Vittorio Frasca

Ovarian hormones and cortical excitability. An rTMS study in humans

OBJECTIVE Ovarian steroids influence neural excitability. Using repetitive transcranial magnetic stimulation (rTMS) we investigated changes in cortical excitability during the menstrual cycle. METHODS Eight women underwent rTMS on Days 1 and 14 of the menstrual cycle. As a control group, 8 age-matched men were also tested twice, with a 14-day interval between the two experimental sessions. Repetitive magnetic pulses were delivered in trains of 10 stimuli (5 Hz frequency and 120% of the motor threshold calculated at rest) to the left motor area of the first dorsal interosseous muscle. RESULTS In women, the motor evoked potential (MEP) size did not increase on Day 1, but it increased progressively during the train on Day 14. The duration of the silent period progressively lengthened during the train on both days. In men the MEP increased in size, and the silent period lengthened to a similar extent on both days. CONCLUSIONS In women, hormone changes related to the menstrual cycle alter cortical excitability. SIGNIFICANCE Low estrogen levels probably reduce cortical excitability because their diminished action on sodium channels reduces recruitment of excitatory interneurons during rTMS thus abolishing the MEP facilitation.

Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: A functional and anatomical study

Functional MRI (fMRI) studies have shown increased activation of ipsilateral motor areas during hand movement in patients with multiple sclerosis (MS). We hypothesized that these changes could be due to disruption of transcallosal inhibitory pathways. We studied 18 patients with relapsing‐remitting MS. Conventional T1‐ and T2‐weighted images were acquired and lesion load (LL) measured. Diffusion tensor imaging (DTI) was performed to estimate fractional anisotropy (FA) and mean diffusivity (MD) in the body of the corpus callosum (CC). fMRI was obtained during a right‐hand motor task. Patients were studied to evaluate transcallosal inhibition (TCI, latency and duration) and central conduction time (CCT). Eighteen normal subjects were studied with the same techniques. Patients showed increased MD (P < 0.0005) and reduced FA (P < 0.0005) in the body of the CC. Mean latency and duration of TCI were altered in 12 patients and absent in the others. Between‐group analysis showed greater activation in patients in bilateral premotor, primary motor (M1), and middle cingulate cortices and in the ipsilateral supplementary motor area, insula, and thalamus. A multivariate analysis between activation patterns, structural MRI, and neurophysiological findings demonstrated positive correlations between T1‐LL, MD in the body of CC, and activation of the ipsilateral motor cortex (iM1) in patients. Duration of TCI was negatively correlated with activation in the iM1. Our data suggest that functional changes in iM1 in patients with MS during a motor task partially represents a consequence of loss of transcallosal inhibitory fibers. Hum Brain Mapp, 2006.

Altered response to rTMS in patients with Alzheimer's disease

OBJECTIVE In this study, we tested the excitability of cortical motor areas in patients with Alzheimers disease. Because repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability, possibly by inducing a short-term increase in synaptic efficacy, we used rTMS to investigate motor cortex excitability in patients with Alzheimers disease. METHODS We tested the changes in the size and threshold of motor evoked potential (MEP) and cortical silent period (CSP) duration evoked by focal rTMS delivered in 10 trains of 10 stimuli at 5Hz frequency and 120% rMth intensity in a group of patients with Alzheimers disease, and age-matched controls. In a further session, rTMS was also delivered at 1Hz frequency (trains of 10 stimuli, 120% rMth). RESULTS Whereas in control subjects, 5Hz-rTMS elicited normal MEPs that progressively increased in size during the train, in patients, it elicited MEPs that decreased in size. The increase in the duration of the CSP was similar in patients and healthy controls. One hertz rTMS left the MEP amplitude unchanged in patients and healthy controls. CONCLUSIONS The lack of MEP facilitation reflects an altered response to 5Hz-rTMS in patients with Alzheimers disease. SIGNIFICANCE Our rTMS findings strongly suggest an altered cortical plasticity in excitatory circuits within motor cortex in patients with Alzheimers disease.

Enhanced brain motor activity in patients with MS after a single dose of 3,4-diaminopyridine

Background: 3,4-Diaminopyridine (3,4-DAP), a potassium (K+) channel blocker, improves fatigue and motor function in multiple sclerosis (MS). Although it was thought to do so by restoring conduction to demyelinated axons, recent experimental data show that aminopyridines administered at clinical doses potentiate synaptic transmission. Objective: To investigate motor cerebral activity with fMRI and transcranial magnetic stimulation (TMS) after a single oral dose of 3,4-DAP in patients with MS. Methods: Twelve right-handed women (mean ± SD age 40.9 ± 9.3 years) underwent fMRI on two separate occasions (under 3,4-DAP and under placebo) during a simple motor task with the right hand. FMRI data were analyzed with SPM99. After fMRI, patients underwent single-pulse TMS to test motor threshold, amplitude, and latency of motor evoked potentials, central conduction time, and the cortical silent period; paired-pulse TMS to investigate intracortical inhibition (ICI) and intracortical facilitation (ICF); and quantitative electromyography during maximal voluntary contraction. Results: FMRI motor-evoked brain activation was greater under 3,4-DAP than under placebo in the ipsilateral sensorimotor cortex and supplementary motor area (p < 0.05). 3,4-DAP decreased ICI and increased ICF; central motor conduction time and muscular fatigability did not change. Conclusion: 3,4-DAP may modulate brain motor activity in patients with MS, probably by enhancing excitatory synaptic transmission.

Differences in short-term primary motor cortex synaptic potentiation as assessed by repetitive transcranial magnetic stimulation in migraine patients with and without aura

&NA; To find out more about glutamatergic and gabaergic transmission in migraine, in this study we investigated glutamate‐dependent short‐term synaptic potentiation and GABA‐dependent inhibitory cortical interneuron excitability as assessed by 5 Hz‐rTMS delivered over primary motor cortex (M1) (motor evoked potential, MEP, amplitude facilitation and cortical silent period, CSP, duration lengthening) in migraine patients with (MA) and without aura (MwoA) and healthy controls. We studied 37 patients with migraine (19 MA and 18 MwoA) and 19 healthy control subjects. 5 Hz‐rTMS was delivered at 120% resting motor threshold to the hand motor area of the left hemisphere with the target muscle at rest and during contraction. Three of the MA patients were also tested at the end of visual aura during a spontaneous migraine attack. ANOVA showed that the MEP significantly increased in size and CSP significantly lengthened during 5 Hz‐rTMS in the three groups tested. The 5 Hz‐rTMS‐induced MEP facilitation differed significantly being highest in MA patients. In the three patients tested both ictally and interictally the MEP increased during the interictal session but remained unchanged when the visual aura ended. Our study shows that the neurophysiological feature that differentiates MA patients from MwoA patients and healthy controls is an abnormal M1 susceptibility to 5 Hz‐rTMS both outside and during the attack suggesting that glutamate‐dependent short‐term M1 cortical potentiation patterns differ in migraine with and without aura.

Acute and chronic effects of ethanol on cortical excitability

OBJECTIVE We designed this study to find out whether 5Hz repetitive transcranial magnetic stimulation (rTMS) would disclose changes in cortical plasticity after acute intake of ethanol and in patients with chronic alcohol consumption. METHODS Ten stimuli-5Hz-rTMS trains were applied over the primary motor cortex in 10 healthy subjects before and after acute ethanol intake and in 13 patients with chronic ethanol abuse, but negative blood ethanol levels when studied. The motor evoked potential (MEP) amplitude and the cortical silent period (CSP) duration during the course of rTMS trains were measured. Short-interval intracortical inhibition (3ms) and intracortical facilitation (10ms) were studied by paired-pulse TMS in 4 healthy subjects and 4 patients. RESULTS In healthy subjects before and after acute ethanol intake, 5Hz-rTMS produced a significant increase in the MEP size and CSP duration during rTMS. The first CSP in the train was significantly longer after than before ethanol intake. In patients 5Hz-rTMS failed to produce the normal MEP facilitation but left the CSP increase unchanged. CONCLUSIONS Acute and chronic ethanol intake alters cortical excitability and short-term plasticity of the primary motor cortex as tested by the MEP size facilitation and CSP lengthening after 5Hz-rTMS. SIGNIFICANCE This finding suggests that rTMS is a valid tool for investigating the effects of ethanol on cortical plasticity in humans.

Synaptic potentiation induced by rTMS: effect of lidocaine infusion

Repetitive transcranial magnetic stimulation (rTMS) delivered at various intensities and frequencies excites cortical motor areas. Trains of stimuli (at 5-Hz frequency, and suprathreshold intensity) progressively increase the size of motor evoked potentials (MEPs) and the duration of the cortical silent period (CSP) in normal subjects. Because antiepileptic drugs, acting mainly on sodium channels, depress MEP facilitation during rTMS, we suggested that rTMS trains facilitate the MEP size by inducing synaptic potentiation primarily involving voltage-gated sodium channels. The aim of this study was to evaluate the effect of lidocaine—a drug that acts selectively on sodium channels—on the rTMS-induced changes in cortical excitability. We tested the changes in motor threshold, MEP size, CSP duration evoked by focal rTMS and the M-wave amplitude in healthy subjects before and after lidocaine infusion. Lidocaine abolished the normal rTMS-induced facilitation of MEPs but left the other rTMS variables and the M-wave unchanged. Our results suggest that the MEP facilitation related to rTMS-induced synaptic potentiation results from an increase in cortical excitatory interneuron excitability that involves voltage-gated sodium channels.

Cannabinoid-induced effects on the nociceptive system: A neurophysiological study in patients with secondary progressive multiple sclerosis

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients’ electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control.

Assistive Device With Conventional, Alternative, and Brain-Computer Interface Inputs to Enhance Interaction With the Environment for People With Amyotrophic Lateral Sclerosis: A Feasibility and Usability Study

OBJECTIVE To evaluate the feasibility and usability of an assistive technology (AT) prototype designed to be operated with conventional/alternative input channels and a P300-based brain-computer interface (BCI) in order to provide users who have different degrees of muscular impairment resulting from amyotrophic lateral sclerosis (ALS) with communication and environmental control applications. DESIGN Proof-of-principle study with a convenience sample. SETTING An apartment-like space designed to be fully accessible by people with motor disabilities for occupational therapy, placed in a neurologic rehabilitation hospital. PARTICIPANTS End-users with ALS (N=8; 5 men, 3 women; mean age ± SD, 60 ± 12 y) recruited by a clinical team from an ALS center. INTERVENTIONS Three experimental conditions based on (1) a widely validated P300-based BCI alone; (2) the AT prototype operated by a conventional/alternative input device tailored to the specific end-users residual motor abilities; and (3) the AT prototype accessed by a P300-based BCI. These 3 conditions were presented to all participants in 3 different sessions. MAIN OUTCOME MEASURES System usability was evaluated in terms of effectiveness (accuracy), efficiency (written symbol rate, time for correct selection, workload), and end-user satisfaction (overall satisfaction) domains. A comparison of the data collected in the 3 conditions was performed. RESULTS Effectiveness and end-user satisfaction did not significantly differ among the 3 experimental conditions. Condition III was less efficient than condition II as expressed by the longer time for correct selection. CONCLUSIONS A BCI can be used as an input channel to access an AT by persons with ALS, with no significant reduction of usability.

Is the cutaneous silent period an opiate-sensitive nociceptive reflex?

In humans, high‐intensity electrical stimuli delivered to the fingers induce an inhibitory effect on C7–T1 motoneurons. This inhibitory reflex, called the cutaneous silent period (CSP) is considered a defense response specific for the human upper limbs. It is not clear whether the CSP—like other defense responses such as the corneal reflex and the R III reflex—is an opiate‐sensitive nociceptive reflex. Because opiates suppress some, but not all, nociceptive reflexes, we studied the effect of the narcotic‐analgesic drug fentanyl on the CSP and the R III reflex. The CSP was recorded from the first dorsal interosseous (FDI) muscle in seven normal subjects during voluntary contraction, before and 10 and 20 min after fentanyl injection. To assess possible fentanyl‐induced changes, we also tested the effect of finger stimulation on motor evoked potentials (MEPs) elicited in the FDI muscle by transcranial magnetic stimulation before and after fentanyl injection. Fentanyl‐induced changes were also studied on the R III reflex recorded from the biceps femoris muscle. Fentanyl, as expected, suppressed the R III reflex but failed to change the inhibitory effect of finger stimulation on FDI motoneurons. Finger stimulation reduced the size of MEPs in the FDI, and fentanyl injection left this inhibitory effect unchanged. The differential fentanyl‐induced modulation of the CSP and R III reflex provides evidence that the CSP circuit is devoid of μ‐opiate receptors and is therefore an opiate‐insensitive nociceptive reflex, which may be useful in the assessment of central‐acting, non‐opioid drugs.