Expression pattern of matrix metalloproteinases-2 and -9 and their tissue inhibitors in patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Matrix metalloproteinases (MMPs) are a heterogeneous family of endopeptidases that play a role in many physiological functions, including the immune response. An imbalance between the activity of MMPs and their physiological tissue inhibitors (TIMPs) has been proposed in the pathophysiology of different autoimmune disorders. We aimed to assess the plasmatic levels of MMP-2, MMP-9, and their inhibitors TIMP-1 and -2 in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). SUBJECTS AND METHODS: Twenty patients with CIDP and 20 age- and sex-matched healthy controls were enrolled. Plasma concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined by the enzyme-linked immunosorbent assay. RESULTS: CIDP subjects had higher MMP-9 concentrations along with TIMP-1 downregulation when compared to controls, with the consequent increase in the MMP-9/TIMP-1 ratio (p<0.000002 for all measures). Conversely, the concentration of MMP-2 was lower in the CIDP group (p<0.01) without changes in the TIMP-2 concentration. The MMP-2/TIMP-2 ratio was decreased in the patients' group (p<0.02). DISCUSSION: We provide first preliminary evidence that the plasmatic pattern of MMPs and TIMPs is markedly altered in patients with CIDP. Future studies are needed to assess the potential usefulness of these new biomarkers in the clinical setting.

Atypical CIDP: diagnostic criteria, progression and treatment response. Data from the Italian CIDP Database.

OBJECTIVES: A few variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been described, but their frequency and evolution to typical CIDP remain unclear. To determine the frequency and characteristics of the CIDP variants, their possible evolution to typical CIDP, and treatment response. METHODS: We applied a set of diagnostic criteria to 460 patients included in a database of Italian patients with CIDP. Clinical characteristics and treatment response were reviewed for each patient. The Kaplan-Meier curve was used to estimate the progression rate from atypical to typical CIDP. RESULTS: At the time of inclusion, 376 (82%) patients had a diagnosis of typical CIDP while 84 (18%) had atypical CIDP, including 34 (7%) with distal acquired demyelinating symmetric neuropathy (DADS), 17 (4%) with purely motor, 17 (4%) with Lewis-Sumner syndrome (LSS) and 16 (3.5%) with purely sensory CIDP. Based on retrospective review of the symptoms and signs present at onset and for at least 1 year, 180 (39%) patients had an initial diagnosis compatible with atypical CIDP that in 96 (53%) patients evolved to typical CIDP. Mean disease duration was longer in patients evolving to typical CIDP than in those not evolving (p=0.0016). Patients with DADS and LSS had a less frequent response to immunoglobulin than those with typical CIDP, while patients with purely motor and sensory CIDP had a similar treatment response. CONCLUSIONS: The proportion of patients with atypical CIDP varies during the disease course. DADS and LSS have a less frequent response to intravenous immunoglobulin compared with typical CIDP, raising the possibility of a different underlying pathogenetic mechanism.

Application of tRNS to improve multiple sclerosis fatigue: a pilot, single-blind, sham-controlled study.

We evaluated the effects of transcranial random noise stimulation (tRNS) on fatigue in 17 subjects with relapsing-remitting multiple sclerosis with low physical disability. Two different patient groups underwent real or sham stimulation for 10 days, targeting the primary motor cortex of the dominant side or contralateral to the most compromised limb. In the 'real group', beneficial effects were observed using the Modified Fatigue Impact Scale (p = 0.04; physical subscale: p = 0.03), the subscales 'change in health' (p = 0.006) and 'role limitations due to physical problems' (p = 0.001) of the Multiple Sclerosis Quality of Life-54, and by assessing the patient impression of perceived fatigue (p = 0.005).

Preliminary experience with a transcranial magnetic resonance-guided focused ultrasound surgery system integrated with a 1.5-T MRI unit in a series of patients with essential tremor and Parkinson's disease.

OBJECTIVE Transcranial magnetic resonance-guided focused ultrasound surgery (tcMRgFUS) is one of the emerging noninvasive technologies for the treatment of neurological disorders such as essential tremor (ET), idiopathic asymmetrical tremor-dominant Parkinson's disease (PD), and neuropathic pain. In this clinical series the authors present the preliminary results achieved with the world's first tcMRgFUS system integrated with a 1.5-T MRI unit. METHODS The authors describe the results of tcMRgFUS in a sample of patients with ET and with PD who underwent the procedure during the period from January 2015 to September 2017. A monolateral ventralis intermedius nucleus (VIM) thalamic ablation was performed in both ET and PD patients. In all the tcMRgFUS treatments, a 1.5-T MRI scanner was used for both planning and monitoring the procedure. RESULTS During the study period, a total of 26 patients underwent tcMRgFUS thalamic ablation for different movement disorders. Among these patients, 18 were diagnosed with ET and 4 were affected by PD. All patients with PD were treated using tcMRgFUS thalamic ablation and all completed the procedure. Among the 18 patients with ET, 13 successfully underwent tcMRgFUS, 4 aborted the procedure during ultrasound delivery, and 1 did not undergo the tcMRgFUS procedure after stereotactic frame placement. Two patients with ET were not included in the results because of the short follow-up duration at the time of this study. A monolateral VIM thalamic ablation in both ET and PD patients was performed. All the enrolled patients were evaluated before the treatment and 2 days after, with a clinical control of the treatment effectiveness using the graphic items of the Fahn-Tolosa-Marin tremor rating scale. A global reevaluation was performed 3 months (17/22 patients) and 6 months (11/22 patients) after the treatment; the reevaluation consisted of clinical questionnaires, neurological tests, and video recordings of the tests. All the ET and PD treated patients who completed the procedure showed an immediate amelioration of tremor severity, with no intra- or posttreatment severe permanent side effects. CONCLUSIONS Although this study reports on a small number of patients with a short follow-up duration, the tcMRgFUS procedure using a 1.5-T MRI unit resulted in a safe and effective treatment option for motor symptoms in patients with ET and PD. To the best of the authors' knowledge, this is the first clinical series in which thalamotomy was performed using tcMRgFUS integrated with a 1.5-T magnet.

Intracortical facilitation within the migraine motor cortex depends on the stimulation intensity. A paired-pulse TMS study.

INTRODUCTION: Connectivity within the primary motor cortex can be measured using the paired-pulse transcranial magnetic stimulation (TMS) paradigm. This evaluates the effect of a first conditioning stimulus on the motor evoked potential (MEP) elicited by a second test stimulus when different interstimulus intervals are used. Aim of the present study was to provide, in patients suffering from migraine without aura (MwoA), additional information on intracortical facilitation (ICF), short intracortical inhibition (SICI), and long intracortical inhibition (LICI), using different intensities of the test stimulus (TS). METHODS: We enrolled 24 patients with episodic MwoA and 24 age- and sex-matched healthy volunteers. Both patients and controls were randomly assigned to two different experimental groups: the first group underwent evaluation of ICF, while in the second group we assessed SICI and LICI. All these measures were assessed by using three different suprathreshold intensities of the TS (110%, 130% and 150% of the resting motor threshold, RMT). Interstimulus intervals (ISIs) of 10 ms were used for testing ICF, while SICI and LICI were carried out by using 2 ms and 100 ms ISIs respectively. All migraine patients underwent the experimental protocol while in the interictal pain-free state. RESULTS: A main finding of the study was that an increased ICF could be seen in migraineurs as compared to the healthy subjects only by using a 110% intensity of the TS. Instead, no significant differences were observed between patients and controls as regards both measures of intracortical inhibition. CONCLUSION: We show that hyperresponsivity of the glutamatergic intracortical circuits can be detected in the migraine motor cortex only by applying a low suprathreshold intensity of stimulation. Our results strengthen the notion that, to be reliable, the assessment of cortical excitability in migraine should always include evaluation of the cortical response to different stimulation intensities.

Motor cortex tRNS improves pain, affective and cognitive impairment in patients with fibromyalgia: preliminary results of a randomised sham-controlled trial.

OBJECTIVES: Fibromyalgia (FM) is a clinical syndrome characterised by widespread musculoskeletal pain, chronic fatigue, cognitive deficits, and sleep and mood disorders. The effectiveness of most pharmacological treatments is limited, and there is a need for new, effective and well-tolerated therapies. It has recently been shown that transcranial direct-current stimulation (tDCS) of the motor cortex reduces pain, and that tDCS of the dorso-lateral prefrontal cortex (DLPFC) improves anxiety, depression and cognitive impairment in FM patients. The new technique of transcranial random noise stimulation (tRNS) using randomly changing alternating currents has very recently been shown to improve working memory and pain in limited series of patients with FM or neuropathic pain. The aim of this study was to investigate the clinical effects of primary motor cortex (M1) tRNS in FM patients. METHODS: Twenty female FM patients aged 26-67 years were randomised to undergo active (real) or placebo (sham) tRNS sessions on five days a week (Monday-Friday) for two weeks. Each patient was evaluated before and after treatment using a visual analogue scale (VAS), the Fibromyalgia Impact Questionnaire (FIQ), the Hospital Anxiety and Depression Scale (HADS), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT), the Forward and Backward Digit Span test, and the FAS verbal fluency test. RESULTS: In comparison with sham treatment, active tRNS of M1 induced a general improvement in the clinical picture of FM, with a significant reduction in pain, depression, anxiety and FIQ scores and a significant improvement in TMT (A), RAVLT and FAS scores. CONCLUSIONS: These findings suggest that tRNS of M1 can be very effective in relieving FM symptoms. Unlike motor cortex tDCS, it seems to counteract both pain and cognitive disturbances, possibly because the invoked mechanism of stochastic resonance synchronises neural firing and thus leads to more widespread and lasting effects.

Ipsilesional and contralesional regions participate in the improvement of poststroke aphasia: a transcranial direct current stimulation study.

In the past few years, noninvasive cerebral stimulations have been used to modulate language task performance in healthy and aphasic patients. In this study, a dual transcranial direct current stimulation (tDCS) on anterior and posterior language areas was applied for 2 weeks to a patient with a possible crossed aphasia following a right hemisphere stroke. Inhibitory cathodal stimulation of the right Brodmann areas (BA) 44/45 and simultaneous anodal stimulation of the left BA 44/45 improved the patient's performance in picture naming. Conversely, the same bilateral montage on BA 39/40 did not produce any significant improvement; finally, electrode polarity inversion over BA 39/40 yielded a further improvement compared with the first anterior stimulation. Our findings suggest that ipsilesional and contralesional areas could be useful in poststroke functional reorganization and provide new evidences for the therapeutic value of tDCS in aphasia.

Social cognition dysfunctions in patients with epilepsy: Evidence from patients with temporal lobe and idiopathic generalized epilepsies.

BACKGROUND AND AIM: Despite an extensive literature on cognitive impairments in focal and generalized epilepsy, only a few number of studies specifically explored social cognition disorders in epilepsy syndromes. The aim of our study was to investigate social cognition abilities in patients with temporal lobe epilepsy (TLE) and in patients with idiopathic generalized epilepsy (IGE). MATERIALS AND METHODS: Thirty-nine patients (21 patients with TLE and 18 patients with IGE) and 21 matched healthy controls (HCs) were recruited. All subjects underwent a basic neuropsychological battery plus two experimental tasks evaluating emotion recognition from facial expression (Ekman-60-Faces test, Ek-60F) and mental state attribution (Story-based Empathy Task, SET). In particular, the latter is a newly developed task that assesses the ability to infer others' intentions (i.e., intention attribution - IA) and emotions (i.e., emotion attribution - EA) compared with a control condition of physical causality (i.e., causal inferences - CI). RESULTS: Compared with HCs, patients with TLE showed significantly lower performances on both social cognition tasks. In particular, all SET subconditions as well as the recognition of negative emotions were significantly impaired in patients with TLE vs. HCs. On the contrary, patients with IGE showed impairments on anger recognition only without any deficit at the SET task. DISCUSSION: Emotion recognition deficits occur in patients with epilepsy, possibly because of a global disruption of a pathway involving frontal, temporal, and limbic regions. Impairments of mental state attribution specifically characterize the neuropsychological profile of patients with TLE in the context of the in-depth temporal dysfunction typical of such patients. CONCLUSION: Impairments of socioemotional processing have to be considered as part of the neuropsychological assessment in both TLE and IGE in view of a correct management and for future therapeutic interventions.

Electrophysiological Investigations of Shape and Reproducibility of Oropharyngeal Swallowing: Interaction with Bolus Volume and Age.

Electrophysiological assessment provides valuable information on physiological and pathophysiological characteristics of human swallowing. Here, new electrophysiological measures for the evaluation of oropharyngeal swallowing were assessed: (1) the activation pattern of the submental/suprahyoid EMG activity (SHEMG); (2) the reproducibility of the oral and pharyngeal phases of swallowing, by calculating the similarity index (SI) of the SHEMG (SI-SHEMG) and of the laryngeal-pharyngeal mechanogram (SI-LPM) during repeated swallows; and (3) kinesiological measures related to the LPM. An electrophysiological-mechanical method for measuring the activation pattern of the SHEMG, the SI-SHEMG, and the SI-LPM, and maximal LPM velocity and acceleration during swallowing was applied in 65 healthy subjects divided into three age groups (18-39, 40-59, 60 years or over). All the measures were assessed during three trials of eight consecutive swallows of different liquid bolus volumes (3, 12, and 20 ml). A high overall reproducibility of oropharyngeal swallowing in healthy humans was recorded. However, while values of SI-SHEMG were similar in all the age groups, the SI-LPM was found to fall significantly in the older age group. Both the SI-SHEMG and the SI-LPM were found to fall with increasing bolus volumes. The activation pattern of the SHEMG and the LPM kinesiological measures were differently modified by bolus volume and age in the older subjects with respect to the others. We describe a new approach to the electrophysiological study of swallowing based on computed semi-automatic analyses. Our findings provide insight into some previously uninvestigated aspects of oropharyngeal swallowing physiology, considered in relation to bolus volume and age. The new electrophysiological measures here described could prove useful in the clinical setting, as it is likely that they could be differently affected in patients with different kinds of dysphagia.

Transcranial direct current stimulation for treatment of freezing of gait: a cross-over study.

BACKGROUND AND OBJECTIVE: Progression of Parkinson's disease (PD) is frequently characterized by the occurrence of freezing of gait (FOG) representing a disabling motor complication. We aim to investigate safety and efficacy of transcranial direct current stimulation of the primary motor cortex of PD patients with FOG. METHODS: In this cross-over, double-blind, sham-controlled study, 10 PD patients with FOG persisting in "on" state underwent anodal and sham direct current stimulation for 5 consecutive days. Clinical assessment over a 1-month period was performed. RESULTS: A significant improvement of gait, as assessed by the Stand Walk Sit test, with reduction in number and duration of FOG episodes, along with a significant reduction in the Unified Parkinson's Disease Rating Scale score, were observed after anodal stimulation. Beneficial effects were more evident after the entire 5-day stimulation session, and persisted until the end of the observation period. CONCLUSIONS: Anodal transcranial direct current stimulation of the motor cortex is safe and has therapeutic potential in PD patients with FOG.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: Twenty-two MwA patients and 20 patients with migraine without aura (MwoA) underwent trains of 5-Hz repetitive transcranial magnetic stimulation at an intensity of 130% of the resting motor threshold, both at baseline and after conditioning by 15 minutes of cathodal or anodal tDCS. Motor cortical responses to the hf-rTMS trains were compared with those of 14 healthy subjects. RESULTS: We observed abnormal inhibitory responses to the hf-rTMS trains given at baseline in both MwA and MwoA patients as compared with the healthy subjects (P < .00001).The main result of the study was that cathodal tDCS, which reduces the cortical excitability level, but not anodal tDCS, which increases it, restored the normal facilitatory response to the hf-rTMS trains in both MwA and MwoA. CONCLUSIONS: The present findings strengthen the notion that, in migraine with and without aura, the threshold for inducing inhibitory mechanisms of cortical excitability might be lower in the interictal period. This could represent a protective mechanism counteracting cortical hyperresponsivity. Our results could be helpful to explain some conflicting neurophysiological findings in migraine and to get insight into the mechanisms underlying recurrence of the migraine attacks.

Pediatric Migraine and Visual Cortical Excitability: A Prospective Observational Study with Sound-Induced Flash Illusions.

The pathophysiological mechanisms underlying migraine are more difficult to investigate in children than in the adult population. Abnormal cortical excitability turns out to be one of the most peculiar aspects of migraine, accounting for the manifestations of migraine attacks. Recently, visual cortical excitability has been explored effectively in adult migraineurs with a technique based on cross-modal audio-visual illusions (with sound-induced flash illusions (SIFIs) being reduced in migraineurs compared to non-migraineur subjects). On such a basis, in this study, we investigated visual cortical excitability in children with migraine using SIFIs using combinations of visual and sound stimuli presented randomly. We evaluated 26 children with migraine without aura and 16 healthy children. Migraineurs did not differ from the age-matched healthy subjects regarding fission or fusion illusions but perceived more flashes in trials of multiple flashes with or without beeps. The higher number of SIFIs in migraineur children compared to adults may be due to a greater propensity of visual stimulation to be driven by auditory stimuli (i.e., acoustic dominance). The increased ability to perceive flashes reveals a hyperfunctional visual cortex, demonstrating that the use of SIFIs is a valid tool for assessing visual cortical responsiveness even in pediatric migraine.

Transcranial direct current stimulation preconditioning modulates the effect of high-frequency repetitive transcranial magnetic stimulation in the human motor cortex.

Experimental studies emphasize the importance of homeostatic plasticity as a mean of stabilizing the properties of neural circuits. In the present work we combined two techniques able to produce short-term (5-Hz repetitive transcranial magnetic stimulation, rTMS) and long-term (transcranial direct current stimulation, tDCS) effects on corticospinal excitability to evaluate whether and how the effects of 5-Hz rTMS can be tuned by tDCS preconditioning. Twelve healthy subjects participated in the study. Brief trains of 5-Hz rTMS were applied to the primary motor cortex at an intensity of 120% of the resting motor threshold, with recording of the electromyograph traces evoked by each stimulus of the train from the contralateral abductor pollicis brevis muscle. This interventional protocol was preconditioned by 15 min of anodal or cathodal tDCS delivered at 1.5 mA intensity. Our results showed that motor-evoked potentials (MEPs) increased significantly in size during trains of 5-Hz rTMS in the absence of tDCS preconditioning. After facilitatory preconditioning with anodal tDCS, 5-Hz rTMS failed to produce progressive MEP facilitation. Conversely, when 5-Hz rTMS was preceded by inhibitory cathodal tDCS, MEP facilitation was not abolished. These findings may give insight into the mechanisms of homeostatic plasticity in the human cerebral cortex, suggesting also more suitable applications of tDCS in a clinical setting.

Frovatriptan versus almotriptan for acute treatment of menstrual migraine: analysis of a double-blind, randomized, cross-over, multicenter, Italian, comparative study.

The objective of the study was to compare the efficacy and safety of frovatriptan and almotriptan in women with menstrually related migraine (IHS Classification of Headache disorders) enrolled in a multicenter, randomized, double-blind, cross-over study. Patients received frovatriptan 2.5 mg or almotriptan 12.5 mg in a randomized sequence: after treating 3 episodes of migraine in no more than 3 months with the first treatment, the patient was switched to the other treatment. 67 of the 96 female patients of the intention-to-treat population of the main study had regular menstrual cycles and were thus included in this subgroup analysis. 77 migraine attacks classified as related to menses were treated with frovatriptan and 78 with almotriptan. Rate of pain relief at 2 and 4 h was 36 and 53 % for frovatriptan and 41 and 50 % for almotriptan (p = NS between treatments). Rate of pain free at 2 and 4 h was 19 and 47 % with frovatriptan and 29 and 54 % for almotriptan (p = NS). At 24 h, 62 % of frovatriptan-treated and 67 % of almotriptan-treated patients had pain relief, while 60 versus 67 % were pain free (p = NS). Recurrence at 24 h was significantly (p < 0.05) lower with frovatriptan (8 vs. 21 % almotriptan). This was the case also at 48 h (9 vs. 24 %, p < 0.05). Frovatriptan was as effective as almotriptan in the immediate treatment of menstrually related migraine attacks. However, it showed a more favorable sustained effect, as shown by a lower rate of migraine recurrence.

Impact of COVID-19 in AChR Myasthenia Gravis and the Safety of Vaccines: Data from an Italian Cohort.

BACKGROUND AND AIMS: Patients with Myasthenia gravis (MG) are considered vulnerable as they may present with respiratory muscle weakness and because they are on immunosuppressive treatment; thereby, COVID-19 may have a detrimental effect on these patients. Vaccines against COVID-19 are currently available and it has been shown as they can prevent severe COVID-19 in vulnerable patients. Notwithstanding their efficacy, vaccine hesitancy has not been completely dispelled in the general population. Unfortunately, there is limited data about the safety of these vaccines in MG patients. The aims of this study are to evaluate the impact of COVID-19 in a MG cohort, the adherence to COVID-19 vaccination in Italy and vaccine safety in MG patients. METHODS: A retrospective cohort study of MG patients attending the Neuromuscular Clinic of the University Hospital "Paolo Giaccone" of Palermo, Italy, was performed. Patients underwent telephone interviews with a dedicated questionnaire on SARS-CoV-2 vaccination and infection. Vaccine safety was assessed though the evaluation of vaccine-related adverse events (AEs) and comparisons of MG-ADL scores before and after vaccination. Patient worsening was defined as two or more point increases in MG-ADL scores. RESULTS: From a total of 90 participants, 75 answered the questionnaire and 70.5% of them (n = 53) received the vaccine; ten patients did not receive vaccination and 3 patients were partially vaccinated. Among the vaccinated patients, about 45% (n = 24) experienced at least one AE, with a complete resolution within one week. No serious AEs and life-threatening conditions were observed. Globally, MG-ADL scores did not worsen after vaccination. Nine unvaccinated patients experienced SARS-CoV2 infection and four of them (44%) died-one patient required respiratory support, whereas three patients were asymptomatic. CONCLUSIONS: COVID-19 significantly impacted MG patients with an increase in mortality due to respiratory sequelae. Vaccines against SARS-CoV-2 showed good short-term safety in MG patients, who may take advantage of vaccination to avoiding life-threatening complications such as COVID-19 pneumonia.

Metalloproteinases and Tissue Inhibitors in Generalized Myasthenia Gravis. A Preliminary Study.

INTRODUCTION: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have recently been proposed as promising biomarkers in different immune-mediated disorders. We evaluated the plasma levels of MMP-9 and MMP-2 and their tissue inhibitors TIMP-1 and TIMP-2 in a patients' cohort with generalized myasthenia gravis (MG). METHODS: Plasma concentrations of MMP-9, MMP-2, TIMP-1 and TIMP-2 were evaluated in 14 patients with generalized MG and 13 age- and sex-matched healthy controls. The severity of disease was assessed by the modified Osserman classification. RESULTS: Compared to the healthy subjects, MG patients had increased plasma concentrations of MMP-9, but reduced plasma levels of MMP-2 and TIMP-1. MG patients also showed a positive correlation between MMP-2 concentrations and disease severity. An increase in MMP-9 levels and MMP-9/TIMP-1 ratio and a decrease in MMP-2 levels and MMP-2/TIMP-2 ratio were detected in patients with generalized MG. Higher levels of MMP-2 correlated with greater disease severity. DISCUSSION: Our preliminary findings suggest that MMPs and TIMPs could play a role in the pathogenesis of MG and might be associated with the risk of clinical deterioration.

Impaired glutamatergic neurotransmission in migraine with aura? Evidence by an input-output curves transcranial magnetic stimulation study.

OBJECTIVE: An imbalance between activity of inhibitory and facilitatory intracortical circuits could play a central role in migraine etiology. We used input-output curves to achieve further information about intracortical excitability of motor cortex in migraine with aura. METHODS: Input-output curves were measured in the right abductor pollicis brevis muscle at rest in 12 patients suffering from migraine with aura and 8 healthy subjects. Stimuli were delivered at intensity ranging from 100% to 160% of resting motor threshold with 10-second inter-stimulus intervals. Seven patients were studied before and during treatment with levetiracetam. RESULTS: Results showed a greater motor-evoked potential amplitude in response to increasing intensity of stimuli in patients compared to controls (P < .02). This increased facilitatory effect was abolished by levetiracetam (P < .005). CONCLUSIONS: Our findings support the hypothesis of an interictal cortical hyper-responsivity in migraine patients that appears to be normalized by levetiracetam. This effect could support the potential therapeutic role of levetiracetam in migraine with aura prevention.

Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex.

Evidence by functional imaging studies suggests the role of left dorsolateral prefrontal cortex (DLPFC) in the inhibitory control of nociceptive transmission system. Repetitive transcranial magnetic stimulation (rTMS) is able to modulate pain response to capsaicin. In the present study, we evaluated the effect of DLPFC activation (through rTMS) on nociceptive control in a model of capsaicin-induced pain. The study was performed on healthy subjects that underwent capsaicin application on right or left hand. Subjects judged the pain induced by capsaicin through a 0-100 VAS scale before and after 5 Hz rTMS over left and right DLPFC at 10 or 20 min after capsaicin application in two separate groups (8 subjects each). Left DLPFC-rTMS delivered either at 10 and 20 min after capsaicin application significantly decreased spontaneous pain in both hands. Right DLPFC rTMS showed no significant effect on pain measures. According to these results, stimulation of left DLPFC seems able to exert a bilateral control on pain system, supporting the critical antinociceptive role of such area. This could open new perspectives to non-invasive brain stimulation protocols of alternative target area for pain treatment.

A double-blind, randomized, multicenter, Italian study of frovatriptan versus almotriptan for the acute treatment of migraine.

The objective of this study was to evaluate patients' satisfaction with acute treatment of migraine with frovatriptan or almotriptan by preference questionnaire. One hundred and thirty three subjects with a history of migraine with or without aura (IHS 2004 criteria), with at least one migraine attack in the preceding 6 months, were enrolled and randomized to frovatriptan 2.5 mg or almotriptan 12.5 mg, treating 1-3 attacks. The study had a multicenter, randomized, double blind, cross-over design, with treatment periods lasting <3 months. At study end patients assigned preference to one of the treatments using a questionnaire with a score from 0 to 5 (primary endpoint). Secondary endpoints were pain free and pain relief episodes at 2 and 4 h, and recurrent and sustained pain free episodes within 48 h. Of the 133 patients (86%, intention-to-treat population) 114 of them expressed a preference for a triptan. The average preference score was not significantly different between frovatriptan (3.1 ± 1.3) and almotriptan (3.4 ± 1.3). The rates of pain free (30% frovatriptan vs. 32% almotriptan) and pain relief (54% vs. 56%) episodes at 2 h did not significantly differ between treatments. This was the case also at 4 h (pain free: 56% vs. 59%; pain relief: 75% vs. 72%). Recurrent episodes were significantly (P < 0.05) less frequent under frovatriptan (30% vs. 44%), also for the attacks treated within 30 min. No significant differences were observed in sustained pain free episodes (21% vs. 18%). The tolerability profile was similar between the two drugs. In conclusion, our study suggests that frovatriptan has a similar efficacy of almotriptan in the short-term, while some advantages are observed during long-term treatment.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: modulatory effects on motor cortex excitability.

Evidence by functional imaging studies suggests the role of left DLPFC in the inhibitory control of nociceptive transmission system. Pain exerts an inhibitory modulation on motor cortex, reducing MEP amplitude, while the effect of pain on motor intracortical excitability has not been studied so far. In the present study, we explored in healthy subjects the effect of capsaicin-induced pain and the modulatory influences of left DLPFC stimulation on motor corticospinal and intracortical excitability. Capsaicin was applied on the dorsal surface of the right hand, and measures of motor corticospinal excitability (test-MEP) and short intracortical inhibition (SICI) and facilitation (ICF) were obtained by paired-pulse TMS on left motor cortex. Evaluations were made before and at different times after capsaicin application in two separate sessions: without and with high-frequency rTMS of left DLPF cortex, delivered 10 min. after capsaicin application. We performed also two control experiments to explore: 1: the effects of Left DLPFC rTMS on capsaicin-induced pain; 2: the modulatory influence of left DLPFC rTMS on motor cortex without capsaicin application. Capsaicin-induced pain significantly reduced test MEP amplitude and decreased SICI leaving ICF unchanged. Left DLPFC rTMS, together with the analgesic effect, was able to revert the effects of capsaicin-induced pain on motor cortex restoring normal MEP and SICI levels. These data support the notion that that tonic pain exerts modulatory influence on motor intracortical excitability; the activation of left DLPFC by hf rTMS could have analgesic effects, reverting also the motor cortex excitability changes induced by pain stimulation.