Alleviation of migraine symptoms by application of repetitive peripheral magnetic stimulation to myofascial trigger points of neck and shoulder muscles - A randomized trial

Migraine is a burdensome disease with an especially high prevalence in women between the age of 15 and 49 years. Non-pharmacological, non-invasive therapeutic methods to control symptoms are increasingly in demand to complement a multimodal intervention approach in migraine. Thirty-seven subjects (age: 25.0 +/- 4.1 years;36 females) diagnosed with high-frequency episodic migraine who presented at least one active myofascial trigger point (mTrP) in the trapezius muscles and at least one latent mTrP in the deltoid muscles bilaterally prospectively underwent six sessions of repetitive peripheral magnetic stimulation (rPMS) over two weeks. Patients were randomly assigned to receive rPMS applied to the mTrPs of the trapezius (n = 19) or deltoid muscles (n = 18). Whereas the trapezius muscle is supposed to be part of the trigemino-cervical complex (TCC) and, thus, involved in the pathophysiology of migraine, the deltoid muscle was not expected to interfere with the TCC and was therefore chosen as a control stimulation site. The headache calendar of the German Migraine and Headache Society (DMKG) as well as the Migraine Disability Assessment (MIDAS) questionnaire were used to evaluate stimulation-related effects. Frequency of headache days decreased significantly in both the trapezius and the deltoid group after six sessions of rPMS (trapezius group: p = 0.005;deltoid group: p = 0.003). The MIDAS score decreased significantly from 29 to 13 points (p = 0.0004) in the trapezius and from 31 to 15 points (p = 0.002) in the deltoid group. Thus, rPMS applied to mTrPs of neck and shoulder muscles offers a promising approach to alleviate headache frequency and symptom burden. Future clinical trials are needed to examine more profoundly these effects, preferably using a sham-controlled setting

11th European Headache Federation Congress jointly with 31st Congress of the Italian Society for the Study of Headaches : Rome, Italy. 01-03 December 2017

. Aims of the study were explore the relationship between peripheral chromatic and central visual dysfunction evaluating also the presence of functional receptor impairment in patients with migraine, with and without aura examined interictally

Interrelations between the cerebral cortex and the trigeminal system: studies in healthy subjects and in migraine patients therapeutic perspectives

Understanding migraine pathophysiology is probably the most challenging point in migrainemanagement, since an efficient acute and preventive treatment should rely on clearpathophysiological bases. Migraine is characterized interictally by a lack of habituation ofevoked responses, possibly due to a decreased preactivation level of sensory cortices. Bycontrast, during an attack and in chronic migraine, the preactivation level increases andhabituation normalizes. New neurostimulation techniques could be useful to durably modifythe activation of the underlying cortex, decreasing the repetition of attacks, giving alsoinsight on the pathophysiology of migraine.The visual cortex plays a pivotal role in migraine pathophysiology, but its effect on thetrigeminal nociceptive system remains poorly understood. On the other hand migraine attackis often associated to photophobia, but the pathophysiological relation between headache andthe discomfort to the light, during the ictal but also the interictal phase, is unclear.This thesis puts a new insight into the relation between the visual cortex modulation and theresponse of the trigeminal nociceptive system, showing a possible inhibitory functionalinterrelation between these structures, via thalamic modulation.The hypothesis is based on our first finding investigating the modulation of the visual cortexby the repetitive transcranial magnetic stimulation on the nociceptive blink reflex in healthysubjects and migraine patients.This role of the activation of the visual cortex is also better understood by using the flash lightstimulation, and thanks to the conception of a new device of flash light stimulation, weperformed several protocols in healthy subjects and migraine patient with the final result aproof-of-concept trial using the flash light stimulation in migraine patients

Investigating the migraine premonitory phase:neural networks regulating migraine initiation

Migraine is a highly disabling neurological disorder, with a prevalence of 15-18% worldwide, with a significantly higher incidence in women over men. It is characterised by a periorbital throbbing pain, together with a set of sensory disturbances; known as the premonitory phase, which can start up to 72 hours prior to the pain, and remain up to 48 hrs after pain resolution (postdrome phase). Clinical imaging data has shown central structures such as the hypothalamus and the locus coeruleus to be altered throughout the premonitory phase and in between attacks during resting conditions.Orexinergic networks emerging from the lateral hypothalamus have demonstrated a differential modulatory action over migraine-associated nuclei such as the trigeminocervical complex in in vivo anaesthetised animal models. In this project we sought to further investigate the role of the orexinergic system in the regulation of trigeminal nociception and migraine-related symptoms using cre-dependent AAVapproaches. We observed a significant decrease in periorbital mechanical withdrawal thresholds in orexin-ablated mice, which is reflective of a sensitisation of the trigeminovascular system. This sensitisation was normalised by chronic intranasal orexin A, while further studies identified a potential mechanism of action of orexin A acting via the orexin 1 receptors in the locus coeruleus.Downstream from the hypothalamus; orexinergic projections are known to densely innervate the locus coeruleus, which is the main source of noradrenaline in the central nervous system. Given the potential action of orexin A via the locus coeruleus and its ability to modulate trigeminal nociception we next sought to optimise a novel retrograde canine-adenovirus 2 (CAV2) vector to permit chemogenetic activation of locus coeruleus noradrenergic neurons in freely behaving rats. Clozapine-N-oxide-mediated activation of these noradrenergic neurons inhibited trigeminal nociception, while pilot work in awake rats highlighted increased mechanical withdrawal thresholds following locus coeruleus activation.Together, the data in this thesis highlights the potential importance of hypothalamic orexinergic and locus coeruleus noradrenergic mechanisms in trigeminal nociception and migraine associated symptomatology (premonitory symptoms). Our data specifically highlights the therapeutic potential of orexin A, targeted activation of the orexin 1 receptor and noradrenergic signalling as potential therapeutic strategies that have the potential to modulate migraine-related neural circuits likely responsible for increased attack susceptibility.<br/

Psychological and psychophysical aspects of spatial orientation.

These studies were undertaken to investigate the psychological and psychophysical factors that mediate spatial orientation/disorientation in both healthy and patient populations. PERCEPTION OF ANGULAR VELOCITY: Using a new method of examining perception of rotation this study found a similarity between the sensation and ocular responses following velocity step stimuli. Both decayed exponentially with a time constant of circa 15 seconds following rotation in yaw; circa 7 seconds following rotation in roll. Both the ocular and sensation responses were significantly reduced following repeated vestibular and optokinetic stimulation. The test was conducted with patients suffering from congenital nystagmus, ophthalmoplegia or cerebellar lesions, all of whom had markedly reduced post-rotational sensation responses of approximately 7 to 9 seconds. ADAPTATION TO OSCILLOPSIA: Labyrinthine defective subjects were found to prefer less self- motion when viewing a moving video-image than either ophthalmoplegia subjects or normal controls. The results suggest that adaptation to oscillopsia may be related to an active approach to recovery (i.e. high external locus of control) and also to increased tolerance to retinal slip. This serves to illustrate the coactive role of psychological and psychophysical mechanisms in adaptation to vestibular disorders. INVESTIGATION OF PSYCHOLOGICAL AND PSYCHOSOCIAL FACTORS: This questionnaire- based study aimed to examine adjustment to illness in patients with balance disorders and with congenital nystagmus. The study identified a greater use of emotion-focused coping strategies than problem-focused strategies. It highlighted the prevaience of anxiety and depression among these patients and pointed towards several psychosocial variables (locus of control, self-esteem and social support) that play a significant role in the coping behaviour of these patients. MENSTRUATION, MIGRAINE AND MOTION SICKNESS: The relationship between hormonal cycles and migraine and motion sickness is poorly understood. The study demonstrated that motion sickness and headache occurred independently although exposure to rough seas could be a specific migraine trigger in certain individuals who did not otherwise suffer attacks. Female subjects were more prone to motion sickness around the period of menstruation and less so around ovulation

The genetics and pathophysiology of cluster headache and associated disorders

Cluster headache (CH) is described as one of the most painful conditions known to humans. It effects approximately 60,000 individuals in the UK and carries significant morbidity. It exhibits hereditability evident by reports of familial aggregation and is categorised as a trigeminal autonomic cephalalgia (TAC). Despite this, the exact pathophysiological and genetic drivers of this condition remain elusive. The purpose of this thesis is to examine the clinical and genetic determinants of CH, and thus gain insights into the underlying neurobiological mechanisms. This work consists of two components. In the first section, I conduct clinical observational studies to further delineate the CH phenotype. I address the postulated association between pituitary adenomas and CH and question the utility of dedicated pituitary imagining in this patient group. I also describe the largest series of Post-Traumatic Headache of Cluster Headache (PTH-CH) and demonstrate its distinct features and increased intractability to treatment. Finally, through meta-analysis, I estimate the prevalence of familial CH to be 6.27% and demonstrate an overlap with concurrent short-Lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) in familial cases. The second section explores the genetics architecture underlying CH. I perform a Genome-Wide Association Study (GWAS) to identify replicable susceptibility loci and conduct a downstream analysis. Subsequent genetic correlation analysis showed an overlap with migraine, depression, bipolar and sleep disturbance implying the possibility of a common genetic driver for these conditions, which frequently present concurrently. I then carry out linkage analysis in CH families and replicate a linked region suggestive of significance on chromosome 2 that also overlaps a genome wide significant locus. Finally, I execute whole exome sequencing and utilise rare variant association tests and segregation analysis to identify causal variants for familial CH

Understanding migraine

Better characterisation of migraine is critical to enhancing its diagnosis, assessment and, ultimately, effective treatments. The aim of this thesis was to better characterise migraine through more detailed investigation of selected headache-related factors and to compare these factors with those seen in other commonly occurring recurrent headaches. The factors investigated in this thesis were neurochemical profile, cervical musculoskeletal impairments, and patient experience, represented by pain and disability characteristics, emotional state and other personal factors. This thesis provides deeper information regarding the nature and characteristics of migraine compared with non-migraine headaches (tension-type and cervicogenic headaches). This thesis has established the potential of GABA as a biomarker for migraine and implies the possible role of GABA in the disease process. This thesis has also characterised migraine according to cervical musculoskeletal impairments and patient experience embodying disability, pain, central sensitisation, and other personal factors. The implications for clinical practice are to assess cervical musculoskeletal impairments and patient experience to facilitate differential diagnosis and prognostication, and to educate patients on the nature of their headaches. Findings from the thesis may also be used by guideline developers, providing stimulus for further discussions on the definition of migraine and reporting of participant selection criteria, with reference to this definition, in clinical trials. Future research directions are identified in validating GABA as a migraine biomarker and elucidating its pathophysiology. By characterising migraine more fully, findings from this thesis will inform the development of effective treatments that could possibly target GABA or clinical characteristics found to be present in migraine. Ultimately this should achieve better health outcomes for people with migraine