Giuseppe Giglia

Modulatory effects of low‐ and high‐frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation

The aim of the present study was to explore further the effects of light deprivation (LD) on visual cortex excitability. Healthy subjects reporting reliable induction of phosphenes by occipital transcranial magnetic stimulation (TMS) underwent 60 min of complete LD. Phosphene threshold (PT) was measured before (T0), after 45 min (T1) and 60 min (T2) of LD, and then every 10 min after light re‐exposure until recovery to T0 values. Repetitive TMS (rTMS) (at 1 or 10 Hz) was applied in separate sessions during the last 15 min of LD. PTs significantly decreased after 45 min of LD. rTMS differentially modified the effects of 60 min LD on PTs depending on stimulation frequency. One hertz rTMS did not change the decreasing of PT values as observed in baseline condition, but significantly prolonged the time to recover T0 PT values after light re‐exposure. By contrast, 10 Hz rTMS significantly increased PT and the time to recover T0 PT values after light re‐exposure was shortened. The results of this study show that the modulatory effects of different rTMS frequencies on visual cortex critically depend on the pre‐existing excitability state of inhibitory and facilitatory circuits, and provide novel insights into the neurophysiological changes that take place in the visual cortex following functional visual deafferentation.

Levetiracetam in the prophylaxis of migraine with aura : A 6-month open-label study

Objective: To evaluate the efficacy of levetiracetam as prophylactic treatment for migraine with aura with high frequency of attacks. Background: Migraine with aura with high frequency of attacks could represent a very demanding therapeutic problem. Efficacy of the antiepileptic drug, lamotrigine, has been reported in this form of migraine. Levetiracetam is a new antiepileptic drug with an excellent tolerability profile. Mechanisms of action of this drug remain largely unknown, but recently, it has been shown to exert inhibitory effects on neuronal-type calcium channels. Methods: We performed a small open-label trial treating 16 patients affected by migraine with aura with high frequency of attacks. After a 1-month run-in period, patients were treated with levetiracetam at a dosage of 1000 mg/d for 6 months. Results: The number of attacks per month was significantly reduced during the first month (compared with run-in; P < 0.001), and it was reduced further during the second (second month vs first month; P < 0.001) and the third months (third month vs second month; P < 0.001) of the treatment. This improvement persisted unchanged for the remaining 3 months of treatment. In 7 (44%) of the 16 patients, the attacks were completely abolished after 3 months of treatment. Severity of headache and duration of headache and aura were also significantly reduced at the third and sixth months of treatment (P < 0.001). Levetiracetam was well tolerated (6 patients complained of slight dizziness, nervousness, and somnolence). Conclusions: Levetiracetam seems to be a safe and effective treatment for migraine with aura. Controlled trials are needed to confirm the observed results.

1 Hz rTMS enhances extrastriate cortex activity in migraine Evidence of a reduced inhibition

We recently reported a paradoxical facilitatory effect of 1 Hz repetitive TMS (rTMS) on the primary visual cortex in migraine possibly due to the failure of inhibitory circuits, unable to be upregulated by low frequency rTMS. To investigate if inhibitory circuit dysfunction extends beyond striate cortex in migraine with aura, we studied the effects of 1 Hz rTMS over the right extrastriate cortex on perception of illusory contours in these patients. Low-frequency rTMS enhanced activity of extrastriate cortex in migraineurs, speeding up reaction times on illusory contour perception. This finding supports the view of a failure of inhibitory circuits also involving the extrastriate cortex in migraine with aura.

A Case Study of Primary Progressive Aphasia: Improvement on Verbs After rTMS Treatment

This case-report shows that high frequency repetitive Transcranial Magnetic Stimulation (hf-rTMS), applied to the left prefrontal cortex, may improve the linguistic skills in Primary Progressive Aphasia (PPA). The patients performance was evaluated on a battery of language production and memory span tasks, before and after two hf-rTMS treatments and one SHAM treatment. We observed a significant and lasting improvement of the patients performance on verb production following the application of hf-rTMS versus Baseline and SHAM conditions. This finding suggests that hf-rTMS may directly strengthen the neural connections within an area of metabolic dysfunction and encourages the use of rTMS as an alternative therapeutic tool for neurodegenerative forms of aphasia.

Low-frequency transcranial magnetic stimulation in patients with cortical dysplasia - a preliminary study.

Sirs: Because of the increasing attention to the potential therapeutic role of repetitive transcranial magnetic stimulation (rTMS) in intractable epilepsy [2, 4], the aim of this study was to find out whether patients with medically refractory epilepsy due to cortical dysplasia could benefit from low-frequency rTMS. 1 Hz rTMS have been able to decrease motor cortex excitability [1]. Lower stimulation frequencies (0,33 and 0.5 Hz) have been successfully employed in the treatment of seizures in humans and experimental animals [2–4]. In this open pilot study we investigated the effect of 0.5 Hz rTMS in four patients (1 M, 3 F mean age 29.5 ± 2.6, range 27–33 years) with very frequent partial and secondary generalized seizures due to a single frontal focus (2 patients: 1a, 2a) or to multiple foci (2 patients: 1b, 2b) of cortical dysplasia evidenced by ictal video-EEG monitoring and MRI. Patients gave their informed consent to participate in the study, which was approved by the local ethics committee. rTMS was performed biweekly for four consecutive weeks by means of a Cadwell high frequency magnetic stimulator with monophasic stimulus configuration (pulse width 200 μs). Each session consisted of 100 pulses at 0.5 Hz frequency delivered at 90 % of motor threshold through a water-cooled eightshaped coil positioned tangential to the scalp with the handle pointing backwards parallel to the midline. Locations for TM stimulation were determined according to 10–20 EEG coordinate system: over the EEG site of focal epileptic activity in patients with single focus and at Cz point (vertex) in patients with multifocal epilepsy. The average stimulus intensity (expressed as % of maximum stimulator output) was 65 ± 3.7 %. Patients tolerated rTMS treatment well and no adverse events were observed. They recorded every definite seizure or any seizure-like event from one month before to one month after the treatment. Patients were on antiepileptic polytherapy with each drug in its therapeutic range (the most effective combination of lamotrigine and sodium valproate in patients with single epileptic focus, and of phenobarbital, carbamazepine and clobazam in patients with multifocal epilepsy). During the study period medication was kept constant. The number of seizures during the month before stimulation (time I) was compared with that of the month during stimulation (time II) and after stimulation (time III). rTMS markedly reduced number and severity of seizures in patients with a single dysplasic focus. The improvement was predominantly in the disappearance of secondary generalization and was still persistent one month after the end of the treatment. The overall number of seizures at times I, II and III was respectively 19,13, and 12 for patient 1a and 19, 11 and 13 for patient 2a (see Fig. 1 A). By contrast, no changes in seizure frequency and severity were observed in patients with multiple foci (the overall number of seizures at times I, II and III was 33, 43, and 27 respectively for patient 1b and 39, 33 and 47 for patient 2b). Our results suggest that a longlasting depression of a cortical dysplasic area may improve intractable epilepsy. Focal phenomena of synaptic plasticity induced by lowfrequency rTMS at the site of stimulation might reduce hyperactivity of the affected hemisphere that would be part of the underlying physiology of the seizure. On such a basis the distance of epileptic foci from the site of stimulation (at the vertex) could explain the inefficacy of the treatment in patients with multifocal epilepsy. In this case it would have been more reasonable to use a non-focal round coil at the vertex to cause a widespread cortical stimulation, but the overheating with the long rTMS trains employed limited its use. On the other hand the effect observed in patients with single focus suggests the opportunity of serial administration of rTMS over each of the dysplasic foci in multifocal epilepsy. These data are preliminary and need to be confirmed by controlled studies with longer follow-up, in larger series of patients.

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.

Abnormal facilitatory mechanisms in motor cortex of migraine with aura

Experimental evidence suggests impairment of inhibitory intracortical circuits in migraine, while not much is known about activity of facilitatory intracortical circuits. In the present work we evaluated the effects of high frequency‐repetitive transcranial magnetic stimulation (hf‐rTMS) on the activity of facilitatory circuits of motor cortex in 18 patients affected by migraine with aura and 18 healthy subjects. Trains of 10 stimuli were applied to the motor cortex at 5‐Hz frequency with recording of the EMG traces from the contralateral abductor pollicis brevis muscle (APB). Two intensities of stimulation (110% and 130% of resting motor threshold) were used in order to explore whether motor cortex excitability was differently modulated. Twelve patients underwent hf‐rTMS both before and during prophylactic treatment with levetiracetam. Results showed that rTMS delivered at 110% intensity of stimulation at rest had a facilitatory effect on MEP size in untreated patients, while left MEP unchanged in controls. Conversely, when rTMS was applied at 130%, we observed MEP potentiation in healthy subjects and paradoxical MEP inhibition in migraineurs. In treated patients, levetiracetam inhibited MEP size at both 110% and 130% intensity of stimulation. Our findings reveal an opposite response of migraine motor cortex to 5‐Hz rTMS when it is delivered at different stimulation intensities, providing evidence of both hyper‐responsivity and self‐limiting hyperexcitability capacity, in line with studies supporting the concept that under conditions of cortical hyperexcitability inhibitory mechanisms of homeostatic plasticity could be activated.

Hemispheric cerebellar rTMS to treat drug-resistant epilepsy: case reports.

Electrical stimulation of the cerebellar cortex by implanted electrodes has been shown to ameliorate refractory epilepsy. We investigated the potential therapeutic role of high-frequency cerebellar rTMS in patients affected by refractory epilepsy due to single or multiple foci. Six patients, three with single and three with multiple epileptic foci, underwent 20 rTMS sessions. Each session was given daily, excluding weekends, and consisted of two trains of 50 stimuli (5 Hz frequency and 90% motor threshold intensity), separated by 50s interval. rTMS was delivered through a focal coil (2 cm below and lateral to the inion) bilaterally in patients with multiple foci (two trains for hemisphere: 100 stimuli each side) and contralaterally to the epileptic focus in the others. Seizure frequency was monitored four weeks before stimulation (pre-rTMS), during the four-week treatment (rTMS) and four weeks after the treatment (post-rTMS). The rTMS over the cerebellar cortex was associated with a significant decrease of rTMS versus pre-rTMS seizure frequency both in patients with single and multiple epileptic foci. However, during the post-rTMS period seizure frequency was back to the pre-rTMS frequency. Although the results are still preliminary, they encourage further studies on larger series of patients. In particular, this rTMS approach, as compared with others, might be more useful in patients with multiple epileptic foci.

High Prevalence and Fast Rising Incidence of Multiple Sclerosis in Caltanissetta, Sicily, Southern Italy

Background: Epidemiological studies conducted in Sicily and Sardinia, the two major Mediterranean islands, showed elevated incidence and prevalence of multiple sclerosis (MS)and a recent increase in disease frequency. Objective: To confirm the central highlands of Sicily as areas of increasing MS prevalence and elevated incidence, we performed a follow-up study based on the town of Caltanissetta (Sicily), southern Italy. Methods: We made a formal diagnostic reappraisal of all living patients found in the previous study performed in 1981. All possible information sources were used to search for patients affected by MS diagnosed according to the Poser criteria. We calculated prevalence ratios, for patients affected by MS who were living and resident in the study area on December 31, 2002. Crude and age- and sex-specific incidence ratios were computed for the period from January 1, 1993, to December 31, 2002. Results: The prevalence of definite MS rose in 20 years from 69.2 (retrospective prevalence rate) to 165.8/100,000 population. We calculated the incidence of definite MS for the period 1970–2000. These rates calculated for 5-year periods increased from 2.3 to 9.2/100,000/year. Conclusion: This survey shows the highest prevalence and incidence figures of MS in the Mediterranean area and confirms central Sicily as a very-high-risk area for MS.

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.