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Background
Granger causality analysis (GCA) has been used to investigate the pathophysiology of migraine. Amygdala plays a key role in pain modulation of migraine attack. However, the detailed neuromechanism remained to be elucidated. We applied GCA to explore the amygdala-based directional effective connectivity in migraine without aura (MwoA) and...
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Background
Menstrual migraine without aura (MRM) is common in female migraineurs and is closely related to cerebral functional abnormalities. However, whether the whole brain networks and directional functional connectivity of MRM patients are altered remains unclear. The purpose of this study was to detect the alterations of resting-state function...
Citations
... 28 Many previous studies have shown that pain can cause abnormal alterations in the functioning of cognitive emotion-related networks; for example, Van Ettinger-Veenstra et al 29 found that the connectivity of the salience network increased in patients with chronic widespread pain and was associated with increased pain sensitivity. The superior temporal gyrus is often considered the auditory-perceptual and emotion-regulatory portion of the human brain, 30 which is critical for individual stress experiences, cognitive processes, and adaptive behaviors, and is more strongly active on the left side. 31 Lan et al 32 in a seed-based FC analysis found reduced FC in the left superior temporal gyrus in patients with chronic pelvic pain syndrome. ...
Objective
To separate the resting-state network of patients with dental pain using independent component analysis (ICA) and analyze abnormal changes in functional connectivity within as well as between the networks.
Patients and Methods
Twenty-three patients with dental pain and 30 healthy controls participated in this study. We extracted the resting-state functional network components of both using ICA. Functional connectivity differences within 14 resting-state brain networks were analyzed at the voxel level. Directional interactions between networks were analyzed using Granger causality analysis. Subsequently, functional connectivity values and causal coefficients were assessed for correlations with clinical parameters.
Results
Compared to healthy controls, we found enhanced functional connectivity in the left superior temporal gyrus of anterior protrusion network and the right Rolandic operculum of auditory network in patients with dental pain (p<0.01 and cluster-level p<0.05, Gaussian random field corrected). In contrast, functional connectivity of the right precuneus in the precuneus network was reduced, and were significantly as well as negatively correlated to those of the Visual Analogue Scale (r=−4.93, p=0.017), Hamilton Anxiety Scale (r=−0.46, p=0.027), and Hamilton Depression Scale (r=−0.563, p<0.01), using the Spearman correlation analysis. Regarding the causal relationship between resting-state brain networks, we found increased connectivity from the language network to the precuneus in patients with dental pain (p<0.05, false discovery rate corrected). However, the increase in causal coefficients from the verbal network to the precuneus network was independent of clinical parameters.
Conclusion
Patients with toothache exhibited abnormal functional changes in cognitive-emotion-related brain networks, such as the salience, auditory, and precuneus networks, thereby offering a new imaging basis for understanding central neural mechanisms in dental pain patients.
... A hyperresponsive brain cortex, peripheral and central alterations in pain processing, and comorbidities could play a role, in a complex interplay with psychological factors, including personality traits, psychological features, and traumatic events, as well as with social and lifestyle factors [6,29]. According to the biopsychosocial model, migraine can be considered a dysfunction of sensory processing, characterized by a heightened connection between sensory areas and areas of the limbic system that regulate emotional life and pain processing [29,31]. ...
Background/Objectives: Alexithymia is characterized by a deficit in identifying and communicating feelings. Emerging evidence suggests that alexithymia is highly prevalent in migraine, in a complex interplay with psychiatric comorbidity. Pericranial/cervical muscle tenderness is a remarkable clinical feature in a large proportion of migraine patients. This pilot study aimed at investigating the relationship between alexithymia and pericranial/cervical muscle tenderness in female migraineurs. Methods: A total of 42 female patients fulfilling the diagnostic criteria for migraine were enrolled into this pilot, observational, cross-sectional study after informed consent was obtained. Each patient underwent a psychological assessment to identify any alexithymia by means of TAS-20, anxiety/mood comorbidity (by means of STAI-Y1 STAI-Y2, BDI-II), and migraine-related disability (by means of HIT-6), and a physical cranial/cervical musculoskeletal examination. Palpation of pericranial and cervical muscles was carried out in the standardized manner. A Cumulative Muscle Tenderness (CUM) score (0–6) was calculated for each patient. A multivariate analysis was performed to investigate any association amongst the TAS-20 score, the CUM score, and the following covariates: BDI-II, STAI-Y1, STAI-Y2, and HIT-6 scores, age, disease duration, monthly migraine days, and average head pain intensity in the previous three months. Results: Overall, 35.6% of the sample had alexithymia. The multivariate analysis detected a linear and independent relationship between the TAS-20 and CUM scores, with a statistically significant (p = 0.017) association. Conclusions: This pilot study suggests that alexithymia plays a role in increasing pericranial/cervical muscle tenderness in migraine, independently from psychiatric comorbidity. A novel therapeutical approach, targeting alexithymia, may well reduce muscular tenderness in female migraineurs.
... Granger causality analysis (GCA) can be used to explore the top-down effective connectivity between the selected node and other brain regions, which reflects causality between cerebral regions (18). Our previous study also demonstrated disruption of directional functional connectivity in the amygdala in migraine patients without aura (19). However, few studies have explored the aberrant brain functional hubs between MRM and NMM patients combining DC and GCA. ...
Background
Menstrual migraine without aura (MRM) is common in female migraineurs and is closely related to cerebral functional abnormalities. However, whether the whole brain networks and directional functional connectivity of MRM patients are altered remains unclear. The purpose of this study was to detect the alterations of resting-state functional networks and directional functional connectivity between MRM and non-menstrual migraine without aura (NMM) patients using functional magnetic resonance imaging (fMRI) with degree centrality (DC) and Granger causality analysis (GCA) methods.
Methods
In this retrospective and cross-sectional study, 45 MRM and 40 NMM patients (matched in age, gender, and years of education) were recruited in the study between May 2018 and June 2022. All participants had undergone resting-state fMRI scanning at the Neurology and Pain Outpatient Department of Nanjing First Hospital. Their brain functions were analyzed in terms of DC and GCA, with the significant threshold at voxel level P<0.01 and cluster level P<0.05, Gaussian random field corrected. Correlation analysis was adopted to assess the relationships between the fMRI results and clinical features (P<0.05, Bonferroni corrected).
Results
Compared with those in the NMM group, MRM patients showed decreased DC in the right insula (T=−4.253). Using the right insula as the seed region, patients with MRM demonstrated enhanced effective connectivity from the right insula to the ipsilateral middle temporal gyrus (T=4.138) and contralateral superior temporal gyrus (T=3.523). Furthermore, the MRM group also showed decreased effective connectivity from several brain regions to the right insula, which included the right inferior occipital gyrus (T=−4.498), left middle frontal gyrus (T=−4.879), right precuneus (T=−4.644), and left inferior parietal gyrus (T=−4.113). The average Self-rating Anxiety Scale score of the MRM group was significantly higher than that of the NMM group [P=0.032, 95% confidence interval (CI): 0.363–7.761]. In the MRM group, disease duration was negatively correlated with the mean value of DC in right insula (r=−0.428, P=0.01).
Conclusions
The present research demonstrated that patients with MRM have disruption in insula resting-state functional networks. Disrupted networks contained regions associated with cognitive processes, emotional perception, and migraine attack in MRM patients. These results may improve our comprehension of the neuromechanism of menstrually-related migraine.
... Compared to HC, MowA showed decreased SC involving the PoG and insula and decreased FC involving the PoG and amygdala, which represent impaired somatosensory area processing, perceived somatic sensation, and dysfunction of cortico-thalamic circuit contributing to trigeminal nociception processing migraine attacks and the migraine mediating trigemino-thalamo-cortical pathway (8,9,19,50). The increased FC involving the PoG and amygdala in our MwoA group was also reported previously, which might attribute to the pain modulation role of the amygdala (9,51). The strength of FC alterations in our MwA group (except FC of MFG-thalamus) was higher than those in the MwoA and HC groups, which may correspond to the theory that CSD may activate the trigeminovascular pathway leading to the more significant alterations in the MwA group (2). ...
... An upregulated inflammatory state and increased metabolism of insula in migraine were found previously, which were associated with headache frequency and disease duration, respectively (49,52). The altered directional connectivity of the amygdala was found to be negatively correlated to disease duration in MwoA (51). Meanwhile, lower fractional plasma volume of the amygdala showed a correlation to the intensity of headache attack in migraine (53). ...
... The extraction of only eight features may be insufficient to detect all the possible patterns of change between MwA and MwoA. Although patients with clinically diagnosed depression and anxiety were excluded, the SAS and SDS results of patients with MwA and those with MwoA in the training sample were at the range of normal or mild level [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] and MwA patients showed higher SDS and SDS results than MwoA patients, which may have led to some bias in the results. More restricted consideration of the effects of depression and anxiety on the results should be considered in the further study. ...
Background
Cortical spreading depression (CSD) has been considered the prominent theory for migraine with aura (MwA). However, it is also argued that CSD can exist in patients in a silent state, and not manifest as aura. Thus, the MwA classification based on aura may be questionable. This study aimed to capture whole-brain connectome-based imaging markers with identifiable signatures for MwA and migraine without aura (MwoA).
Methods
A total of 88 migraine patients (32 MwA) and 49 healthy controls (HC) underwent a diffusion tensor imaging and resting-state functional magnetic resonance imaging scan. The whole-brain structural connectivity (SC) and functional connectivity (FC) analysis was employed to extract imaging features. The extracted features were subjected to an all-relevant feature selection process within cross-validation loops to pinpoint attributes demonstrating substantial efficacy for patient categorization. Based on the identified features, the predictive ability of the random forest classifiers constructed with the 88 migraine patients’ sample was tested using an independent sample of 32 migraine patients (eight MwA).
Results
Compared to MwoA and HC, MwA showed two reduced SC and six FC (five increased and one reduced) features [all P<0.01, after false discovery rate (FDR) correction], involving frontal areas, temporal areas, visual areas, amygdala, and thalamus. A total of four imaging features were significantly correlated with clinical rating scales in all patients (r=−0.38 to 0.47, P<0.01, after FDR correction). The predictive ability of the random forest classifiers achieved an accuracy of 78.1% in the external sample to identify MwA.
Conclusions
The whole-brain connectivity features in our results may serve as connectome-based imaging markers for MwA identification. The alterations of SC and FC strength provide possible evidence in further understanding the heterogeneity and mechanism of MwA which may help for patient-specific decision-making.
... Both preclinical [10][11][12][13]15,19,57] and clinical [58][59][60][61][62][63][64][65][66][67][68] studies have highlighted the role of the amygdala in pain processing and pain modulation. In particular, the lateral and capsular regions of the CeA have been regarded as the "nociceptive amygdala" in reference to the abundance of neurons in these regions that encode nociceptive information and modulate pain-related behaviors [11,13,18]. ...
Chronic pain presents a therapeutic challenge due to the highly complex interplay of sensory, emotional-affective and cognitive factors. The mechanisms of the transition from acute to chronic pain are not well understood. We hypothesized that neuroimmune mechanisms in the amygdala, a brain region involved in the emotional-affective component of pain and pain modulation, play an important role through high motility group box 1 (Hmgb1), a pro-inflammatory molecule that has been linked to neuroimmune signaling in spinal nociception. Transcriptomic analysis revealed an upregulation of Hmgb1 mRNA in the right but not left central nucleus of the amygdala (CeA) at the chronic stage of a spinal nerve ligation (SNL) rat model of neuropathic pain. Hmgb1 silencing with a stereotaxic injection of siRNA for Hmgb1 into the right CeA of adult male and female rats 1 week after (post-treatment), but not 2 weeks before (pre-treatment) SNL induction decreased mechanical hypersensitivity and emotional-affective responses, but not anxiety-like behaviors, measured 4 weeks after SNL. Immunohistochemical data suggest that neurons are a major source of Hmgb1 in the CeA. Therefore, Hmgb1 in the amygdala may contribute to the transition from acute to chronic neuropathic pain, and the inhibition of Hmgb1 at a subacute time point can mitigate neuropathic pain.
... fear and anxiety 46 , whilst the frontal cortex is involved with executive function and the cognitive control of pain 47 . These regions share reciprocal anatomical connections 48,49 and stronger rsFC between these areas have been observed in migraine 50,51 , chronic neck pain 20 and complex regional pain syndrome 52 . The role of the left amygdala in pain modulation however remains unclear 45 , with either no effect on pain modulation, dampened pro-nociceptive function, or anti-nociceptive function 53 . ...
Endogenous pain modulation in humans is frequently investigated with conditioned pain modulation (CPM). Deficient pain inhibition is a proposed mechanism that contributes to neuropathic pain (NP) after spinal cord injury (SCI). Recent studies have combined CPM testing and neuroimaging to reveal neural correlates of CPM efficiency in chronic pain. This study investigated differences in CPM efficiency in relation to resting-state functional connectivity (rsFC) between 12 SCI-NP subjects and 13 age- and sex-matched healthy controls (HC). Twelve and 11 SCI-NP subjects were included in psychophysical and rsFC analyses, respectively. All HC were included in the final analyses. Psychophysical readouts were analysed to determine CPM efficiency within and between cohorts. Group differences of rsFC, in relation to CPM efficiency, were explored with seed-to-voxel rsFC analyses with pain modulatory regions, e.g. ventrolateral periaqueductal gray (vlPAG) and amygdala. Overall, pain inhibition was not deficient in SCI-NP subjects and was greater in those with more intense NP. Greater pain inhibition was associated with weaker rsFC between the vlPAG and amygdala with the visual and frontal cortex, respectively, in SCI-NP subjects but with stronger rsFC in HC. Taken together, SCI-NP subjects present with intact pain inhibition, but can be differentiated from HC by an inverse relationship between CPM efficiency and intrinsic connectivity of supraspinal regions. Future studies with larger cohorts are necessary to consolidate the findings in this study.
... Multiple pain studies have applied GC to brain imaging data (Seth et al., 2015;Wen et al., 2013b). Huang et al. found that when compared with healthy controls (HCs), patients with migraine without aura (MwoA) showed significantly decreased effective connectivity from right amygdala to right superior temporal gyrus, left superior temporal gyrus and right precentral gyrus (Huang et al., 2021). They further indicated that decreased connectivity in each hemisphere from amygdala to superior temporal gyrus in MwoA patients may represent temporal processing impairment. ...
Trigeminal neuralgia (TN) is a highly debilitating facial pain condition. Magnetic resonance imaging (MRI) is the main method for generating insights into the central mechanisms of TN pain in humans. Studies have found both structural and functional abnormalities in various brain structures in TN patients as compared with healthy controls. Whereas studies have also examined aberrations in brain networks in TN, no studies have to date investigated causal interactions in these brain networks and related these causal interactions to the levels of TN pain. We recorded fMRI data from 39 TN patients who either rested comfortably in the scanner during the resting state session or tracked their pain levels during the pain tracking session. Applying Granger causality to analyze the data and requiring consistent findings across the two scanning sessions, we found 5 causal interactions, including: (1) Thalamus -> dACC, (2) Caudate -> Inferior temporal gyrus, (3) Precentral gyrus -> Inferior temporal gyrus, (4) Supramarginal gyrus -> Inferior temporal gyrus, and (5) Bankssts -> Inferior temporal gyrus, that were consistently associated with the levels of pain experienced by the patients. Utilizing these 5 causal interactions as predictor variables and the pain score as the predicted variable in a linear multiple regression model, we found that in both pain tracking and resting state sessions, the model was able to explain ~36% of the variance in pain levels, and importantly, the model trained on the 5 causal interaction values from one session was able to predict pain levels using the 5 causal interaction values from the other session, thereby cross-validating the models. These results, obtained by applying novel analytical methods to neuroimaging data, provide important insights into the pathophysiology of TN and could inform future studies aimed at developing innovative therapies for treating TN.
... In this mate analysis, we enrolled 31 original studies and detected that MwoA patients had increased gray matter in the left amygdala, bilateral parahippocampus, right hippocampus, and left lingual gyrus. Furthermore, some other studies also found that MwoA patients manifested altered synchronization of functional activity in the medial temporal gyrus [42,43] and that interventions such as transcutaneous auricular vagus nerve stimulation [44] and acupuncture [45] had significant modulating effects on these disturbed functional activity patterns of patients. This phenomenon suggested that there were consistent structural-functional variations in the medial inferior temporal gyrus in MwoA patients and that the cortical plasticity in the medial inferior temporal gyrus might be an important neuropathological feature of MwoA. ...
Background
The aberrance of gray matter morphology in migraineurs has been widely investigated. However, it remains largely unknown whether there are illness duration-related hierarchical changes in the gray matter structure.
Methods
A total of 86 migraine without aura (MwoA) patients and 73 healthy controls were included. The Voxel-Based Morphometry approach was utilized to compare the gray matter volume (GMV) differences between MwoA patients and healthy controls. The Structural Covariance Network analysis was conducted to quantify the cross-regional synchronous alterations of gray matter structure in MwoA patients. The Causal Structural Covariance Network analysis was performed to describe the progressive and hierarchical changes in the gray matter network of patients in the pathological progression of migraine.
Results
MwoA patients had duration-stage related GMV hypertrophy in the left parahippocampus, as well as synergistic GMV aberrance in the parahippocampus and the medial inferior temporal gyrus and cerebellum. Moreover, the GMV alteration of the parahippocampus, and the surrounding hippocampus, amygdala, and bilateral anterior cerebellum, preceded and causally influenced the morphological changes of lateral parietal-temporal-occipital gyrus, as well as the motor cortex and prefrontal gyrus with the increasing illness duration in MwoA patients.
Conclusion
The current study indicated that gray matter structural alterations in the medial inferior temporal gyrus, especially the parahippocampus, is a critical pathological characteristic in MwoA patients, which drives the gray matter structure alteration of other regions. These findings provide further evidence for understanding the progressive gray matter morphological changes in migraine and may facilitate the development of neuromodulation therapies targeting this procession.
... In recent clinical and functional magnetic resonance imaging (f-MRI) studies, disrupted limbic system (both amygdala and hippocampus) functional connectivity to pain-related cortex regions of modulation and encoding was reported (52,53). Resting-state functional abnormalities of the limbic system may lead to impairment of the pain process in patients with MwoA, resulting in increased pain intensity and hypersensitive response to external stimuli (52,54). The magnitude of the neural responses in the complex network regulating pain (pain matrix) is correlated with the intensity of the perceived pain in migraine attacks (55,56). ...
... Regions which demonstrated higher Pag-eRank in migraineurs, including the right STSvp, and right amygdala, may be demonstrating compensatory changes. The potential changes in the left superior temporal region in the context of the language network has been previously discussed, however, the amygdala is also a key region of nociceptive and emotional processing, and has demonstrated FC changes in migraine [65]. One study in fact demonstrated that these changes were lateralized to the left, which may explain the increased hubness of the right amygdala in our dataset [20]. ...
Background
Migraine is a complex disorder characterized by debilitating headaches. Despite its prevalence, its pathophysiology remains unknown, with subsequent gaps in diagnosis and treatment. We combined machine learning with connectivity analysis and applied a whole-brain network approach to identify potential targets for migraine diagnosis and treatment.
Methods
Baseline anatomical T1 magnetic resonance imaging (MRI), resting-state functional MRI(rfMRI), and diffusion weighted scans were obtained from 31 patients with migraine, and 17 controls. A recently developed machine learning technique, Hollow Tree Super (HoTS) was used to classify subjects into diagnostic groups based on functional connectivity (FC) and derive networks and parcels contributing to the model. PageRank centrality analysis was also performed on the structural connectome to identify changes in hubness.
Results
Our model attained an area under the receiver operating characteristic curve (AUC-ROC) of 0.68, which rose to 0.86 following hyperparameter tuning. FC of the language network was most predictive of the model’s classification, though patients with migraine also demonstrated differences in the accessory language, visual and medial temporal regions. Several analogous regions in the right hemisphere demonstrated changes in PageRank centrality, suggesting possible compensation.
Conclusions
Although our small sample size demands caution, our preliminary findings demonstrate the utility of our method in providing a network-based perspective to diagnosis and treatment of migraine.
