Decoding Visual Responses: Insights into Chronic Migraine and Medication Overuse Headache with Electrophysiological Analysis.

Background/Objectives: Habituation and sensitization are opposite phenomena that play a role in the pathophysiology of episodic migraine and its progression to chronic migraine (CM). There have been just a few studies that have investigated these phenomena in patients with medication overuse headache (MOH) in comparison to those with chronic migraine (CM) and healthy controls (HCs), and the findings have been inconsistent. Methods: We measured and examined visual evoked potentials (VEPs) in 81 patients with MOH and 24 patients with CM, as well as 24 HCs. The VEPs were used to assess sensitization by analysing the amplitude of the first block (100 sweeps) and to evaluate habituation by measuring the amplitude response decrement after six blocks. We further examined patients diagnosed with MOH based on their acute medication type and after a 3-week acute medication withdrawal program. Results: There were no significant differences between groups in terms of the first N1-P1 VEP amplitude block and its habituation. It was found that patients with MOH had a greater drop in the amplitude of the VEP P1-N2 complex after repeated stimulation than patients with CM or HC. The VEP parameters showed no significant differences based on the specific overused drug and after a 3-week acute medication withdrawal. Conclusions: We propose that the results obtained in patients with MOH indicate an abnormal activation of inhibitory circuits in the parieto-occipital region in response to repeated modulatory stimuli.

Subsegmentation of the hippocampus in subgroups of migraine with aura patients: advanced structural neuroimaging study.

BACKGROUND: This study investigated for a possible contributing role of hippocampus in the different clinical phenotypic manifestations of migraine aura. METHODS: Herein, patients were categorized as those with pure visual aura (MwAv), those who reported additional somatosensory and dysphasic symptoms (MwAvsd), and healthy controls (HCs). Neuroimaging data obtained using FreeSurfer-based segmentation of hippocampal subfields were compared between HCs and patients with migraine with aura, as well as between HCs and those with MwAv and MwAvsd. The average migraine aura complexity score (MACS) was calculated for each patient to investigate the correlation between hippocampal subfield volume and migraine aura complexity. RESULTS: Herein, 46 patients with migraine with aura (28 MwAvsd and 18 MwAv) and 31 HCs were included. There were no significant differences in the hippocampal subfields between HCs and patients with migraine with aura. The average MACS negatively correlated with the volumes of the left and right hippocampi, Cornu Ammonis (CA) 1, CA3, CA4, molecular layer, left granule cell layer of the dentate gyrus, hippocampal fissure, and hippocampus-amygdala transition area. The MwAvsd subgroup had significantly smaller whole hippocampal volumes in both hemispheres, as well as in both subicula, compared with the MwAv subgroup and HCs. In addition, the left molecular layer, right CA1, and hippocampal fissures were significantly smaller in the MwAvsd group than in the MwAv subgroup and HCs. CONCLUSIONS: Smaller left and right hippocampal volumes, particularly of the subiculum/CA1 area, may play an important role in the pathophysiology of somatosensory and dysphasic symptoms in migraine with aura.

Quantification Approaches in Non-Target LC/ESI/HRMS Analysis: An Interlaboratory Comparison.

Nontargeted screening (NTS) utilizing liquid chromatography electrospray ionization high-resolution mass spectrometry (LC/ESI/HRMS) is increasingly used to identify environmental contaminants. Major differences in the ionization efficiency of compounds in ESI/HRMS result in widely varying responses and complicate quantitative analysis. Despite an increasing number of methods for quantification without authentic standards in NTS, the approaches are evaluated on limited and diverse data sets with varying chemical coverage collected on different instruments, complicating an unbiased comparison. In this interlaboratory comparison, organized by the NORMAN Network, we evaluated the accuracy and performance variability of five quantification approaches across 41 NTS methods from 37 laboratories. Three approaches are based on surrogate standard quantification (parent-transformation product, structurally similar or close eluting) and two on predicted ionization efficiencies (RandFor-IE and MLR-IE). Shortly, HPLC grade water, tap water, and surface water spiked with 45 compounds at 2 concentration levels were analyzed together with 41 calibrants at 6 known concentrations by the laboratories using in-house NTS workflows. The accuracy of the approaches was evaluated by comparing the estimated and spiked concentrations across quantification approaches, instrumentation, and laboratories. The RandFor-IE approach performed best with a reported mean prediction error of 15× and over 83% of compounds quantified within 10× error. Despite different instrumentation and workflows, the performance was stable across laboratories and did not depend on the complexity of water matrices.

Lack of a direct link between macular cones function and photophobia in interictal migraine.

BACKGROUND: It is still debatable whether the mechanisms underlying photophobia are related to altered visual cortex excitability or specific abnormalities of colour-related focal macular retino-thalamic information processing. METHODS: This cross-sectional study examined Ganzfeld blue-red (B-R) and blue-yellow (B-Y) focal macular cone flash ERG (ffERG) and focal-flash visual evoked potentials (ffVEPs) simultaneously in a group of migraine patients with (n = 18) and without (n = 19) aura during the interictal phase, in comparison to a group of healthy volunteers (HVs) (n = 20). We correlate the resulting retinal and cortical electrophysiological responses with subjective discomfort from exposure to bright light verified on a numerical scale. RESULTS: Compared to HVs, the amplitude and phase of the first and second harmonic of ffERG and ffVEPs were non-significantly different in migraine patients without aura and migraine patients with aura for both the B-R and the B-Y focal stimuli. Pearson's correlation test did not disclose correlations between clinical variables, including the photophobia scale and electrophysiological variables. CONCLUSIONS: These results do not favour interictal functional abnormalities in L-M- and S-cone opponent visual pathways in patients with migraine. They also suggest that the discomfort resulting from exposure to bright light is not related to focal macular retinal-to-visual cortex pathway.

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.

Decoding pain through facial expressions: a study of patients with migraine.

BACKGROUND: The present study used the Facial Action Coding System (FACS) to analyse changes in facial activities in individuals with migraine during resting conditions to determine the potential of facial expressions to convey information about pain during headache episodes. METHODS: Facial activity was recorded in calm and resting conditions by using a camera for both healthy controls (HC) and patients with episodic migraine (EM) and chronic migraine (CM). The FACS was employed to analyse the collected facial images, and intensity scores for each of the 20 action units (AUs) representing expressions were generated. The groups and headache pain conditions were then examined for each AU. RESULTS: The study involved 304 participants, that is, 46 HCs, 174 patients with EM, and 84 patients with CM. Elevated headache pain levels were associated with increased lid tightener activity and reduced mouth stretch. In the CM group, moderate to severe headache attacks exhibited decreased activation in the mouth stretch, alongside increased activation in the lid tightener, nose wrinkle, and cheek raiser, compared to mild headache attacks (all corrected p < 0.05). Notably, lid tightener activation was positively correlated with the Numeric Rating Scale (NRS) level of headache (p = 0.012). Moreover, the lip corner depressor was identified to be indicative of emotional depression severity (p < 0.001). CONCLUSION: Facial expressions, particularly lid tightener actions, served as inherent indicators of headache intensity in individuals with migraine, even during resting conditions. This indicates that the proposed approach holds promise for providing a subjective evaluation of headaches, offering the benefits of real-time assessment and convenience for patients with migraine.

The blink reflex and its modulation - Part 2: Pathophysiology and clinical utility.

The blink reflex (BR) is integrated at the brainstem; however, it is modulated by inputs from various structures such as the striatum, globus pallidus, substantia nigra, and nucleus raphe magnus but also from afferent input from the peripheral nervous system. Therefore, it provides information about the pathophysiology of numerous peripheral and central nervous system disorders. The BR is a valuable tool for studying the integrity of the trigemino-facial system, the relevant brainstem nuclei, and circuits. At the same time, some neurophysiological techniques applying the BR may indicate abnormalities involving structures rostral to the brainstem that modulate or control the BR circuits. This is a state-of-the-art review of the clinical application of BR modulation; physiology is reviewed in part 1. In this review, we aim to present the role of the BR and techniques related to its modulation in understanding pathophysiological mechanisms of motor control and pain disorders, in which these techniques are diagnostically helpful. Furthermore, some BR techniques may have a predictive value or serve as a basis for follow-up evaluation. BR testing may benefit in the diagnosis of hemifacial spasm, dystonia, functional movement disorders, migraine, orofacial pain, and psychiatric disorders. Although the abnormalities in the integrity of the BR pathway itself may provide information about trigeminal or facial nerve disorders, alterations in BR excitability are found in several disease conditions. BR excitability studies are suitable for understanding the common pathophysiological mechanisms behind various clinical entities, elucidating alterations in top-down inhibitory systems, and allowing for follow-up and quantitation of many neurological syndromes.

Pathophysiology of cluster headache: From the trigeminovascular system to the cerebral networks.

BACKGROUND: Despite advances in neuroimaging and electrophysiology, cluster headache's pathogenesis remains unclear. This review will examine clinical neurophysiology studies, including electrophysiological and functional neuroimaging, to determine if they might help us construct a neurophysiological model of cluster headache. RESULTS: Clinical, biochemical, and electrophysiological research have implicated the trigeminal-parasympathetic system in cluster headache pain generation, although the order in which these two systems are activated, which may be somewhat independent, is unknown. Electrophysiology and neuroimaging have found one or more central factors that may cause seasonal and circadian attacks. The well-known posterior hypothalamus, with its primary circadian pacemaker suprachiasmatic nucleus, the brainstem monoaminergic systems, the midbrain, with an emphasis on the dopaminergic system, especially when cluster headache is chronic, and the descending pain control systems appear to be involved. Functional connection investigations have verified electrophysiological evidence of functional changes in distant brain regions connecting to wide cerebral networks other than pain. CONCLUSION: We propose that under the impact of external time, an inherited misalignment between the primary circadian pacemaker suprachiasmatic nucleus and other secondary extra- suprachiasmatic nucleus clocks may promote disturbance of the body's internal physiological clock, lowering the threshold for bout recurrence.

The evolving concept of multimorbidity and migraine.

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature.

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far. Probands were enrolled in five different centres and underwent neurological examination, clinical cognitive assessment, column imaging for scoliosis assessment, ophthalmologic examination, brain imaging, GBA2 activity in peripheral blood cells and genetic testing. Their phenotype was consistent with HSP, with notable features like upper gaze palsy and movement disorders. We review demographic, genetic, biochemical and clinical information from all documented cases in the existing literature, focusing on the global distribution of cases, the features of the syndrome, its variable presentation, new potential identifying features and the significance of measuring GBA2 enzyme activity.

Local Dynamic Stability of Trunk During Gait is Responsive to Rehabilitation in Subjects with Primary Degenerative Cerebellar Ataxia.

This study aimed to assess the responsiveness to the rehabilitation of three trunk acceleration-derived gait indexes, namely the harmonic ratio (HR), the short-term longest Lyapunov's exponent (sLLE), and the step-to-step coefficient of variation (CV), in a sample of subjects with primary degenerative cerebellar ataxia (swCA), and investigate the correlations between their improvements (∆), clinical characteristics, and spatio-temporal and kinematic gait features. The trunk acceleration patterns in the antero-posterior (AP), medio-lateral (ML), and vertical (V) directions during gait of 21 swCA were recorded using a magneto-inertial measurement unit placed at the lower back before (T0) and after (T1) a period of inpatient rehabilitation. For comparison, a sample of 21 age- and gait speed-matched healthy subjects (HSmatched) was also included. At T1, sLLE in the AP (sLLEAP) and ML (sLLEML) directions significantly improved with moderate to large effect sizes, as well as SARA scores, stride length, and pelvic rotation. sLLEML and pelvic rotation also approached the HSmatched values at T1, suggesting a normalization of the parameter. HRs and CV did not significantly modify after rehabilitation. ∆sLLEML correlated with ∆ of the gait subscore of the SARA scale (SARAGAIT) and ∆stride length and ∆sLLEAP correlated with ∆pelvic rotation and ∆SARAGAIT. The minimal clinically important differences for sLLEML and sLLEAP were ≥ 36.16% and ≥ 28.19%, respectively, as the minimal score reflects a clinical improvement in SARA scores. When using inertial measurement units, sLLEAP and sLLEML can be considered responsive outcome measures for assessing the effectiveness of rehabilitation on trunk stability during walking in swCA.

Gait analysis, trunk movements, and electromyographic patterns after minimally invasive spine surgery for lumbar instability: An observational prospective study.

Objective: The aim of the present study was to investigate trunk kinematics and spine muscle activation during walking after minimally invasive surgery in patients with L4-L5 degenerative spondylolisthesis suffering from lumbar instability (LI). Methods: Eleven patients suffering from LI and 13 healthy controls (HC) were enrolled. Trunk kinematics and spine muscle activation patterns during walking were collected. Maximal trunk ranges of motion were also recorded from standing position. Assessments were performed pre-operatively (T0), 1 month (T1) and 3 months (T2) after MIS. Results: We found significant improvement in spine muscle activation during walking at T2 compared to T0, mainly involving right/left symmetry at the operated level (L4-L5) and up-down synchronization from L3 to S1. Significant improvements in trunk rotation nearing to the HC group during walking were also found at T2 after surgery, though no changes were observed in the maximal range of motion of the trunk during standing. Furthermore, trunk rotation improvement correlated with a lower grade of residual disability. Conclusions: Our findings indicate that trunk rotation improves after surgery, and impaired aspects of spine muscle activation can be improved with surgery. These biomechanical parameters could represent novel tools for monitoring the effect of surgery in LI and preventing impaired spine mobility and muscle activation.

What has neurophysiology revealed about migraine and chronic migraine?

Since the first electroencephalographic recordings obtained by Golla and Winter in 1959, researchers have used a variety of neurophysiological techniques to determine the mechanisms underlying recurrent migraine attacks. Neurophysiological methods have shown that the brain during the interictal phase of an episodic migraine is characterized by a general hyperresponsiveness to sensory stimuli, a malfunction of the monoaminergic brainstem circuits, and by functional alterations of the thalamus and thalamocortical loop. All of these alterations vary plastically during the phases of the migraine cycle and interictally with the days following the attack. Both episodic migraineurs recorded during an attack and chronic migraineurs are characterized by a general increase in the cortical amplitude response to peripheral sensory stimuli; this is an electrophysiological hallmark of a central sensitization process that is further reinforced through medication overuse. Considering the large-scale functional involvement and the main roles played by the brainstem-thalamo-cortical network in selection, elaboration, and learning of relevant sensory information, future research should move from searching for one specific primary site of dysfunction at the macroscopic level, to the chronic, probably genetically determined, molecular dysfunctions at the synaptic level, responsible for short- and long-term learning mechanisms.

Long-Term Treatment Over 52 Weeks with Monthly Fremanezumab in Drug-Resistant Migraine: A Prospective Multicenter Cohort Study.

BACKGROUND: Real-world studies on fremanezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention, are few and with limited follow-up. OBJECTIVE: We aimed to evaluate the long-term (up to 52 weeks) effectiveness and tolerability of fremanezumab in high-frequency episodic migraine and chronic migraine. METHODS: This s an independent, prospective, multicenter cohort study enrolling outpatients in 17 Italian Headache Centers with high-frequency episodic migraine or chronic migraine and multiple preventive treatment failures. Patients were treated with fremanezumab 225 mg monthly. The primary outcomes included changes from baseline (1 month before treatment) in monthly headache days, response rates (reduction in monthly headache days from baseline), and persistence in medication overuse at months 3, 6, and 12 (all outcome timeframes refer to the stated month). Secondary outcomes included changes from baseline in acute medication intake and disability questionnaires scores at the same timepoints. A last observation carried forward analysis was also performed. RESULTS: A total of 90 patients who received at least one dose of fremanezumab and with a potential 12-month follow-up were included. Among them, 15 (18.0%) patients discontinued treatment for the entire population, a reduction in monthly headache days compared with baseline was reported at month 3, with a significant median [interquartile range] reduction in monthly headache days (- 9.0 [11.5], p < 0.001). A statistically different reduction was also reported at month 6 compared with baseline (- 10.0 [12.0]; p < 0.001) and at 12 months of treatment (- 10.0 [14.0]; p < 0.001). The percentage of patients with medication overuse was significantly reduced compared with baseline from 68.7% (57/83) to 29.6% (24/81), 25.3% (19/75), and 14.7% (10/68) at 3, 6, and 12 months of treatment, respectively (p < 0.001). Acute medication use (days and total number) and disability scores were also significantly reduced (p < 0.001). A ≥ 50% response rate was achieved for 51.9, 67.9, and 76.5% of all patients at 3, 6, and 12 months, respectively. Last observation carried forward analyses confirmed these findings. Fremanezumab was well tolerated, with just one patient discontinuing treatment because of adverse events. CONCLUSIONS: This study provides evidence for the real-world effectiveness of fremanezumab in treating both high-frequency episodic migraine and chronic migraine, with meaningful and sustained improvements in multiple migraine-related variables. No new safety issue was identified.

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.

Central sensitization mechanisms in chronic migraine with medication overuse headache: a study of thalamocortical activation and lateral cortical inhibition.

BACKGROUND: It is unclear whether cortical hyperexcitability in chronic migraine with medication overuse headache (CM-MOH) is due to increased thalamocortical drive or aberrant cortical inhibitory mechanisms. METHODS: Somatosensory evoked potentials (SSEP) were performed by electrical stimulation of the median nerve (M), ulnar nerve (U) and simultaneous stimulation of both nerves (MU) in 27 patients with CM-MOH and, for comparison, in 23 healthy volunteers (HVs) of a comparable age distribution. We calculated the degree of cortical lateral inhibition using the formula: 100 - [MU/(M + U) × 100] and the level of thalamocortical activation by analyzing the high frequency oscillations (HFOs) embedded in parietal N20 median SSEPs. RESULTS: Compared to HV, CM-MOH patients showed higher lateral inhibition (CM-MOH 52.2% ± 15.4 vs. HV 40.4% ± 13.3; p = 0.005), which positively correlated with monthly headache days, and greater amplitude of pre-synaptic HFOs (p = 0.010) but normal post-synaptic HFOs (p = 0.122). CONCLUSION: Our findings suggest that central neuronal circuits are highly sensitized in CM-MOH patients, at both thalamocortical and cortical levels. The observed changes could be due to the combination of dysfunctional central pain control mechanisms, hypersensitivity and hyperresponsiveness directly linked to the chronic intake of acute migraine drugs.

Electrophysiological findings in migraine may reflect abnormal synaptic plasticity mechanisms: A narrative review.

BACKGROUND: The cyclical brain disorder of sensory processing accompanying migraine phases lacks an explanatory unified theory. METHODS: We searched Pubmed for non-invasive neurophysiological studies on migraine and related conditions using transcranial magnetic stimulation, electroencephalography, visual and somatosensory evoked potentials. We summarized the literature, reviewed methods, and proposed a unified theory for the pathophysiology of electrophysiological abnormalities underlying migraine recurrence. RESULTS: All electrophysiological modalities have determined specific changes in brain dynamics across the different phases of the migraine cycle. Transcranial magnetic stimulation studies show unbalanced recruitment of inhibitory and excitatory circuits, more consistently in aura, which ultimately results in a substantially distorted response to neuromodulation protocols. Electroencephalography investigations highlight a steady pattern of reduced alpha and increased slow rhythms, largely located in posterior brain regions, which tends to normalize closer to the attacks. Finally, non-painful evoked potentials suggest dysfunctions in habituation mechanisms of sensory cortices that revert during ictal phases. CONCLUSION: Electrophysiology shows dynamic and recurrent functional alterations within the brainstem-thalamus-cortex loop varies continuously and recurrently in migraineurs. Given the central role of these structures in the selection, elaboration, and learning of sensory information, these functional alterations suggest chronic, probably genetically determined dysfunctions of the synaptic short- and long-term learning mechanisms.