The BDNF Val66Met polymorphism is associated with the functional connectivity dynamics of pain modulatory systems in primary dysmenorrhea.
ABSTRACT: 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.
Project description: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.
Project description: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.
Project description:Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions.Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N?=?8) to migraineurs with no ictal allodynia (N?=?8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N?=?38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls.Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls.Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.
Project description:Primary dysmenorrhea (PDM) is a common complaint in women throughout the menstrual years. Acupuncture has been shown to be effective in dysmenorrhea; however, there are large interindividual differences in patients' responses to acupuncture treatment. Fifty-four patients with PDM were recruited and randomized into real or sham acupuncture treatment groups (over the course of three menstrual cycles). Pain-related functional connectivity (FC) matrices were constructed at baseline and post-treatment period. The different neural mechanisms altered by real and sham acupuncture were detected with multivariate analysis of variance. Multivariate pattern analysis (MVPA) based on a machine learning approach was used to explore whether the different FC patterns predicted the acupuncture treatment response in the PDM patients. The results showed that real but not sham acupuncture significantly relieved pain severity in PDM patients. Real and sham acupuncture displayed differences in FC alterations between the descending pain modulatory system (DPMS) and sensorimotor network (SMN), the salience network (SN) and SMN, and the SN and default mode network (DMN). Furthermore, MVPA found that these FC patterns at baseline could predict the acupuncture treatment response in PDM patients. The present study verified differentially altered brain mechanisms underlying real and sham acupuncture in PDM patients and supported the use of neuroimaging biomarkers for individual-based precise acupuncture treatment in patients with PDM.
Project description:The aims of this study were to 1) compare resting state functional connectivity (rs-fc) of the periaqueductal gray (PAG), a key region in the descending pain modulatory system (DPMS) between migraine without aura (MwoA) patients and healthy controls (HC), and 2) investigate how an effective treatment can influence the PAG rs-fc in MwoA patients. One hundred MwoA patients and forty-six matched HC were recruited. Patients were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting state fMRI data were collected and seed based functional connectivity analysis was applied. Compared with HC, MwoA patients showed reduced rs-fc between the PAG and rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC), key regions in the DPMS and other pain related brain regions. The reduced rs-fc between the PAG and rACC/mPFC was associated with increased migraine headache intensity at the baseline. After treatments, rs-fc between the PAG and the rACC in MwoA patients significantly increased. The changes of rs-fc among the PAG, rACC and ventral striatum were significantly associated with headache intensity improvement. Impairment of the DPMS is involved in the neural pathophysiology of migraines. Impaired DPMS in migraine patients can be normalized after effective treatment.
Project description:The periaqueductal gray (PAG) modulates nociception via a descending pathway that relays in the rostral ventromedial medulla (RVM) and terminates in the spinal cord. Previous behavioral pharmacology and electrophysiological evidence suggests that brain-derived neurotrophic factor (BDNF) plays an important role in descending pain modulation, likely through the PAG-RVM pathway. However, detailed information is still lacking on the distribution of BDNF, activation of BDNF-containing neurons projecting to RVM in the condition of pain, and neurochemical properties of these neurons within the PAG. Through fluorescent in situ hybridization (FISH) and immunofluorescent staining, the homogenous distributions of BDNF mRNA and protein were observed in the four subregions of PAG. Both neurons and astrocytes expressed BDNF, but not microglia. By combining retrograde tracing methods and formalin pain model, there were more BDNF-containing neurons projecting to RVM being activated in the ventrolateral subregion of PAG (vlPAG) than other subregions of PAG. The neurochemical properties of BDNF-containing projection neurons in the vlPAG were investigated. BDNF-containing projection neurons expressed the autoreceptor TrkB in addition to serotonin (5-HT), neurotensin (NT), substance P (SP), calcitonin gene related peptide (CGRP), nitric oxide synthase (NOS), and parvalbumin (PV) but not tyrosine decarboxylase (TH). It is speculated that BDNF released from projection neurons in the vlPAG might participate in the descending pain modulation through enhancing the presynaptic release of other neuroactive substances (NSs) in the RVM.
Project description:Migraineurs show hypersensitivity to sensory stimuli at various stages throughout the migraine cycle. A number of putative processes have been implicated including a dysfunction in the descending pain modulatory system in which the periaqueductal gray (PAG) is considered to play a crucial role. Recurring migraine attacks could progressively perturb this system, lowering the threshold for future attacks, and contribute to disease chronification. Here, we investigated PAG connectivity with other brain regions during a noxious thermal stimulus to determine changes in migraineurs, and associations with migraine frequency. 21 episodic migraine patients and 22 matched controls were included in the study. During functional MRI, a thermode was placed on the subjects' temple delivering noxious and non-noxious heat stimuli. A psychophysiological interaction (PPI) analysis was carried out to examine pain-induced connectivity of the PAG with other brain regions. The PPI analysis showed increased PAG connectivity with the S1 face representation area and the supplementary motor area, an area involved with pain expectancy, in patients with higher frequency of migraine attacks. PAG connectivity with regions involved with the descending pain modulatory system (i.e., prefrontal cortex) was decreased in the migraineurs versus healthy individuals. Our results suggest that high frequency migraineurs may have diminished resistance to cephalic pain and a less efficient inhibitory pain modulatory response to external stressor (i.e., noxious heat). The findings support the notion that in migraine there is less effective pain modulation (<i>viz</i>., decreased pain inhibition or increased pain facilitation), potentially contributing to increased occurrence of attacks/chronification of migraine.
Project description:Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG-vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG-insula and PAG-amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest.
Project description:The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine.Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain-free state, versus 17 gender- and age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia.Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases, whereas a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions, and anterior cingulate compared to migraineurs without allodynia.These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory circuits, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas.
Project description:OBJECTIVES:The primary aim was to assess the psychometric properties (including internal consistency, construct validity, reproducibility, and factor structure) of the Central Sensitization Inventory (CSI), adapted and validated for a Brazilian population (CSI-BP). Additionally, we evaluated the relationship between the CSI-BP and the serum brain-derived neurotrophic factor (BDNF) and determined if the symptoms elicited by the CSI-BP discriminate between subjects who do/do not respond to the conditioned pain modulation (CPM) task, as assessed by change in numeric pain scale (0-10) score. PATIENTS AND METHODS:A cross-sectional study was conducted in a pain clinic in a tertiary teaching hospital. A total of 222 adults with chronic musculoskeletal pain and 63 healthy control subjects completed the CSI-BP and the Brazilian Portuguese pain-catastrophizing scale (BP-PCS). A team of experts translated the CSI according to the international guidelines. Test-retest, item analysis, convergent validity, and factor analysis were performed. Later, a random subsample (n=77) was used to correlate the CSI-BP adjusted index with change in numeric pain-scale score during the CPM task and a BDNF blood sample. RESULTS:The CSI-BP presented strong psychometric properties (test-retest reliability 0.91, Cronbach's ?=0.91). Confirmatory factor analysis yielded a four-factor structure, supporting the original English version. The CSI-BP adjusted index showed moderate positive correlation with the BP-PCS, and classified more than 80% of patients correctly vs healthy controls. Serum BDNF levels explained 27% of the variation in the CSI-BP adjusted index. Subjects with impairment in the descending modulatory system had higher CSI-BP adjusted index scores than subjects who responded normally to the CPM task: 49.35 (12.1) vs 39.5 (12.33), respectively (P<0.05). CONCLUSION:The CSI-BP was found to be a psychometrically strong and reliable instrument, with primary evidence of validity. Higher scores on the CSI-BP were correlated positively with serum BDNF and with greater dysfunction of the descending pain-modulatory system.