Roberta Baschi

Cyclical changes of cortical excitability and metaplasticity in migraine: evidence from a repetitive transcranial magnetic stimulation study.

Summary Insight is provided into the pathophysiological mechanisms underlying the abnormal regulation of cortical function and its periodicity in episodic and chronic migraine. ABSTRACT The primary brain dysfunctions leading to the onset of a migraine attack remain largely unknown. Other important open questions concern the mechanisms of initiation, continuation, and termination of migraine pain, and the changes in brain function underlying migraine transformation. Brief trains of high‐frequency repetitive transcranial magnetic stimulation (rTMS), when applied to the primary motor cortex at suprathreshold intensity (≥120% of resting motor threshold [RMT]), elicit in healthy subjects a progressive, glutamate‐dependent facilitation of the motor evoked potentials (MEP). Conversely, in conditions of increased cortical excitability, the rTMS trains induce inhibitory MEP responses likely mediated by cortical homeostatic mechanisms. We enrolled 66 migraine‐without‐aura patients, 48 migraine‐with‐aura patients, 14 patients affected by chronic migraine (CM), and 20 healthy controls. We assessed motor cortical response to 5‐Hz rTMS trains of 10 stimuli given at 120% RMT. Patients with episodic migraine were studied in different phases of the migraine cycle: interictal, preictal, ictal, and postictal states. Results showed a facilitatory MEP response during the trains in patients evaluated in the preictal phase, whereas inhibitory responses were observed during and after a migraine attack, as well as in CM patients. In the interictal phase, different responses were observed, depending on attack frequency: facilitation in patients with low and inhibition in those with high attack recurrence. Our findings suggest that changes in cortical excitability and fluctuations in the threshold for inhibitory metaplasticity underlie the migraine attack recurrence, and could be involved in the process of migraine transformation.

Visual cortex hyperexcitability in migraine in response to sound-induced flash illusions

Objective: Sound-induced flash illusions depend on visual cortical excitability. In this study, we explored whether sound-induced flash illusions are perceived differently in migraine, a condition associated with pathologic cortical hyperexcitability. Methods: Sound-induced flash illusions were examined in 59 migraine patients (mean age = 32 ± 16 years; 36 females), 32 without aura and 27 with aura, and in 24 healthy controls (mean age = 42 ± 17 years; 16 females). Patients were studied during attacks and interictally. Visual stimuli (flashes) accompanied by sounds (beeps) were presented in different combinations: a single flash with multiple beeps was given to induce the perception of multiple flashes (“fission” illusion), and multiple flashes with a single beep were used to reduce the number of perceived flashes (“fusion” illusion). Results: For migraineurs, the fission illusion was reduced, especially during the attack, and almost abolished when a single flash was combined with 2 beeps (except for those without aura tested interictally); the fusion illusion was less consistently reported in both migraine groups, but not completely disrupted. Conclusions: Results from this study add novel clues to our understanding of visual cortex hyperexcitability in migraine, especially migraine with aura. Furthermore, these analyses underscore how pathologic changes in cortical excitability affect multisensory interactions. Cross-modal illusions represent a valid tool for exploration of functional connectivity between sensory areas, which likely has an important role in the pathophysiology of migraine.

Reduced threshold for inhibitory homeostatic responses in migraine motor cortex? A tDCS/TMS study.

Neurophysiological studies in migraine have reported conflicting findings of either cortical hyper‐ or hypoexcitability. In migraine with aura (MwA) patients, we recently documented an inhibitory response to suprathreshold, high‐frequency repetitive transcranial magnetic stimulation (hf‐rTMS) trains applied to the primary motor cortex, which is in contrast with the facilitatory response observed in the healthy subjects. The aim of the present study was to support the hypothesis that in migraine, because of a condition of basal increased cortical responsivity, inhibitory homeostatic‐like mechanisms of cortical excitability could be induced by high magnitude stimulation. For this purpose, the hf‐rTMS trains were preconditioned by transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique able to modulate the cortical excitability state.

Genetic epidemiology of autosomal recessive hypercholesterolemia in Sicily: Identification by next-generation sequencing of a new kindred

BACKGROUND Autosomal recessive hypercholesterolemia (ARH) is a rare inherited lipid disorder. In Sardinia, differently from other world regions, the mutated allele frequency is high. It is caused by mutations in the low-density lipoprotein receptor adaptor protein 1 gene. Fourteen different mutations have been reported so far; in Sardinia, 2 alleles (ARH1 and ARH2) explain most of the cases. Four ARH patients, all carriers of the ARH1 mutation, have been identified in mainland Italy and 2 in Sicily. OBJECTIVE The objectives of the study were to improve the molecular diagnosis of familial hypercholesterolemia (FH) and to estimate the frequency of the ARH1 allele in 2 free-living Sicilian populations. METHODS We sequenced by targeted next-generation sequencing 20 genes related to low-density lipoprotein metabolism in 50 hypercholesterolemic subjects. Subjects from 2 free-living populations from Northern (Ventimiglia Heart Study, 848 individuals) and Southern Sicily (Zabut Zabùt Aging Project, 1717 individuals) were genotyped for ARH1 allele. RESULTS We identified 1 homozygous carrier of the ARH1 mutation among the 50 hypercholesterolemic outpatients. Population-based genotyping of ARH1 in 2565 subjects allowed the identification of 1 heterozygous carrier. The overall estimated allele frequency of ARH1 in Sicily was 0.0002 (0.02%). CONCLUSIONS The identification of a new case of ARH in Sicily among 50 clinically diagnosed FH highlights the importance of next-generation sequencing analysis as tool to improve the FH diagnosis. Our results also indicate that ARH1 carrier status is present in ∼1:2500 of Sicilian inhabitants, confirming that ARH is extremely rare outside Sardinia.

O047. The sound-induced flash illusions reveal visual cortex hyperexcitability in cluster headache

Objectives Pathophysiology of cluster headache (CH) is not wellknown. Although posterior hypothalamus has been suggested to play a pivotal role, evidence exists of a more diffuse involvement of the central nervous system including brainstem and cerebral cortex. In this regard, we recently observed increased motor cortical excitability in episodic CH patients both outside and inside bout [1]. The sound-induced flash illusions (SIFI) represent an example of multisensory integration, and provide a tool to indirectly explore the excitability state of the visual cortex [2]. SIFI are classified as “fission” and “fusion” illusions. When one visual stimulus (flash) is accompanied by two or more auditory stimuli (beeps), it is often perceived as multiple flashes (fission illusion). Conversely, fusion illusion occurs when subjects perceive less number of flashes when these are presented with only one beep. On such bases, here we used SIFI to explore excitability of visual cortex in CH patients.

O069. Menstrual cycle affects cortical excitability differently in females with migraine and in healthy controls: a new perspective by cross modal sound induced flash illusions

The sound-induced flash illusions (SIFI) represent a valid tool to explore multimodal perception and are critically dependent on visual and acoustic cortical excitability [1, 2]. In a previous study [3], we observed a significant reduction of illusions in migraine patients with respect to healthy controls, probably due to a condition of visual cortex hyperexcitability. Aim of the present study was to evaluate SIFI perceptions in healthy women and patients with menstrual migraine and to describe the effects of cyclical change of steroid hormones and cortical responsiveness.

P072. The visual cortical excitability in pediatric migraine as tested by sound-induced flash illusions

Objectives Sound-induced flash illusions (SIFI) depend on visual cortex (V1) excitability [1]. In adults with migraine, in response to visual-acoustic illusions, V1 is hyperexcitable [2]. Susceptibility to SIFI is increased in children than adults. During childhood there is a change in sensory dominance: acoustic dominant switching to a visual [3]. Here we used SIFI to evaluate V1 excitability in children with migraine assessing also age-related differences in cross-modal audio-visual perception.

O046. Color vision and visual cortex excitability are impaired in episodic migraine. Simply coexisting or pathophysiologically related dysfunctions

Background and objectives Evidence of abnormal color vision processing in migraine comes from observation of positive symptoms during visual aura, effects of strong color contrast triggering attacks and of colored-spectacles reducing migraine frequency. Although the central or peripheral basis of such color misperception remains unclear, several authors reported a selective deficit of shortwavelength cones (S-cones) [1]. Sound-induced flash illusions (SIFI) are a simple way to describe visual distorsion induced by acoustic perception. SIFI critically depend on excitability of primary visual cortex (V1) as they are reduced by facilitatory anodal transcranial direct current stimulation (tDCS) over V1 in healthy subjects [2]. We observed diminished SIFI in episodic migraine patients, especially in those with aura (MA) and during the attack [3] in agreement with the hypothesis of visual cortex hyperexcitability. Aim of the present study was to explore the potential correlation between cones dysfunction (evaluated by colorimetric scales) and visual cortex hyperexcitability (tested by SIFI) in episodic migraine without aura patients (MoA). Materials and methods Twenty-two MoA patients (4 M; mean age 35.8±11.1 years) and 12 unimpaired healthy volunteers with no family history of migraine (9 M; mean age 27.7±13.2 years) were enrolled. Migraine patients were tested interictally. None of the patients enrolled had taken any prophylactic drug during the 3 months prior to the

EHMTI-0337. Visual evoked potential abnormalities in migraineurs: is there a correlation with alpha power and photic driving on the EEG?

Results Twenty-two patients were in interictal and 15 in(peri) ictal phase. As described before, PR-VEP habituation tended to be reduced between attacks and overall the habituation deficit was associated with lower initial PRVEP amplitude. Between attacks, power of the 20Hz frequency band during photic stimulation, i.e. photic driving, tended to be lower (p=0.08) and baseline alpha power higher (p = 0.06). Photic driving was also positively correlated with PR-VEP amplitudes and negatively with PR-VEP habituation (p < 0.05). During attacks, alpha power was associated with increased PR-VEP habituation (p < 0.05).

EHMTI-0220. Cortical excitability in episodic cluster headache

Methods Twenty-five patients with episodic CH and thirteen healthy subjects underwent an experimental session where we evaluated, in both hemispheres, motor-cortical response to: 1) single-pulse TMS: i.e. motor threshold (MT); input-output (IO) curves and cortical silent period (CSP) and 2) paired-pulse TMS: i.e. intracortical facilitation (ICF) and short intracortical inhibition (SICI). Thirteen patients were evaluated outside bout, while the remaining twelve patients were inside bout at the time of recording.