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.

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.

Transient visual disturbances are associated with disability and suicide risk in patients with migraine without aura.

BACKGROUND: To investigate the characteristics and clinical correlates of transient visual disturbances (TVDs) in patients with migraine without aura (MO). Patients with MO frequently report TVDs, which differ from typical visual aura, but the clinical significance of these TVDs has not been determined. METHODS: Patients with MO who attended our headache clinics were enrolled. Structured questionnaires were used to acquire data on participants' headache profiles, disability, comorbidities, and lifetime suicidal ideation and suicide attempts. A semistructured visual phenomenon questionnaire was used to characterize TVDs. Headache specialists interviewed the participants for diagnosis and the verification of questionnaire responses. RESULTS: Patients with MO (n = 7200; female/male ratio = 3.56, mean age 40.1 ± 13.4 years) were divided into two groups based on the presence (n = 2488) or absence (n = 4712) of TVDs. Patients with TVDs had more headache-related disability, psychiatric comorbidities, and photophobia than did those without TVDs. Suicidal ideation and suicide attempts were more common among patients with than among those without TVDs [ideation: odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.71-2.15, p < 0.001; suicide attempt: OR = 2.23, 95% CI 1.80-2.75, p < 0.001]. CONCLUSION: The presence of TVDs may imply greater migraine-related disability, photophobia, and suicidal ideation/suicide attempt risk in patients with MO.

Intracranial Vertebrobasilar Artery Dissection with Silent Rapid Progression.

PURPOSE: Intracranial vertebrobasilar artery dissection (iVBD) is a potentially lethal disease, and progression of the dissected vessels is not uncommon. Our report is aimed at providing further clinical experience of the timing of follow-up vascular imaging or endovascular intervention in iVBD patients. CASE REPORT: We report a case of iVBD with silent rapid progression. The 48-year-old woman presented as transient right limbs weakness. Brain MRI showed a small acute infarct over the left cerebellum, and MRA revealed a short segment of dissection over the left distal vertebral artery extending to proximal basilar artery. With no new clinical symptoms and signs, follow-up of vascular imaging within 1 week showed progressive critical narrowing of the dissected vertebrobasilar arteries. The blood flow of the vertebrobasilar system was restored by endovascular stenting. CONCLUSION: iVBD might progress without clinical manifestations. Early follow-up of vascular imaging should be considered in the patients with high risk for progression.

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.

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.

Non-aura visual disturbance with high visual aura rating scale scores has stronger association with migraine chronification than typical aura.

OBJECTIVES: To investigate the clinical correlates of visual symptoms in patients with migraine. METHOD: Patients with migraine that attended our headache clinics were enrolled. Headache profiles, disability, and comorbidities were acquired with structured questionnaires. A semi-structured visual phenomenon questionnaire was also used to assess the characteristics of visual symptoms, including visual aura in patients with migraine with aura and transient visual disturbance in patients with migraine without aura. Headache specialists interviewed with the participants for the ascertainment of diagnosis and verification of the questionnaires. RESULT: Migraine with aura patients with visual aura (n = 743, female/male = 2.3, mean age: 34.7 ± 12.2 years) and migraine without aura patients with non-aura transient visual disturbance (n = 1,808, female/male = 4.4, mean age: 39.4 ± 12.6 years) were enrolled. Patients with transient visual disturbance had higher headache-related disability and more psychiatric comorbidities. Chronic migraine was more common in migraine without aura than migraine with aura patients (41.9% vs. 11.8%, OR = 5.48 [95% CI: 4.33-7.02], p < 0.001). The associations remained after adjusting confounding factors. CONCLUSION: Presence of non-aura transient visual disturbance may suggest a higher migraine-related disability and is linked to higher risk of chronic migraine than typical migraine aura in migraine patients. Further studies are needed to elucidate the potential mechanism.

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.

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.

Right anterior insula is associated with pain generalization in patients with fibromyalgia.

ABSTRACT: Despite diffuse tenderness, patients with fibromyalgia (FM) have reported a wide range of areas with musculoskeletal pain. This study investigated the neural structures and neuroanatomical networks associated with self-reported widespread pain in FM using magnetic resonance imaging. We collected clinical profiles and brain magnetic resonance imaging data of newly diagnosed patients with FM. A total of 138 patients with FM were divided into 3 subgroups based on the number of pain areas, with 3 to 8, 9 to 12, and 13 to 19 areas, respectively. Using voxel-based morphometry analysis, we first identified the neural structure that showed a trend of volumetric change across the 3 subgroups. We then used it as a candidate seed of interest with a seed-to-voxel analytical approach to explore the structural covariance (SC) networks of the whole brain. Finally, we studied the trend of changes in the distribution and strength of SC networks across subgroups of patients. We found a decreasing trend in the volumes of the right anterior insular cortex (rAIC) across the 3 subgroups that had an increased number of pain areas. An increasing trend in the number of neural substrates over the subcortical regions, especially the basal ganglion, showed SC to the rAIC, and a decreasing trend of SC strength was shown between the rAIC and the precuneus, frontal cortex, anterior and posterior cingulate, and lingual gyri, across the patient subgroups with increased pain areas. The rAIC and its altered connection with specific brain regions indicates widespread pain in patients with FM.

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.

Etiology and risk factors of intracranial hemorrhage and ischemic stroke in young adults.

BACKGROUND: Young stroke incidence has increased worldwide with lifestyle changes. Etiology and risk factors for both ischemic and hemorrhagic stroke in young Asians remain underexplored. METHODS: We retrospectively reviewed consecutive acute stroke patients aged 16-45 years admitted to the Taipei Veterans General Hospital between 2009 and 2019 to analyze etiologic subtypes, risk factors, and serial modified Rankin Scale scores for 1 year and compare the age groups of 16-30 and 31-45 years. RESULTS: Among 670 young Taiwanese patients (mean age at onset 37.5 ± 7.0 years; male 65.1%), there were 366 nontraumatic spontaneous hemorrhagic stroke (including 259 intracerebral hemorrhage [ICH] and 107 subarachnoid hemorrhage, SAH), 292 ischemic stroke and 12 cerebral venous thromboses. Notably, ICH was more prevalent in patients aged 16-30 than in those aged 31-45 (54.8% vs 36.8%). Specifically, structural vasculopathy (e.g., arteriovenous malformation, cavernoma) was the most common etiologic subtype in patients aged 16-30 (p < 0.001), whereas hypertensive ICH was the most common subtype in patients aged 31-45 (p < 0.001). On the other hand, the top ischemic subtype for both age groups was other determined diseases (e.g., arterial dissection, autoimmune diseases, moyamoya disease, etc.) rather than large artery atherosclerosis. Hyperlipidemia, diabetes, and cigarette smoking were more common risk factors for infarction than ICH. Familial stroke patients whose first- or second-degree relatives had a stroke by age 80 (n = 104, 15.5%) had more infarctions than those without a familial stroke history. In multivariate analyses, initial stroke severity, and infarction type were important predictors of favorable outcomes after 3 months. At the 1-year follow-up, patients with ICH and SAH had worse functional outcomes and survival rates than those with infarction. CONCLUSION: An aggressive approach to elucidate the etiology of stroke is indicated because structural vasculopathy-induced ICH and other determined infarction are distinctively prevalent in young adults, particularly those aged 16-30.

Somatosensory Gating Responses Are Associated with Prognosis in Patients with Migraine.

Sensory gating, a habituation-related but more basic protective mechanism against brain sensory overload, is altered in patients with migraine and linked to headache severity. This study investigated whether somatosensory (SI) gating responses determined 3-months treatment outcomes in patients with episodic migraine (EM) and chronic migraine (CM). A 306-channel magnetoencephalography (MEG) with paired-pulse stimulation paradigm was used to record their neuromagnetic responses. To calculate the peak amplitude and latency and compute the gating ratios (second vs. first amplitude), the first and second responses to the paired stimuli from the primary somatosensory cortex were obtained. All patients were assigned to subgroups labeled good or poor according to their headache frequency at baseline compared with at the third month of treatment. The gating ratio in the CM group (n = 37) was significantly different between those identified as good and poor (p = 0.009). In the EM group (n = 30), the latency in the second response differed by treatment outcomes (p = 0.007). In the receiver operating characteristic analysis, the areas under the curve for the CM and EM groups were 0.737 and 0.761, respectively. Somatosensory gating responses were associated with treatment outcomes in patients with migraine; future studies with large patient samples are warranted.

Salivary cortisol is associated with cognitive changes in patients with fibromyalgia.

Fibromyalgia (FM) is a stress-related chronic pain disorder with common cognitive complaints. This study characterized cognitive dysfunction in patients with FM and explored whether these changes are linked to altered cortisol levels. Consecutive 44 patients with FM and 48 healthy controls were enrolled for the assessments of subjective and objective cognitive functions and diurnal levels of salivary cortisol (sampled at awakening, 30 min after awakening, 3 pm, and bedtime). All measurements were compared between the groups and evaluated for clinical correlation. The FM group had more subjective cognitive complaints and performed poorer in objective cognitive testing in memory (delayed recall in Chinese Version Verbal Learning Test and Taylor Complex Figure Test), language (Boston Naming Test), and executive domains (Wisconsin Card Sorting Test) after adjustments for education. The diurnal cortisol levels of patients with FM tended to be lower, especially at 30 min after awakening and bedtime. Moreover, moderate positive correlations existed between the Chinese Version Verbal Learning Test, Boston Naming Test and the morning cortisol levels within the FM group. We suggested the altered cognitive function in FM may be linked to stress maladaptation. Future studies are warranted to elucidate whether stress management improves cognitive performance in patients with FM.

Quantitative CT angiography predicts large artery occlusion types and successful thrombectomy in acute ischemic stroke.

BACKGROUND: Clinical and radiological outcomes of endovascular thrombectomy (EVT) are related to etiologies of large vessel occlusion (LVO) in acute stroke. However, preprocedural computed tomography angiography (CTA) or CT perfusion imaging can hardly distinguish embolic occlusion from atherosclerotic occlusion. We hypothesized that quantitative multiphase CTA (mCTA) of LVO may predict occlusion types and thrombectomy outcome. METHODS: We retrospectively evaluated the consecutive stroke patients who had undergone mCTA and EVT <6 hours of onset at two independent medical centers. The intra-arterial radiodensities of Hounsfield unit (HU) were measured to examine the HUdistal/proximal ratio using receiver operating characteristic curve analysis. The derived cut-off value was re-examined in an independent cohort. RESULTS: In the derivation cohort (n = 102), 81 patients (79.4%) were embolic occlusion without severe residual intracranial atherosclerotic stenosis (ICAS[-]) and 21 patients were atherosclerosis-related occlusion (ICAS[+]) based on digital subtraction angiography (DSA). The optimal cut-off to predict embolic occlusion was HU ratio <0.6 measured at 2 mm from the occlusion site (maximum area under the curve = 0.87; sensitivity 96%; specificity 81%). This cut-off also independently predicted successful recanalization using stent-retrievers and/or contact aspiration (modified Treatment in Cerebral Ischemia score ≥2b; p = 0.002) after adjusting for age, atrial fibrillation, and collateral circulation score, but not predicted favorable outcome at 3 months post stroke. Importantly, in the validation cohort (n = 95, 80% embolic occlusion), this HU ratio cut-off similarly predicted occlusion types and recanalization outcome, respectively. CONCLUSION: The mCTA-based quantitative radiodensities of acute LVO provides preprocedural predictive values of DSA-determined occlusion types and thrombectomy outcomes.

Machine learning-based prediction of heat pain sensitivity by using resting-state EEG.

INTRODUCTION: The development of quantitative, objective signatures or predictors to evaluate pain sensitivity is crucial in the clinical management of pain and in precision medicine. This study combined multimodal (neurophysiology and psychometrics) signatures to classify the training dataset and predict the testing dataset on individual heat pain sensitivity. METHODS: Healthy individuals were recruited in this study. Individual heat pain sensitivity and psychometric scores, as well as the resting-state electroencephalography (EEG) data, were obtained from each participant. Participants were divided into low-sensitivity and high-sensitivity subgroups according to their heat pain sensitivity. Psychometric data obtained from psychometric measurements and power spectral density (PSD) and functional connectivity (FC) derived from resting-state EEG analysis were subjected to feature selection with an independent t test and were then trained and predicted using machine learning models, including support vector machine (SVM) and k-nearest neighbor. RESULTS: In total, 85 participants were recruited in this study, and their data were divided into training (n = 65) and testing (n = 20) datasets. We identified the resting-state PSD and FC, which can serve as brain signatures to classify heat pain as high-sensitive or low-sensitive. Using machine learning algorithms of SVM with different kernels, we obtained an accuracy of 86.2%-93.8% in classifying the participants into thermal pain high-sensitivity and low-sensitivity groups; moreover, using the trained model of cubic SVM, an accuracy of 80% was achieved in predicting the pain sensitivity of an independent dataset of combined PSD and FC features of resting-state EEG data. CONCLUSION: Acceptable accuracy in classification and prediction by using the SVM model indicated that pain sensitivity could be achieved, leading to considerable possibilities of the use of objective evaluation of pain perception in clinical practice. However, the predictive model presented in this study requires further validation by studies with a larger dataset.

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.

Neuromagnetic Amygdala Response to Pain-Related Fear as a Brain Signature of Fibromyalgia.

INTRODUCTION: Fibromyalgia (FM) is a chronic pain condition characterized by impaired emotional regulation. This study explored the brain response to pain-related fear as a potential brain signature of FM. METHODS: We used a conditioned fear task and magnetoencephalography to record pain-related fear responses in patients with FM. Two blocks of 30 fear responses were collected to compute the response strength in the first block and the strength difference between the first and second blocks (fear habituation). These measurements were investigated for their clinical relevance and compared with measurements obtained from healthy controls and patients with chronic migraine (CM), a different chronic pain condition often comorbid with FM. RESULTS: Pain-related fear clearly activated the bilateral amygdala and anterior insula in patients with FM (n = 52), patients with CM (n = 50), and the controls (n = 30); the response strength in the first block was consistent across groups. However, fear habituation in the right amygdala decreased in the FM group (vs. CM and control groups, both p ≤ 0.001, no difference between CM and control groups). At the 3-month follow-up, the patients with FM reporting < 30% improvement in pain severity (n = 15) after pregabalin treatment exhibited lower fear habituation in the left amygdala at baseline (vs. ≥ 30% improvement, n = 22, p = 0.019). Receiver operating characteristic analysis confirmed that amygdala fear habituation is a suitable predictor of diagnosis and treatment outcomes of FM (area under the curve > 0.7). CONCLUSIONS: Amygdala activation to pain-related fear is maladaptive and linked to treatment outcomes in patients with FM. Because the aberrant amygdala response was not observed in the CM group, this response is a potential brain signature of FM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02747940.

Premature Atrial Contractions and Their Association with Stroke Features and Outcome.

BACKGROUND: Frequent premature atrial contractions (PACs) are associated with atrial fibrillation, stroke, and mortality. However, the cut-off value for PAC counts that could identify patients with different stroke features is unclear, and the association of PACs to outcome is not determined. METHODS: The study retrospectively included patients with acute ischemic stroke who had underwent both a 24 h Holter recording and a brain MRI in Taipei Veterans General Hospital from January 2015 to May 2016. Patients were categorized into four groups according to their PAC frequencies on 24 h Holter recording. We compared the clinical severity, neuroimage features, stroke subtypes, and functional outcome among the four groups of patients. RESULTS: Among the 278 patients, the lower, middle, and upper quartiles of the PAC counts were 23, 74, and 459.5, respectively. In contrast to the 1st quartile of patients, the 3rd (PAC 75-459/24 h) and the 4th (PAC ≥460/24 h) quartiles of patients had higher NIH Stroke Scale (NIHSS) at admission (p = 0.014 and p = 0.002, respectively). The frequencies of cryptogenic stroke were not different among the 4 quartiles of the patients, but cryptogenic stroke patients with ≥ 75PACs/24hours had higher stroke severity compared to those with PACs < 75counts/24 h (NIHSS 9.1 vs. 5.2, p = 0.043). There was an increased trend in infarcts of multiple vascular territories and in mortality at 1 year among the four groups of patients with increased PAC frequency (p = 0.045 and p = 0.002, respectively). The 4th PAC quartile was associated with poor functional outcome (modified Rankin Scale ≥ 4) at 3 months in univariate analysis (OR: 5.66, CI: 2.69-11.91, p < 0.001), but was not an independent predictor after controlling for initial stroke severity. CONCLUSIONS: PACs ≥ 75 counts/24 h was associated with higher clinical severity in patients with acute ischemic stroke.