Impaired Glymphatic and Meningeal Lymphatic Functions in Patients with Chronic Migraine.

OBJECTIVE: This study was undertaken to investigate migraine glymphatic and meningeal lymphatic vessel (mLV) functions. METHODS: Migraine patients and healthy controls (HCs) were prospectively recruited between 2020 and 2023. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index for glymphatics and dynamic contrast-enhanced magnetic resonance imaging parameters (time to peak [TTP]/enhancement integral [EI]/mean time to enhance [MTE]) for para-superior sagittal (paraSSS)-mLV or paratransverse sinus (paraTS)-mLV in episodic migraine (EM), chronic migraine (CM), and CM with and without medication-overuse headache (MOH) were analyzed. DTI-ALPS correlations with clinical parameters (migraine severity [numeric rating scale]/disability [Migraine Disability Assessment (MIDAS)]/bodily pain [Widespread Pain Index]/sleep quality [Pittsburgh Sleep Quality Index (PSQI)]) were examined. RESULTS: In total, 175 subjects (112 migraine + 63 HCs) were investigated. DTI-ALPS values were lower in CM (median [interquartile range] = 0.64 [0.12]) than in EM (0.71 [0.13], p = 0.005) and HCs (0.71 [0.09], p = 0.004). CM with MOH (0.63 [0.07]) had lower DTI-ALPS values than CM without MOH (0.73 [0.12], p < 0.001). Furthermore, CM had longer TTP (paraSSS-mLV: 55.8 [12.9] vs 40.0 [7.6], p < 0.001; paraTS-mLV: 51.2 [8.1] vs 44.0 [3.3], p = 0.002), EI (paraSSS-mLV: 45.5 [42.0] vs 16.1 [9.2], p < 0.001), and MTE (paraSSS-mLV: 253.7 [6.7] vs 248.4 [13.8], p < 0.001; paraTS-mLV: 252.0 [6.2] vs 249.7 [1.2], p < 0.001) than EM patients. The MIDAS (p = 0.002) and PSQI (p = 0.002) were negatively correlated with DTI-ALPS index after Bonferroni corrections (p < q = 0.01). INTERPRETATION: CM patients, particularly those with MOH, have glymphatic and meningeal lymphatic dysfunctions, which are highly clinically relevant and may implicate pathogenesis for migraine chronification. ANN NEUROL 2024;95:583-595.

Abnormal heart rate variability and its application in predicting treatment efficacy in patients with chronic migraine: An exploratory study.

AIM: This study aimed to investigate the extent of autonomic nervous system dysfunction in patients with chronic migraine using heart rate variability analysis. In addition, we explored the potential association between heart rate variability and treatment outcomes in patients receiving preventive treatment. METHODS: In this cross-sectional and prospective study, we compared heart rate variability profiles in 81 preventive-naïve chronic migraine patients and 58 healthy controls. In addition, treatment responses of patients, who received a 12-week treatment with flunarizine, were assessed in relation to baseline heart rate variability. RESULTS: We observed that chronic migraine patients had a reduced heart rate variability, signifying autonomic dysfunction in comparison to healthy controls. Furthermore, patients presenting normal heart rate variability, characterized by a standard deviation exceeding 30 milliseconds in normal-to-normal RR intervals, experienced a superior response to flunarizine treatment. This improvement was exemplified by a significantly larger reduction in monthly headache days for patients with higher heart rate variability compared to those with lower heart rate variability: -9.7 (5.9) vs. -6.2 (6.0) days (p = .026). CONCLUSIONS: Autonomic dysfunction occurs in chronic migraine as evaluated by heart rate variability. A preserved function is associated with a better treatment outcome to flunarizine.Trial registration: Neurologic Signatures of Chronic Pain Disorders, NCT02747940. Registered 22 April 2016, https://clinicaltrials.gov/ct2/show/NCT02747940.

Brain morphometry changes with fatigue severity in fibromyalgia.

OBJECTIVES: This study investigated brain morphometry changes associated with fatigue severity in fibromyalgia (FM). METHODS: Clinical profiles and brain-MRI data were collected in patients with FM. Patients were divided into three groups based on their fatigue severity. Using voxel-based morphometry analysis and trend analysis, neural substrates showing volumetric changes associated with fatigue severity across the three groups were identified. Their seed-to-voxel structural covariance (SC) networks with the whole brain were studied in distribution and strength. RESULTS: Among the 138 enrolled patients with FM, 23, 57, and 58 were categorised into the mild, moderate, and severe fatigue groups, respectively. The number of musculoskeletal pain regions and intensity of pain were not associated with fatigue severity, but somatic symptoms and psychiatric distress, including waking unrefreshed, depression, and anxiety, were associated with fatigue severity. After adjusting for anxiety and depression, decreased bilateral thalamic volumes were associated with higher fatigue severity. The SC distributions of the thalamic seed were more widespread to the frontal, parietal, subcortical, and limbic regions in patients with higher fatigue severity. In addition, increased right inferior temporal cortex volumes were associated with higher fatigue severity. The SC distributions of the right inferior temporal seed were more over the temporal cortex and the SC strengths of the seed were higher with the bilateral occipital cortex in patients with higher fatigue severity. CONCLUSIONS: The thalamus and the right inferior temporal cortex are implicated in the manifestation of fatigue severity in FM. Future therapeutic strategies targeting these regions are worthy of investigation.

Prediction of individual trigeminal pain sensitivity from gray matter structure within the sensorimotor network.

OBJECTIVE: To determine whether multivariate pattern regression analysis based on gray matter (GM) images constrained to the sensorimotor network could accurately predict trigeminal heat pain sensitivity in healthy individuals. BACKGROUND: Prediction of individual pain sensitivity is of clinical relevance as high pain sensitivity is associated with increased risks of postoperative pain, pain chronification, and a poor treatment response. However, as pain is a subjective experience accurate identification of such individuals can be difficult. GM structure of sensorimotor regions have been shown to vary with pain sensitivity. It is unclear whether GM structure within these regions can be used to predict pain sensitivity. METHODS: In this cross-sectional study, structural magnetic resonance images and pain thresholds in response to contact heat stimulation of the left supraorbital area were obtained from 79 healthy participants. Voxel-based morphometry was used to extract segmented and normalized GM images. These were then constrained to a mask encompassing the functionally defined resting-state sensorimotor network. The masked images and pain thresholds entered a multivariate relevance vector regression analysis for quantitative prediction of the individual pain thresholds. The correspondence between predicted and actual pain thresholds was indexed by the Pearson correlation coefficient (r) and the mean squared error (MSE). The generalizability of the model was assessed by 10-fold and 5-fold cross-validation. Non-parametric permutation tests were used to estimate significance levels. RESULTS: Trigeminal heat pain sensitivity could be predicted from GM structure within the sensorimotor network with significant accuracy (10-fold: r = 0.53, p < 0.001, MSE = 10.32, p = 0.001; 5-fold: r = 0.46, p = 0.001, MSE = 10.54, p < 0.001). The resulting multivariate weight maps revealed that accurate prediction relied on multiple widespread regions within the sensorimotor network. CONCLUSION: A multivariate pattern of GM structure within the sensorimotor network could be used to make accurate predictions about trigeminal heat pain sensitivity at the individual level in healthy participants. Widespread regions within the sensorimotor network contributed to the predictive model.

Characteristic oscillatory brain networks for predicting patients with chronic migraine.

To determine specific resting-state network patterns underlying alterations in chronic migraine, we employed oscillatory connectivity and machine learning techniques to distinguish patients with chronic migraine from healthy controls and patients with other pain disorders. This cross-sectional study included 350 participants (70 healthy controls, 100 patients with chronic migraine, 40 patients with chronic migraine with comorbid fibromyalgia, 35 patients with fibromyalgia, 30 patients with chronic tension-type headache, and 75 patients with episodic migraine). We collected resting-state magnetoencephalographic data for analysis. Source-based oscillatory connectivity within each network, including the pain-related network, default mode network, sensorimotor network, visual network, and insula to default mode network, was examined to determine intrinsic connectivity across a frequency range of 1-40 Hz. Features were extracted to establish and validate classification models constructed using machine learning algorithms. The findings indicated that oscillatory connectivity revealed brain network abnormalities in patients with chronic migraine compared with healthy controls, and that oscillatory connectivity exhibited distinct patterns between various pain disorders. After the incorporation of network features, the best classification model demonstrated excellent performance in distinguishing patients with chronic migraine from healthy controls, achieving high accuracy on both training and testing datasets (accuracy > 92.6% and area under the curve > 0.93). Moreover, in validation tests, classification models exhibited high accuracy in discriminating patients with chronic migraine from all other groups of patients (accuracy > 75.7% and area under the curve > 0.8). In conclusion, oscillatory synchrony within the pain-related network and default mode network corresponded to altered neurophysiological processes in patients with chronic migraine. Thus, these networks can serve as pivotal signatures in the model for identifying patients with chronic migraine, providing reliable and generalisable results. This approach may facilitate the objective and individualised diagnosis of migraine.

Association between impaired dynamic cerebral autoregulation and BBB disruption in reversible cerebral vasoconstriction syndrome.

BACKGROUND: Half of the sufferers of reversible cerebral vasoconstriction syndrome (RCVS) exhibit imaging-proven blood-brain barrier disruption. The pathogenesis of blood-brain barrier disruption in RCVS remains unclear and mechanism-specific intervention is lacking. We speculated that cerebrovascular dysregulation might be associated with blood-brain barrier disruption in RCVS. Hence, we aimed to evaluate whether the dynamic cerebral autoregulation is altered in patients with RCVS and could be associated with blood-brain barrier disruption. METHODS: A cross-sectional study was conducted from 2019 to 2021 at headache clinics of a national tertiary medical center. Dynamic cerebral autoregulation was evaluated in all participants. The capacity of the dynamic cerebral autoregulation to damp the systemic hemodynamic changes, i.e., phase shift and gain between the cerebral blood flow and blood pressure waveforms in the very-low- and low-frequency bands were calculated by transfer function analysis. The mean flow correlation index was also calculated. Patients with RCVS received 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize blood-brain barrier disruption. RESULTS: Forty-five patients with RCVS (41.9 ± 9.8 years old, 29 females) and 45 matched healthy controls (41.4 ± 12.5 years old, 29 females) completed the study. Nineteen of the patients had blood-brain barrier disruption. Compared to healthy controls, patients with RCVS had poorer dynamic cerebral autoregulation, indicated by higher gain in very-low-frequency band (left: 1.6 ± 0.7, p = 0.001; right: 1.5 ± 0.7, p = 0.003; healthy controls: 1.1 ± 0.4) and higher mean flow correlation index (left: 0.39 ± 0.20, p = 0.040; right: 0.40 ± 0.18, p = 0.017; healthy controls: 0.31 ± 0.17). Moreover, patients with RCVS with blood-brain barrier disruption had worse dynamic cerebral autoregulation, as compared to those without blood-brain barrier disruption, by having less phase shift in very-low- and low-frequency bands, and higher mean flow correlation index. CONCLUSIONS: Dysfunctional dynamic cerebral autoregulation was observed in patients with RCVS, particularly in those with blood-brain barrier disruption. These findings suggest that impaired cerebral autoregulation plays a pivotal role in RCVS pathophysiology and may be relevant to complications associated with blood-brain barrier disruption by impaired capacity of maintaining stable cerebral blood flow under fluctuating blood pressure.

Pain sensitivities predict prophylactic treatment outcomes of flunarizine in chronic migraine patients: A prospective study.

BACKGROUND: We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment. METHODS: In this prospective open-label study, preventive-naïve chronic migraine and healthy controls were recruited, and cold, heat, mechanical punctate, and pressure pain thresholds over the dermatomes of first branch of trigeminal nerve and first thoracic nerve were measured by quantitative sensory testing at baseline. Chronic migraines were treated with flunarizine and treatment response was defined as ≥50% reduction in the number of monthly headache days over the 12-week treatment period. RESULTS: Eighty-four chronic migraines and fifty age-and-sex-matched healthy controls were included in the analysis. The chronic migraine had higher cold pain thresholds over the dermatomes of the first branch of trigeminal nerve and the first thoracic nerve (p < 0.001 and < 0.001), lower pressure pain thresholds over the dermatomes of the first thoracic nerve (p = 0.003), heat pain thresholds over the dermatomes of the first branch of the trigeminal nerve and the first thoracic nerve (p < 0.001 and p = 0.015) than healthy controls. After treatment, 24/84 chronic migraine had treatment response. The responders with relatively normal pain sensitivity had higher heat pain thresholds over the dermatome of the first branch of the trigeminal nerve (p = 0.002), mechanical punctate pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.023), and pressure pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.026) than the hypersensitive non-responders. Decision tree analysis showed that patients with mechanical punctate pain threshold over the dermatomes of the first branch of the trigeminal nerve > 158 g (p = 0.020) or heat pain threshold over the dermatome of the first branch of the trigeminal nerve > 44.9°C (p = 0.002) were more likely to be responders. CONCLUSIONS: Chronic migraine were generally more sensitive compared to healthy controls. Preventive treatment with flunarizine should be recommended particularly for chronic migraine who have relatively normal sensitivity to mechanical punctate or heat pain.Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT02747940).

Resting State Electrophysiological Cortical Activity: A Brain Signature Candidate for Patients with Migraine.

PURPOSE OF REVIEW: Studies on event-related evoked potentials have indicated that altered cortical processing of sensory stimuli is associated with migraine. However, the results depend on the experimental method and patients. Electrophysiology of resting state cortical activity has revealed compelling results regarding the pathophysiology of migraine. This review summarized the available information related to patients with episodic and chronic migraine to determine whether certain features can be used as signatures for migraine. RECENT FINDINGS: A recent study examined differences in resting state functional connectivity among the pain-related regions and revealed that beta connectivity was attenuated in migraine and that altered connectivity in the anterior cingulate cortex was linked to migraine chronification. These findings suggested that chronification leads to neuroplasticity in the pain areas of higher-level processing rather than in areas involved in basic sensory discrimination (i.e., primary and secondary somatosensory areas). Another study discovered that the betweenness centrality of delta band in right precuneus was significantly lower in those with longer history of migraine. Electroencephalogram may also predict the treatment outcomes in patients with chronic migraine that those with lower pre-treatment occipital alpha power tend to show greater reduction in headache frequency. Studies on resting state activity have yielded convincing findings regarding aberrant oscillatory power and functional connectivity in relation to migraine, thus contributing to identifying brain signatures for migraine. The role of such assessment in precision medicine should be further investigated.

Dynamic brainstem and somatosensory cortical excitability during migraine cycles.

BACKGROUND: Migraine has complex pathophysiological characteristics and episodic attacks. To decipher the cyclic neurophysiological features of migraine attacks, in this study, we compared neuronal excitability in the brainstem and primary somatosensory (S1) region between migraine phases for 30 consecutive days in two patients with episodic migraine. METHODS: Both patients underwent EEG recording of event-related potentials with the somatosensory and paired-pulse paradigms for 30 consecutive days. The migraine cycle was divided into the following phases: 24-48 h before headache onset (Pre2), within 24 h before headache onset (Pre1), during the migraine attack (Ictal), within 24 h after headache offset (Post1), and the interval of ˃48 h between the last and next headache phase (Interictal). The normalised current intensity in the brainstem and S1 and gating ratio in the S1 were recorded and examined. RESULTS: Six migraine cycles (three for each patient) were analysed. In both patients, the somatosensory excitability in the brainstem (peaking at 12-14 ms after stimulation) and S1 (peaking at 18-19 ms after stimulation) peaked in the Pre1 phase. The S1 inhibitory capability was higher in the Ictal phase than in the Pre1 phase. CONCLUSION: This study demonstrates that migraine is a cyclic excitatory disorder and that the neural substrates involved include the somatosensory system, starting in the brainstem and spanning subsequently to the S1 before the migraine occurs. Further investigations with larger sample sizes are warranted.

Resting-state magnetoencephalographic oscillatory connectivity to identify patients with chronic migraine using machine learning.

To identify and validate the neural signatures of resting-state oscillatory connectivity for chronic migraine (CM), we used machine learning techniques to classify patients with CM from healthy controls (HC) and patients with other pain disorders. The cross-sectional study obtained resting-state magnetoencephalographic data from 240 participants (70 HC, 100 CM, 35 episodic migraine [EM], and 35 fibromyalgia [FM]). Source-based oscillatory connectivity of relevant cortical regions was calculated to determine intrinsic connectivity at 1-40 Hz. A classification model that employed a support vector machine was developed using the magnetoencephalographic data to assess the reliability and generalizability of CM identification. In the findings, the discriminative features that differentiate CM from HC were principally observed from the functional interactions between salience, sensorimotor, and part of the default mode networks. The classification model with these features exhibited excellent performance in distinguishing patients with CM from HC (accuracy ≥ 86.8%, area under the curve (AUC) ≥ 0.9) and from those with EM (accuracy: 94.5%, AUC: 0.96). The model also achieved high performance (accuracy: 89.1%, AUC: 0.91) in classifying CM from other pain disorders (FM in this study). These resting-state magnetoencephalographic electrophysiological features yield oscillatory connectivity to identify patients with CM from those with a different type of migraine and pain disorder, with adequate reliability and generalizability.

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan.

BACKGROUND: Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan. METHODS: We conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed. RESULTS: We enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10-16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10-13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10-8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache. CONCLUSIONS: This study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

Mechanical punctate pain threshold is associated with headache frequency and phase in patients with migraine.

OBJECTIVE: Previous studies regarding the quantitative sensory testing are inconsistent in migraine. We hypothesized that the quantitative sensory testing results were influenced by headache frequency or migraine phase. METHODS: This study recruited chronic and episodic migraine patients as well as healthy controls. Participants underwent quantitative sensory testing, including heat, cold, and mechanical punctate pain thresholds at the supraorbital area (V1 dermatome) and the forearm (T1 dermatome). Prospective headache diaries were used for headache frequency and migraine phase when quantitative sensory testing was performed. RESULTS: Twenty-eight chronic migraine, 64 episodic migraine and 32 healthy controls completed the study. Significant higher mechanical punctate pain thresholds were found in episodic migraine but not chronic migraine when compared with healthy controls. The mechanical punctate pain thresholds decreased as headache frequency increased then nadired. In episodic migraine, mechanical punctate pain thresholds were highest (p < 0.05) in those in the interictal phase and declined when approaching the ictal phase in both V1 and T1 dermatomes. Linear regression analyses showed that in those with episodic migraine, headache frequency and phase were independently associated with mechanical punctate pain thresholds and accounted for 29.7% and 38.9% of the variance in V1 (p = 0.003) and T1 (p < 0.001) respectively. Of note, unlike mechanical punctate pain thresholds, our study did not demonstrate similar findings for heat pain thresholds and cold pain thresholds in migraine. CONCLUSION: Our study provides new insights into the dynamic changes of quantitative sensory testing, especially mechanical punctate pain thresholds in patients with migraine. Mechanical punctate pain thresholds vary depending on headache frequency and migraine phase, providing an explanation for the inconsistency across studies.

Individual pain sensitivity is associated with resting-state cortical activities in healthy individuals but not in patients with migraine: a magnetoencephalography study.

BACKGROUND: Pain sensitivity may determine the risk, severity, prognosis, and efficacy of treatment of clinical pain. Magnetic resonance imaging studies have linked thermal pain sensitivity to changes in brain structure. However, the neural correlates of mechanical pain sensitivity remain to be clarified through investigation of direct neural activities on the resting-state cortical oscillation and synchrony. METHODS: We recorded the resting-state magnetoencephalographic (MEG) activities of 27 healthy individuals and 30 patients with episodic migraine (EM) and analyzed the source-based oscillatory powers and functional connectivity at 2 to 59 Hz in pain-related cortical regions, which are the bilateral anterior cingulate cortex (ACC), medial orbitofrontal (MOF) cortex, lateral orbitofrontal (LOF) cortex, insula cortex, primary somatosensory cortex (SI), primary motor cortex (MI), and posterior cingulate cortex (PCC). The mechanical punctate pain threshold (MPPT) was obtained at the supraorbital area (the first branch of the trigeminal nerve dermatome, V1) and the forearm (the first thoracic nerve dermatome, T1) and further correlated with MEG measures. RESULTS: The MPPT is inversely correlated with the resting-state relative powers of gamma oscillation in healthy individuals (all corrected P < 0.05). Specifically, inverse correlation was noted between the MPPT at V1 and gamma powers in the bilateral insula (r = - 0.592 [left] and - 0.529 [right]), PCC (r = - 0.619 and - 0.541) and MI (r = - 0.497 and - 0.549) and between the MPPT at T1 and powers in the left PCC (r = - 0.561) and bilateral MI (r = - 0.509 and - 0.520). Furthermore, resting-state functional connectivity at the delta to beta bands, especially between frontal (MOF, ACC, LOF, and MI), parietal (PCC), and sensorimotor (bilateral SI and MI) regions, showed a positive correlation with the MPPT at V1 and T1 (all corrected P < 0.05). By contrast, in patients with EM, the MPPT was not associated with resting-state cortical activities. CONCLUSIONS: Pain sensitivity in healthy individuals is associated with the resting-state gamma oscillation and functional connectivity in pain-related cortical regions. Further studies must be conducted in a large population to confirm whether resting-state cortical activities can be an objective measurement of pain sensitivity in individuals without clinical pain.

Investigating the Effects of Peripheral Electrical Stimulation on Corticomuscular Functional Connectivity Stroke Survivors.

BACKGROUND: Electrical stimulation (ES) in the periphery can induce brain plasticity and has been used clinically to promote motor recovery in patients with central nervous system lesion. Electroencephalogram (EEG) and electromyogram (EMG) are readily applicable in clinical settings and can detect real-time functional connectivity between motor cortex and muscles with EEG-EMG (corticomuscular) coherence. OBJECTIVE: The purpose of this study was to determine whether EEG-EMG coherence can detect changes in corticomuscular control induced by peripheral ES. METHODS: Fifteen healthy young adults and 15 stroke survivors received 40-min electrical stimulation session on median nerve. The stimulation (1-ms rectangular pulse, 100 Hz) was delivered with a 20-s on-20-s off cycle, and the intensity was set at the subjects' highest tolerable level without muscle contraction or pain. Both before and after the stimulation session, subjects performed a 20-s steady-hold thumb flexion at 50% maximal voluntary contraction (MVC) while EEG and EMG were collected. RESULTS: Our results demonstrated that after ES, EEG-EMG coherence in gamma band increased significantly for 22.1 and 48.6% in healthy adults and stroke survivors, respectively. In addition, after ES, force steadiness was also improved in both groups, as indicated by the decrease in force fluctuation during steady-hold contraction (-1.7% MVC and -3.9%MVC for healthy and stroke individuals, respectively). CONCLUSIONS: Our results demonstrated that EEG-EMG coherence can detect ES-induced changes in the neuromuscular system. Also, because gamma coherence is linked to afferent inputs encoding, improvement in motor performance is likely related to ES-elicited strong sensory input and enhanced sensorimotor integration.

Estimating the tendency of motor unit recruitment during steady-hold and rapid contractions using surface EMG and Turns-amplitude analysis.

PURPOSE: The purpose of this study was to investigate changes in the interference pattern in surface electromyography (EMG), and its relationship with the tendency of motor unit (MU) recruitment during steady-hold and rapid muscle contractions. METHODS: Fifteen healthy adults (eight females and seven males, 22.6 ± 1.5 years old) performed steady-hold and rapid isometric contractions of the bicep brachii, adductor pollicis, and tibialis anterior muscles at various force levels. Surface EMG recordings were analyzed using Turns-Amplitude Analysis (TAA). RESULTS: During steady-hold contractions, the number of turns per second (T/s) increased exponentially with force during submaximal contractions, and plateaued after force levels of 66, 70 and 57 % MVC for the tibialis anterior, bicep brachii and adductor pollicis muscles, respectively. These force levels were proximate to the maximal recruitment threshold (MaxRT) reported previously. The slopes of the T/s-force relationships before the MaxRT were significantly greater than the slopes after the MaxRT for all three muscles tested. During rapid contraction, the slopes of the T/s-force relationships were significantly lower than the slopes of the steady-hold contraction at 20-40 % MVC in all three muscles, and for 40-60 % MVC in TA muscles. CONCLUSIONS: Our results suggested that the changes in the number of turns in surface EMG with respect to muscle force can be used to estimate the force levels at which the majority of the MUs to be recruited, and completion of MU recruitment was observed at lower force levels during rapid muscle contraction.

Salivary Testosterone Levels and Pain Perception Exhibit Sex-Specific Association in Healthy Adults But Not in Patients With Migraine.

This study investigated the sex-specific associations between pain perception and testosterone levels in healthy controls (HCs) and patients with migraine. Male and female HCs and migraine patients were recruited. A series of questionnaires were completed by the participants to evaluate their psychosocial profiles, which included data on mood, stress, and sleep quality. Heat pain thresholds and suprathreshold pain ratings at 45 °C (referred to as the pain perception score [PPS]) were assessed using the Thermode system. Salivary testosterone levels were analyzed using a commercial enzyme-linked immunosorbent assay kit. A total of 88 HCs (men/women: 41/47, age: 29.9 ± 7.7 years) and 75 migraine patients (men/women: 30/45, age: 31.1 ± 7.7 years) completed all assessments. No significant differences were observed in either the psychosocial profiles or heat pain thresholds and PPSs between the sexes in the control and migraine groups. A positive correlation between testosterone levels and PPSs was identified in the male controls (r = .341, P = .029), whereas a negative correlation was identified in the female controls (r = -.407, P = .005). No such correlations were identified in the migraine group. This study confirms that a negative association is present between PPSs and testosterone levels in female controls, which is in line with the findings that testosterone is associated with reduced pain perception. Our study is the first to demonstrate a sex-specific association between PPSs and testosterone levels in HCs. Moreover, this study also revealed that the presence of migraine appears to disrupt this association. PERSPECTIVE: This study revealed that testosterone levels demonstrate opposite associations with pain perception in healthy men and women. However, the presence of migraine appears to disrupt this sex-specific association.

The normative values of pain thresholds in healthy Taiwanese.

OBJECTIVE: Quantitative sensory testing is widely used in clinical and research settings to assess the sensory functions of healthy subjects and patients. It is of importance to establish normative values in a healthy population to provide reference for studies involving patients. Given the absence of normative values for pain thresholds in Taiwan, the aim of this study was to report the normative values for future reference in the Taiwanese population and compare the differences between male and female participants. METHODS: Healthy adults without any chronic or acute pain condition were recruited. The pain thresholds were assessed over the cephalic (supraorbital area and masseter muscle) and extracephalic (medio-volar forearm and thenar eminence) areas. The heat, cold, mechanical punctate, and pressure pain thresholds were measured with a standardized protocol. Comparisons between male and female participants were performed. RESULTS: One hundred and thirty healthy participants (55 males: 30.4 ± 7.4 years; 75 females: 30.5 ± 8.1 years) finished the assessments. Male participants were less sensitive to mechanical stimuli, including pressure over masseter muscle (male vs. female: 178.5 ± 56.7 vs. 156.6 ± 58.4 kPa, p = .034) and punctate over medio-volar forearm (male vs. female: 116.4 ± 45.2 vs. 98.7 ± 65.4 g, p = .011), compared to female participants. However, female participants were less sensitive to cold stimuli, indicated by lower cold pain thresholds over the supraorbital area (male vs. female: 18.6 ± 8.4 vs. 13.6 ± 9.3°C, p = .004), compared to male participants. No significant differences were found between sexes in other pain threshold parameters. CONCLUSIONS: We provided the normative values of healthy male and female adults in Taiwan. This information is crucial for comparison in future pain-related studies to identify potential hypoalgesia or hyperalgesia of tested subjects.

Resting-state occipital alpha power is associated with treatment outcome in patients with chronic migraine.

ABSTRACT: Preventive treatment is crucial for patients with chronic migraine (CM). This study explored the association between resting-state cortical oscillations and 3-month treatment outcome in patients with CM. Treatment-naïve patients with CM were recruited with their demographic data, psychosocial data, and headache profiles as well as the healthy controls (HCs). Resting-state cortical activities were recorded using an electroencephalogram and analysed using source-based and electrode-based spectral power method. The regions of interest were the bilateral primary somatosensory (S1) and visual (V1) cortices. After 3-month treatment with flunarizine, patients with CM were categorized into responders and nonresponders. Demographic, clinical, and electroencephalogram data from 72 patients with CM and 50 HCs were analysed. Elevated anxiety, depression, and stress were observed in patients with CM. Theta power in bilateral S1 and alpha and gamma powers in the right S1 increased in patients with CM. Nonresponders (n = 34) exhibited larger alpha powers in bilateral V1 than those in responders (n = 38). Alpha powers also exhibited significant correlations with changes of monthly headache days. Notably, in responders and nonresponders, occipital alpha powers did not differ at baseline and in the third month. In conclusion, patients with CM who were not responsive to preventive treatment were associated with augmented resting-state occipital alpha activity. Moreover, changes in migraine attack frequency were associated with baseline occipital alpha power. However, the prognostic feature of visual alpha oscillation seems to be inherent because it is not altered by flunarizine treatment. These findings may be useful for developing personalised migraine treatment plans.

Mechanical Punctate Pain Thresholds in Patients With Migraine Across Different Migraine Phases: A Narrative Review.

PURPOSE OF THE REVIEW: We reviewed the studies of mechanical punctate pain thresholds (MPTs) in patients with migraine and summarized their findings focusing on the differences in MPT measurement and MPTs in different phases of migraine. METHODS: We searched the English-written articles that investigate the MPTs in the migraine population published in peer-reviewed journals with full-text using the PubMed, Web of Science, and Google Scholar databases. Moreover, we manually searched the references from the articles for possibly related studies. MAIN FINDINGS: We collected 276 articles and finally included twelve studies in this review. Most of the studies that included MPTs were measured with traditional von Frey filaments. The cephalic areas were always included in the assessment. Most studies compared the inter-ictal MPT in patients with migraine to controls. Among them, the majority found no significant differences; however, there were studies found either higher or lower levels of MPTs in migraine. Even though the studies provided the criteria to define the inter-ictal phase, not all of them followed up with the subjects regarding the next migraine attack. In studies that compared MPT between phases, lower MPTs were found during peri-ictal phases. SUMMARY: Changes to MPT in migraine patients were inconclusive. The selection of measurement methods as well as properly defined migraine phases should be considered for future studies.

Migraine chronification is associated with beta-band connectivity within the pain-related cortical regions: a magnetoencephalographic study.

ABSTRACT: Pain disorders are associated with aberrant oscillations in the pain-related cortical regions; however, few studies have investigated the relationship between the functional cortical network and migraine chronification through direct neural signals. Magnetoencephalography was used to record the resting-state brain activity of healthy controls as well as patients with episodic migraine (EM) and chronic migraine (CM). The source-based oscillatory dynamics of the pain-related cortical regions, which comprises 10 node regions (the bilateral primary [SI] and secondary somatosensory cortices, insula, medial frontal cortex, and anterior cingulate cortex [ACC]), were calculated to determine the intrinsic connectivity and node strength at 1 to 40 Hz. The total node strength within the pain-related cortical regions was smaller in the beta band in patients with migraine (70 EM and 80 CM) than in controls (n = 65). In the beta band, the node strength and functional connectivity values of patients with CM and patients with EM differed from those of controls in specific cortical areas, notably the left SI (EM < control) and bilateral ACC (CM < control); moreover, the node strength was lower in patients with CM than in those with EM. In all patients with migraine, negative correlations were observed between headache frequency and node strength in the bilateral ACC. In conclusion, migraine is characterized by reduced beta oscillatory connectivity within the pain-related cortical regions. Reduced beta connectivity in the ACC is linked to migraine chronification. Longitudinal studies should verify whether this oscillation change is a brain signature and a potential neuromodulation target for migraine.