the default mode network from the noxious heat stimulus. The fact that a similar response was not observed in the non-painful periovulatory phase indicates an adaptive mechanism aimed at reducing the impact of menstrual pain on the brain with an inhibitory effect on central sensitization. Here we propose that adaptive pain responses in the default mode network may contribute to the absence of central sensitization among Asian PDM females. Variations in clinical manifestations among different PDM populations can be attributed to differences in central pain processing.

MEG-based Classification and Grad-CAM Visualization for Major Depressive and Bipolar Disorders with Semi-CNN.

Major depressive disorder (MDD) and bipolar disorder (BD) are two major mood disorders with partly overlapped symptoms but different treatments. However, their misdiagnosis and mistreatment are common based on the DSM-V criteria, lacking objective and quantitative indicators. This study aimed to develop a novel approach that accurately classifies MDD and BD based on their resting-state magnetoencephalography (MEG) signals during euthymic phases. A revisited 3D CNN model, Semi-CNN, that could automatically detect brainwave patterns in spatial, temporal, and frequency domains was implemented to classify wavelet-transformed MEG signals of normal controls and MDD and BD patients. The model achieved a test accuracy of 96.05% and an average of 95.71% accuracy for 5-fold cross-validation. Furthermore, saliency maps of the model were estimated using Grad-CAM++ to visualize the proposed classification model and highlight disease-specific brain regions and frequencies. Clinical Relevance - Our model provides a stable pipeline that accurately classifies MDD, BD, and healthy individuals based on resting-state MEG signals during the euthymic phases, opening the potential for quantitative and accurate brain-based diagnosis for the highly misdiagnosed MDD/BD patients.

Brain Dynamics Altered by Photic Stimulation in Patients with Alzheimer's Disease and Mild Cognitive Impairment.

Individuals with mild cognitive impairment (MCI) are at high risk of developing Alzheimer's disease (AD). Repetitive photic stimulation (PS) is commonly used in routine electroencephalogram (EEG) examinations for rapid assessment of perceptual functioning. This study aimed to evaluate neural oscillatory responses and nonlinear brain dynamics under the effects of PS in patients with mild AD, moderate AD, severe AD, and MCI, as well as healthy elderly controls (HC). EEG power ratios during PS were estimated as an index of oscillatory responses. Multiscale sample entropy (MSE) was estimated as an index of brain dynamics before, during, and after PS. During PS, EEG harmonic responses were lower and MSE values were higher in the AD subgroups than in HC and MCI groups. PS-induced changes in EEG complexity were less pronounced in the AD subgroups than in HC and MCI groups. Brain dynamics revealed a "transitional change" between MCI and Mild AD. Our findings suggest a deficiency in brain adaptability in AD patients, which hinders their ability to adapt to repetitive perceptual stimulation. This study highlights the importance of combining spectral and nonlinear dynamical analysis when seeking to unravel perceptual functioning and brain adaptability in the various stages of neurodegenerative diseases.

A novel beamformer-based imaging of phase-amplitude coupling (BIPAC) unveiling the inter-regional connectivity of emotional prosody processing in women with primary dysmenorrhea.

Objective. Neural communication or the interactions of brain regions play a key role in the formation of functional neural networks. A type of neural communication can be measured in the form of phase-amplitude coupling (PAC), which is the coupling between the phase of low-frequency oscillations and the amplitude of high-frequency oscillations. This paper presents a beamformer-based imaging method, beamformer-based imaging of PAC (BIPAC), to quantify the strength of PAC between a seed region and other brain regions.Approach. A dipole is used to model the ensemble of neural activity within a group of nearby neurons and represents a mixture of multiple source components of cortical activity. From ensemble activity at each brain location, the source component with the strongest coupling to the seed activity is extracted, while unrelated components are suppressed to enhance the sensitivity of coupled-source estimation.Main results. In evaluations using simulation data sets, BIPAC proved advantageous with regard to estimation accuracy in source localization, orientation, and coupling strength. BIPAC was also applied to the analysis of magnetoencephalographic signals recorded from women with primary dysmenorrhea in an implicit emotional prosody experiment. In response to negative emotional prosody, auditory areas revealed strong PAC with the ventral auditory stream and occipitoparietal areas in the theta-gamma and alpha-gamma bands, which may respectively indicate the recruitment of auditory sensory memory and attention reorientation. Moreover, patients with more severe pain experience appeared to have stronger coupling between auditory areas and temporoparietal regions.Significance. Our findings indicate that the implicit processing of emotional prosody is altered by menstrual pain experience. The proposed BIPAC is feasible and applicable to imaging inter-regional connectivity based on cross-frequency coupling estimates. The experimental results also demonstrate that BIPAC is capable of revealing autonomous brain processing and neurodynamics, which are more subtle than active and attended task-driven processing.

Interactions of BDNF Val66Met Polymorphism and Menstrual Pain on Brain Complexity.

The irregularity and uncertainty of neurophysiologic signals across different time scales can be regarded as neural complexity, which is related to the adaptability of the nervous system and the information processing between neurons. We recently reported general loss of brain complexity, as measured by multiscale sample entropy (MSE), at pain-related regions in females with primary dysmenorrhea (PDM). However, it is unclear whether this loss of brain complexity is associated with inter-subject genetic variations. Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin in the brain and is crucial to neural plasticity. The BDNF Val66Met single-nucleotide polymorphism (SNP) is associated with mood, stress, and pain conditions. Therefore, we aimed to examine the interactions of BDNF Val66Met polymorphism and long-term menstrual pain experience on brain complexity. We genotyped BDNF Val66Met SNP in 80 PDM females (20 Val/Val, 31 Val/Met, 29 Met/Met) and 76 healthy female controls (25 Val/Val, 36 Val/Met, 15 Met/Met). MSE analysis was applied to neural source activity estimated from resting-state magnetoencephalography (MEG) signals during pain-free state. We found that brain complexity alterations were associated with the interactions of BDNF Val66Met polymorphism and menstrual pain experience. In healthy female controls, Met carriers (Val/Met and Met/Met) demonstrated lower brain complexity than Val/Val homozygotes in extensive brain regions, suggesting a possible protective role of Val/Val homozygosity in brain complexity. However, after experiencing long-term menstrual pain, the complexity differences between different genotypes in healthy controls were greatly diminished in PDM females, especially in the limbic system, including the hippocampus and amygdala. Our results suggest that pain experience preponderantly affects the effect of BDNF Val66Met polymorphism on brain complexity. The results of the present study also highlight the potential utilization of resting-state brain complexity for the development of new therapeutic strategies in patients with chronic pain.

Neuroimaging Studies of Primary Dysmenorrhea.

Primary dysmenorrhea (PDM), cyclic menstrual pain in the absence of pelvic anomalies, is one of the most common gynecological disorders in reproductive females. Classified as chronic pelvic pain syndrome, PDM encompasses recurrent spontaneous painful ("on") and pain-free ("off") states and is thus a good clinical model to study state- and trait-related changes of pain in the brain. In this chapter, we summarize state-of-the-art neuroimaging studies of primary dysmenorrhea from phenotype and endophenotype to genotype facets. Structural and functional brain alterations associated with primary dysmenorrhea are discussed.

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.

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.

The OPRM1 A118G polymorphism modulates the descending pain modulatory system for individual pain experience in young women with primary dysmenorrhea.

The mu-opioid receptor (OPRM1) A118G polymorphism underpins different pain sensitivity and opioid-analgesic outcome with unclear effect on the descending pain modulatory system (DPMS). Primary dysmenorrhea (PDM), the most prevalent gynecological problem with clear painful and pain free conditions, serves as a good clinical model of spontaneous pain. The objective of this imaging genetics study was therefore to explore if differences in functional connectivity (FC) of the DPMS between the OPRM1 A118G polymorphisms could provide a possible explanation for the differences in pain experience. Sixty-one subjects with PDM and 65 controls participated in the current study of resting-state functional magnetic resonance imaging (fMRI) during the menstruation and peri-ovulatory phases; blood samples were taken for genotyping. We studied 3 aspects of pain experience, namely, mnemonic pain (recalled overall menstrual pain), present pain (spontaneous menstrual pain), and experimental pain (thermal pain) intensities. We report that G allele carriers, in comparison to AA homozygotes, exhibited functional hypo-connectivity between the anterior cingulate cortex (ACC) and periaqueductal gray (PAG). Furthermore, G allele carriers lost the correlation with spontaneous pain experience and exhibited dysfunctional DPMS by means of PAG-seeded FC dynamics. This OPRM1 A118G-DPMS interaction is one plausible neurological mechanism underlying the individual differences in pain experience.

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.

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

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.