Background and Aims:

It is believed that the hypothalamus plays an important role during the prodromal phase of a migraine attack. Less is known about the role played by the hypothalamus during the pain-free period and its relationship with the different neurocognitive networks that were previously involved in migraine pathophysiology.

Methods:

We collected MRI data from 20 untreated migraines without aura between attacks (MO) and 20 healthy controls (HC). We studied fractional anisotropy, mean (MD), radial (RD), and axial diffusivity of the hypothalamus from diffusion tensor imaging (DTI). Moreover, from resting-state functional MRI, we estimated Higuchi’s fractal dimension (FD), an index of temporal complexity sensible to describe non-periodic patterns characterizing BOLD signature. Finally, we correlated neuroimaging data with migraine clinical features.

Results:

In comparison to HC, MO had significantly higher MD and RD values within the hypothalamus. Patients showed higher FD values within the salience network (SN) and the cerebellum, and lower FD values within the primary visual (PV) network compared to HC. In patients, the higher the cerebellar and SN FD values, the higher the severity of migraine.

Conclusions:

Our study shows that the hypothalamus carries structural abnormalities between migraine attacks, which may be part of the neuroanatomical basis favoring the beginning of the prodromal phase and, therefore, the ignition of an attack. The peculiar fractal dimensionality we found in PV, SN, and cerebellum may reflect an abnormal efficiency demand of brain networks devoted to the integration of sensory, emotional, and cognitive information related to the severity of migraine.

Background and Aims:

Surrounding environment perception can be studied using sound-induced flash illusions (SIFI): single flashes presented with two or more beeps are perceived as multiple flashes (fission illusion); the extent of such illusions is associated to changes in visual cortical excitability, known to be altered in migraineurs. We aim to evaluate SIFI changes in migraineurs after three months erenumab therapy.

Methods:

We selected chronic migraineurs (CMs) without aura who started erenumab therapy (140mg monthly) and healthy subjects (HSs) of similar age. A software showed transient flashes with concurrent beeps. Participants counted flashes seen (5 tests randomly presented several times: 1FxB, x from 0 to 4; F=flash, B=beep). Patients were examined at baseline (t0) and after 3 months treatment (t3). Comparisons were performed through rmANOVAs with a Duncan’s test for post-hoc analysis.

Results:

30 CMs (mean age 50yrs+1.8; 24F), and 30 HSs (25F) were enrolled. HSs referred a higher number of flashes compared to CMs at baseline (p=0.0002) and at t3 (p<0.0001). Differently, no significant changes of SIFI scores were observed in patients between t0 and t3 (p=0.4393, graph 1). However, single comparisons showed a significant increase of 1F4B scores (p=0.0280).

Conclusions:

As expected, CMs showed less fission illusions than HSs. 3-month erenumab 140 mg therapy did not restore normal fissions illusions in CMs, even if a slight effect was observed for 1F4B condition. Visual cortical hyperexcitability of CMs patients may be disease-pertinent and, as such, hardly modifiable by treatment; alternately, more time is needed for such changes to occur.

Background and Aims:

Previous studies on brain morphologiy in chronic cluster headache (CCH) revealed inconsistent findings, maybe due to limitations of VBM. We investigated telencephalic and cerebellar cortical thickness in CCH patients employing two highly robust state-of-the-art approaches for thickness estimation (Freesurfer and CERES).

Methods:

CCH patients (n=28; 23 males; age 45±11.7) and sex- and age-matched healthy individuals were scanned with a 3T-MRI for 3D-T1 images. No other pain, vascular or psychiatric comorbidities were admitted.

We used Freesurfer version 6 to obtain surface-based individual telencephalic cortical thickness estimates. CCH and controls were compared with a vertex-wise between-group analysis. Results were considered significant with a vertex-wise threshold of p<0.001 and a cluster-wise threshold of 50 mm².

The mean cortical thickness of the bilateral anterior, posterior and flocculonodular cerebellar lobes were computed with the automated pipeline CERES software, and compared between CCH and controls with two-tailed t-tests. Results were considered significant with a p<0.05, with Holm-Bonferroni correction.

Results:

CCH patients showed significant cortical thinning in the right midcingulate cortex (MCC,p<0.0001), the left posterior insula (postIC,p=0.0003), the left superior temporal sulcus (STS, p<0.0001) and the left collateral/lingual sulcus (CLS, p=0.0001).

No differences were found in cerebellar cortical thickness.

Conclusions:

In this study CCH patients show abnormalities in key regions of pain processing (MCC, postIC), belonging to the spino-thalamo-cortical tract involved in sensory-motivational aspects of nociception.

CCH patients also had alterations in areas involved in social cognition (STS, CLS) a possible expression of behavioral/psychological vulnerability of CCH patients.

Acknowledgements

This work was supported by the Italian Ministry of Health (RF-2016-02364909)

Background and Aims:

OnabotulinumtoxinA (BoNT-A) proved effective in the prevention of chronic migraine in large pivotal trials.

In this exploratory, open label, single-arm trial (NCT 04578782 clinicaltrials.gov) we evaluated the efficacy and safety of BoNT-A (Allergan-AbbVie) in the prevention of high-frequency episodic migraine (HFEM, 8-14 migraine days/month in the previous 3 months).

Methods:

We enrolled 32 HFEM subjects (age 44.8±11.9 yrs, 11.0±2.2 migraine days,11.5±2.1 headache days, 7 females). After a 28-day baseline period, subjects underwent 4 subsequent BoNT-A treatments according to the PREEMPT paradigm, delivered 12 weeks apart. The primary outcome measure was the monthly migraine days (MMD) reduction in the 12-week period after the last BoNT-A treatment as compared to baseline.

Results:

BoNT-A reduced the number of MMD by 3.68 days (-33.1%, p<0.01). Thirthy-nine % of the patients experienced a >50% reduction in MMD. BoNT-A significantly reduced also the number of headache days (-33.9%, p<0.01) and the intake of acute medications (-22.9%, p=0.03). Disability and QoL scores improved markedly (MIDAS -41.7%, p<0.01 and MSQ -31.7%, p<0.01). Adverse events were transient and mild-to-moderate in severity. Only one patient discontinued the study due to a cutaneous adverse reaction.

Conclusions:

BoNT-A administered according to the PREMPT paradigm proved effective in the preventive treatment of HFEM. This observation may have important clinical implications since HFEM subjects are a population at high risk of chronification and/or medication overuse.

Financial support

This study is an investigator-initiated research study partially supported by Allergan – Abbvie

Background and Aims:

Evaluating the efficacy of one-year treatment with erenumab in a cohort of patients with chronic migraine, with and without medication overuse headache, who previously failed at least 3 preventive therapies.

Methods:

We analyzed 82 patients (F59, M23, mean age:49.5+9.8, chronic migraine history: 12.9+10.7yrs). The most represented comorbidities (59%) were psychiatric conditions (e.g. depression and anxiety). Erenumab (70-140mg) was administered monthly for 13 treatments (T1 through T13). Our primary outcome measure was the pattern reversal of migraine from chronic to episodic. Thirteen patients(16%) interrupted treatment, 11 subjects for poor efficacy, after a mean of 7.3 months. We collected clinical data on headache features (diaries), disability (MIDAS, HIT-6), allodynia, anxiety and depression scales (questionnaires) at baseline and quarterly.

Results:

Patients with a pattern reversal from chronic to episodic migraine (i.e.>50%responders) were 33.3% at T1, rising to 71% at T13(Fig.1). Super-responders (i.e.>75%responders) were 9.7% at T1 reaching 34.3% at T13. A significant improvement in migraine days and symptomatic intake was detected already at T1 and persisted over the one-year treatment(Fig.2). An improvement in MIDAS and HIT-6 scores was detected from T3(p<0.001), while allodynia intensity decreased significantly from T6(p<0.001)(Fig.3) and anxiety and depression scores after T9 (HADS-A p=0.03,HADS-D p=0.01). Mild side effects were reported by 50% of patients (predominantly constipation, cutaneous reactions and fatigue).

Conclusions:

Erenumab induced a high percentage of pattern reversal in difficult-to-treat patients with chronic migraine. Reduction of monthly migraine days was already significant after the 1^st month of treatment, other clinical parameters improved significantly over time. Erenumab benefit persisted for the entire treatment period.

Background and Aims:

Abnormal cortical excitability has a role in migraine but the link with beginning and stop of migraine attacks remains unclear. Critical insight could come by excitability changes across the migraine cycle. Here we explore it through sound induced flash illusions (SIFI). SIFI are cross-modal illusory percepts critically dependent on visual cortical excitability (less illusions=increased excitability) that have been found to be altered in episodic and chronic migraine(1-2).

Methods:

We performed SIFI on 108 patients with episodic migraine without aura (mean age 38; 60 females) and 24 healthy controls. Patients were studied across migraine cycle: 24 during the postictal phase, 20 ictal, 20 interictal, 20 preictal. SIFI were performed presenting a single flash accompanied by multiple beeps to evoke a “fission” illusion (see multiple flashes), and multiple flashes accompanied by a single beep to evoke a “fusion” illusion (less flashes seen).

Results:

We found a significant decrease of the number of fission illusions during the preictal phase compared to the interictal one (p<.03) and during the postictal phase compared to the interictal one (p<.01). Furthermore, fission illusions were reduced in patients observed interictally than in controls (p<.01). As reduced illusions mean increased excitability, excitability, that interictally is greater than controls, increases further in preictal phase, reaches a maximum during attack, and then decreases till to the lowest interictally.

Conclusions:

The study shows a “cortical excitability” cycle, close to the clinical migraine cycle, supporting the idea that increasing cortical excitability could be well at the basis of both attacks susceptibility and precipitation in migraine disease.

Background and Aims:

The structural substrates enabling functional communications among brain connectome, characterized by high stability and reproducibility, have not been investigated in migraine by means of graph analysis approach.
We hypothesize that a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas involved in pain perception, processing and modulation may characterize migraine patients.

Methods:

We investigated, using high angular resolution diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain “connectome”, a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared with 91 healthy controls.

Results:

We observed in migraine patients: i) higher local and global network efficiency (p< 0.001) and ii) higher local and global clustering coefficient (p< 0.001). Moreover, we found changes in the hubs topology in migraine patients: i) posterior cingulate cortex and inferior parietal lobule assuming the hub role and ii) fronto-orbital cortex, involved in emotional aspects, and the visual areas, involved in migraine pathophysiology, losing the hub role. Finally, we found a higher connection probability (edges) between cortical nodes involved in pain perception as well as in cognitive and affective attribution of pain experiences, in migraine patients (p< 0.001).

Conclusions:

The imbalance between the need of investing resources to promote network efficiency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients’ susceptibility to triggers. Such change in connectome topography suggest an intriguing pathophysiological model of migraine as brain “connectopathy”.