The exciting migraine brain: towards neurophysiological prediction of migraine attacks

The aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of methodologies to measure brain excitability over the migraine cycle, with special emphasis on identifying changes in excitability of the visual system and the occipital cortex. Applying such measures over the course of a migraine cycle could help elucidate factors that initiate the migraine attack, and might lead to better (or better timing of) preventive measures. The research described in this thesis is divided into two parts. The first part reports on the development and application of several methodologies to measure excitability of the visual system including the cortex in migraine patients and a migraine mouse model. The second part consists of two studies employing transcranial magnetic stimulation (TMS) in combination with concurrent electroencephalography (EEG) recordings to provide direct measures of cortical excitability in migraine and epilepsy.LUMC / Geneeskund

Stretch reflex augmentation by subthreshold TMS is evidence for corticospinal signal integration

Reflex adaptation to environment and task at hand plays a key role in motor control. In search for cortical reflex modulation mechanisms, transcranial magnetic stimulation (TMS) has been found to augment muscle stretch reflexes as recorded by electromyography (EMG). However, instead of reflecting true integration of efferent sensory with cortical activity, this augmentation can alternatively be explained by spinal summation of the stretch response with TMS induced motor evoked potentials (MEP). The goal of this study was to confirm true peripheral-cortical signal integration by combining muscle reflex responses with timed subthreshold TMS. Mechanically induced ramp-and-hold stretches (duration: 40 ms, velocity: 1.5 rad/s) of the m. flexor carpi radialis were combined with TMS pulses at 96% of active motor threshold applied between 10 ms before and 120 ms after stretch onset with a resolution of 5 to 10 ms. Significant MEP like augmentation of the EMG response was found when TMS was timed to arrive between 60 and 90 ms after stretch onset with a consistent and short delay between estimated TMS arrival time and peak EMG activity of 5 to 10 ms. Timing and nature of muscle stretch reflex activity augmentation by subthreshold TMS reflect supraspinal integration of peripheral sensory afferent with cortical efferent signals as a mechanism of supraspinal reflex adaptation

EEG-based visual deviance detection in freely behaving mice

The mouse is widely used as an experimental model to study visual processing. To probe how the visual system detects changes in the environment, functional paradigms in freely behaving mice are strongly needed. We developed and validated the first EEG-based method to investigate visual deviance detection in freely behaving mice. Mice with EEG implants were exposed to a visual deviant detection paradigm that involved changes in light intensity as standard and deviant stimuli. By subtracting the standard from the deviant evoked waveform, deviant detection was evident as bi-phasic negativity (starting around 70 ms) in the difference waveform. Additionally, deviance-associated evoked (beta/gamma) and induced (gamma) oscillatory responses were found. We showed that the results were stimulus-independent by applying a "flip-flop " design and the results showed good repeatability in an independent measurement. Together, we put forward a validated, easy-to-use paradigm to measure visual deviance processing in freely behaving mice.Functional Genomics of Muscle, Nerve and Brain Disorder

Unilateral increased visual sensitivity in cluster headache: a cross-sectional study

Background and Objectives Increased sensitivity to light and patterns is typically associated with migraine, but has also been anecdotally reported in cluster headache, leading to diagnostic confusion. We wanted to assess whether visual sensitivity is increased ictally and interictally in cluster headache.Methods We used the validated Leiden Visual Sensitivity Scale (L-VISS) questionnaire (range 0-36 points) to measure visual sensitivity in people with episodic or chronic cluster headache: (i) during attacks; (ii) in-between attacks; and in episodic cluster headache (iii) in-between bouts. The L-VISS scores were compared with the L-VISS scores obtained in a previous study in healthy controls and participants with migraine.Results Mean L-VISS scores were higher for: (i) ictal vs interictal cluster headache (episodic cluster headache: 11.9 +/- 8.0 vs. 5.2 +/- 5.5, chronic cluster headache: 13.7 +/- 8.4 vs 5.6 +/- 4.8; p < 0.001); (ii) interictal cluster headache vs controls (5.3 +/- 5.2 vs 3.6 +/- 2.8, p < 0.001); (iii) interictal chronic cluster headache vs interictal ECH in bout (5.9 +/- 0.5 vs 3.8 +/- 0.5, p = 0.009), and (iv) interictal episodic cluster headache in bout vs episodic cluster headache out-of-bout (5.2 +/- 5.5 vs. 3.7 +/- 4.3, p < 0.001). Subjective visual hypersensitivity was reported by 110/121 (91%; 9 missing) participants with cluster headache and was mostly unilateral in 70/110 (64%) and ipsilateral to the ictal pain in 69/70 (99%) participants.Conclusion Cluster headache is associated with increased ictal and interictal visual sensitivity. In contrast to migraine, this is mostly unilateral and ipsilateral on the side of the ictal pain.Paroxysmal Cerebral Disorder

Cold extremities in migraine: a marker for vascular dysfunction in women

Background and purpose: Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self-reported cold extremities were investigated as a marker for vascular dysfunction in migraine. Secondly, it was hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency. Methods: In this case–control study, a random sample of 1084 migraine patients and 348 controls (aged 22–65 years) from the LUMINA migraine cohort were asked to complete questionnaires concerning cold extremities, sleep quality and migraine. Results: A total of 594 migraine patients and 199 controls completed the questionnaires. In women, thermal discomfort and cold extremities (TDCE) were more often reported by migraineurs versus controls (odds ratio 2.3, 95% confidence interval 1.4–3.7; P < 0.001), but not significantly so in men (odds ratio 2.5, 95% confidence interval 0.9–6.9; P = 0.09). There was no difference in TDCE comparing migraine with or without aura. Female migraineurs who reported TDCE had higher attack frequencies compared to female migraineurs without TDCE (4 vs. 3 attacks per month; P = 0.003). The association between TDCE and attack frequency was mediated by the presence of difficulty initiating sleep (P = 0.02). Conclusion: Women with migraine more often reported cold extremities compared with controls, possibly indicating a sex-specific vascular vulnerability. Female migraineurs with cold extremities had higher attack frequencies, partly resulting from sleep disturbances. Future studies need to demonstrate whether cold extremities in female migraineurs are a predictor for cardiovascular and cerebrovascular events

Assessing cortical involvement in stretch reflex response using subthreshold TMS

In movement control cortical signals are integrated with afferent feedback from reflexes. Disturbed integration is suggested to underlie many movement disorders. Cortical and afferent signals can integrate in the spinal cord and at supraspinal centres, though the exact location and mechanism of integration are unknown yet. The goal of this study is to assess the cortical involvement during the stretch reflex response. Mechanically induced stretches of the muscle flexor carpi radialis where combined with subthreshold transcranial magnetic stimulation (TMS, 97% of active motor threshold) at interstimulus intervals ranging from 35 to 80 ms. Muscle response was measured using high-density electromyography (EMG), providing additional spatial muscle activation patterns. Magnitude of resulting EMG reflex activity, i.e. short (M1, 20-50 ms) and long (M2, 55-100 ms) latency reflex responses were compared to stretch-only trials. Subthreshold TMS was found to significantly increase the stretch evoked EMG response (p < 0.001) when TMS pulses were timed to arrive at the muscle in the time window of the M2 response. Absence of facilitation of the spinally mediated M1 response indicates that integration of cortical and afferent feedback signals in M2 occurs at a supraspinal level. Spatial muscle activation patterns of suprathreshold TMS were consistent over trials, while spatial patterns due to stretch reflexes were less consistent. Spatial patterns of combined trials are therefore not conclusive about the mechanism of integration.BMEBioMechanical EngineeringMechanical, Maritime and Materials Engineerin

TMS Brain Mapping in Less Than Two Minutes

Paroxysmal Cerebral Disorder

Visual hypersensitivity in patients treated with anti-calcitonin gene-related peptide (receptor) monoclonal antibodies

ObjectiveTo evaluate the effect of treatment with anti-calcitonin gene–related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine.BackgroundIncreased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light-aversive behavior.MethodsIn this prospective follow-up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L-VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e-diary, treatment effectiveness was assessed in weeks 9–12 compared to a 4-week pre-treatment baseline period. L-VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L-VISS scores and the reduction in monthly migraine days (MMD) was investigated.ResultsAt 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L-VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L-VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L-VISS (β = 0.2, p = 0.010) and the reduction in ictal L-VISS (β = 0.3, p = 0.001).ConclusionA decrease in visual hypersensitivity in patients with migraine after treatment with anti-CGRP (receptor) antibodies is positively associated with clinical response on migraine.Paroxysmal Cerebral Disorder

Visual sensitivity in migraine: development and validation of the visual sensitivity questionnaire

Paroxysmal Cerebral Disorder

Quantifying visual allodynia across migraine subtypes: the Leiden Visual Sensitivity Scale

Scientific Assessment and Innovation in Neurosurgical Treatment Strategie