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Background: Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex., Objective: The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression., Methods: Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared., Results: The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate., Conclusions: Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Behavioral and neurophysiological changes have been reported after exposure to extremely low frequency magnetic fields (ELF-MF) both in animals and in humans. The physiological bases of these effects are still poorly understood. In vitro studies analyzed the effect of ELF-MF applied in pulsed mode (PEMFs) on neuronal cultures showing an increase in excitatory neurotransmission. Using transcranial brain stimulation, we studied noninvasively the effect of PEMFs on several measures of cortical excitability in 22 healthy volunteers, in 14 of the subjects we also evaluated the effects of sham field exposure. After 45 min of PEMF exposure, intracortical facilitation produced by paired pulse brain stimulation was significantly enhanced with an increase of about 20%, while other parameters of cortical excitability remained unchanged. Sham field exposure produced no effects. The increase in paired-pulse facilitation, a physiological parameter related to cortical glutamatergic activity, suggests that PEMFs exposure may produce an enhancement in cortical excitatory neurotransmission. This study suggests that PEMFs may produce functional changes in human brain.

Previous studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) suppresses motor-evoked potentials (MEPs) evoked by single pulse TMS. The aim of the present paper was to investigate the central nervous system level at which rTMS produces a suppression of MEP amplitude. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after 1 Hz rTMS in five conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. One of the patients had Parkinson's disease and was studied on medication. Repetitive TMS significantly suppressed the amplitude of later I-waves, and reduced the amplitude of concomitantly recorded MEPs. The earliest I-wave was not significantly modified by rTMS. The present results show that 1 Hz rTMS may decrease the amplitude of later descending waves, consistent with a cortical origin of the effect of 1 Hz rTMS on MEPs.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (TMS). When applied to motor cortex it leads to after-effects on corticospinal and corticocortical excitability that may reflect LTP/LTD-like synaptic effects. An inhibitory form of TBS (continuous, cTBS) suppresses MEPs, and spinal epidural recordings show this is due to suppression of the I1 volley evoked by TMS. Here we investigate whether the excitatory form of TBS (intermittent, iTBS) affects the same I-wave circuitry. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after iTBS in three conscious patients who had an electrode implanted in the cervical epidural space for the control of pain. As in healthy subjects, iTBS increased MEPs, and this was accompanied by a significant increase in the amplitude of later I-waves, but not the I1 wave. In two of the patients we tested the excitability of the contralateral cortex and found a significant suppression of the late I-waves. The extent of the changes varied between the three patients, as did their age. To investigate whether age might be a significant contributor to the variability we examined the effect of iTBS on MEPs in 18 healthy subjects. iTBS facilitated MEPs evoked by TMS of the conditioned hemisphere and suppressed MEPs evoked by stimulation of the contralateral hemisphere. There was a slight but non-significant decline in MEP facilitation with age, suggesting that interindividual variability was more important than age in explaining our data. In a subgroup of 10 subjects we found that iTBS had no effect on the duration of the ipsilateral silent period suggesting that the reduction in contralateral MEPs was not due to an increase in ongoing transcallosal inhibition. In conclusion, iTBS affects the excitability of excitatory synaptic inputs to pyramidal tract neurones that are recruited by a TMS pulse, both in the stimulated hemisphere and in the contralateral hemisphere. However the circuits affected differ from those influenced by the inhibitory, cTBS, protocol. The implication is that cTBS and iTBS may have different therapeutic targets.

Objective: Changes in cerebral cortex excitability have been demonstrated after a stroke and are considered relevant for recovery. Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate cerebral cortex excitability and, when rTMS is given as theta burst stimulation (TBS), LTP- or LTD-like changes can be induced. The aim of present study was to evaluate the effects of TBS on cortical excitability in acute stroke., Methods: In 12 acute stroke patients, we explored the effects of facilitatory TBS of the affected hemisphere and of inhibitory TBS of the unaffected hemisphere on cortical excitability to single-pulse transcranial magnetic stimulation (TMS) on both sides. The effects produced by TBS in patients were compared with those observed in a control group of age-matched healthy individuals., Results: In patients, both the facilitatory TBS of the affected motor cortex and the inhibitory TBS of the unaffected motor cortex produced a significant increase of the amplitude of MEPs evoked by stimulation of the affected hemisphere. The effects observed in patients were comparable to those observed in controls., Conclusions: Facilitatory TBS over the stroke hemisphere and inhibitory TBS over the intact hemisphere in acute phase enhance the excitability of the lesioned motor cortex., Significance: TBS might be useful to promote cortical plasticity in stroke patients.

Objective: To investigate if different interneuronal circuits in human motor cortex mediate inhibition through different subtypes of the gamma-aminobutyric acid A receptor (GABAAR)., Methods: Two distinct forms of motor cortical inhibition were measured in 10 healthy subjects by established transcranial magnetic stimulation (TMS) protocols: short interval intracortical inhibition (SICI) and short latency afferent inhibition (SAI). Their modification by a single oral dose of three different positive GABAAR modulators (20 mg of diazepam, 2.5 mg of lorazepam and 10 mg of zolpidem) with different affinity profiles at the various alpha-subunit bearing subtypes of the GABAAR (diazepam: non-selective, lorazepam: unknown, zolpidem: 10-fold higher affinity to alpha1- than alpha2- or alpha3-subunit bearing GABAARs, no affinity to alpha5-subunits) was tested in a randomized crossover design. In addition, the sedative drug effects were recorded by a visual analogue scale., Results: Diazepam and lorazepam increased SICI, whereas zolpidem did not change SICI. In contrast, diazepam had no effect on SAI, whereas lorazepam and zolpidem decreased SAI. The sedative effects were not different between drugs., Conclusions: The dissociating patterns of drug modification of SICI versus SAI strongly suggest that different GABAAR subtypes are involved in SICI and SAI., Significance: We provide evidence, for the first time, for a dissociation of effects of diazepam and zolpidem on SAI and confirm the previously reported differential effect of zolpidem and of diazepam and lorazepam on SICI. The differential effects of the three benzodiazepines on SAI and SICI suggest that neuronal circuits in human motor cortex that mediate inhibition through different GABAAR subtypes can be segregated by TMS.

Objective: To investigate the central nervous system level at which paired-pulse repetitive transcranial magnetic stimulation at I-wave periodicity (iTMS) produces a facilitation of motor evoked potential (MEP) amplitude., Methods: In one conscious patient who had an electrode implanted in the cervical epidural space for the control of pain, we recorded corticospinal volleys evoked before, during and after iTMS of the motor cortex. Moreover, we compared MEPs to TMS and cervico-medullary junction stimulation before and after iTMS in a separate group of five healthy subjects., Results: In the patient with the epidural electrode, during iTMS there was progressive increase of MEP amplitude, and by the end of the intervention period MEP increased by more than 300%. The pronounced increase in MEP amplitude was paralleled by a slight increase in the amplitude of epidural volleys. An increased MEP amplitude (more than 200%) was still evident 3 min after the end of iTMS. In the five healthy subjects, iTMS produced a facilitation of MEPs evoked by transcranial magnetic stimulation but had no effect on CMEPs evoked by cervico-medullary junction stimulation., Conclusions: The results indicate that iTMS leads to an increase in corticomotor excitability at a supraspinal level, and that this may include circuits in addition to those involved in I-wave generation., Significance: iTMS increases cortical excitability more widely than the I-wave networks that it targets.

Repetitive transcranial magnetic stimulation (rTMS) of brain can modulate cortical neurotransmission, a novel paradigm of repetitive stimulation termed continuous theta-burst stimulation (cTBS) produces a pronounced and prolonged suppression of motor cortex excitability. The aim of this preliminary study was to investigate whether cTBS of motor cortex could have any beneficial effect in patients with amyotrophic lateral sclerosis (ALS). We performed a double-blind, placebo-controlled trial. Twenty patients with definite ALS were randomly allocated to blinded active or placebo stimulation. Repetitive stimulation of the motor cortex was performed for five consecutive days every month for six consecutive months. The primary outcome was the rate of decline as evaluated with the ALS functional rating scale. The treatment was well tolerated by the patients. Fifteen patients (seven active and eight sham) completed the study and were included in the 6-months analysis. Both active and sham patients deteriorated during treatment, however, active patients showed a modest but significant slowing of the deterioration rate. Though we cannot be sure whether the effects observed can be attributed to cTBS, because of the restricted number of patients studied, further investigation on a larger group of ALS patients is warranted. The results of the pilot study might open up a new therapeutic perspective in ALS based on neuromodulation.

Background and Purpose: Preliminary studies suggest that electrical stimulation of the damaged cortex may be able to enhance motor recovery after stroke. The hypothesis has been that this increases cortical excitability, making it easier for the system to respond to and learn from conventional physiotherapy. However, there is no direct evidence that the cortex of patients with stroke can respond in this fashion; hence, the basis of these new approaches has been questioned., Methods: We had the opportunity to evaluate directly the effects of noninvasive cortical stimulation on the excitability of corticospinal output from the damaged hemisphere of a chronic stroke patient who had epidural electrodes implanted in the upper dorsal cord for treatment of pain., Results: We found that it was possible to enhance corticospinal activity evoked by single test stimuli., Conclusions: This study confirms directly that it is possible to noninvasively manipulate cortical excitability in stroke.

A magnetic transcranial conditioning stimulus given over the motor cortex at intensities below active threshold for obtaining motor-evoked potentials (MEPs) facilitates EMG responses evoked at rest in hand muscles by a suprathreshold magnetic stimulus given 10-25 ms later. This is known as intracortical facilitation (ICF). We recorded descending volleys produced by single and paired magnetic motor cortex stimulation through high cervical epidural electrodes implanted for pain relief in six conscious patients. At interstimulus intervals (ISIs) of 10 and 15 ms, although MEP was facilitated, there was no change in the amplitude or number of descending volleys. An additional I wave sometimes was observed at 25 ms ISI. In one subject, we also evaluated the effects of reversing the direction of the induced current in the brain. At 10 ms ISI, the facilitation of the MEPs disappeared and was replaced by slight suppression; at 2 ms ISI, there was a pronounced facilitation of epidural volleys. Subsequent experiments on healthy subjects showed that a conditioning stimulus capable of producing ICF of MEPs had no effect on the EMG response evoked by transmastoidal electrical stimulation of corticospinal tract. We conclude that ICF occurs because either 1) the conditioning stimulus has a (thus far undetected) effect on spinal cord excitability that increases its response to the same amplitude test volley or 2) that it can alter the composition (but not the amplitude) of the descending volleys set up by the test stimulus such that a larger proportion of the activity is destined for the target muscle.

In four conscious patients who had electrodes implanted in the cervical epidural space for the control of pain, we recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation (TMS) over the motor cortex before and after a 20 s period of continuous theta-burst stimulation (cTBS). It has previously been reported that this form of repetitive TMS reduces the amplitude of motor-evoked potentials (MEPs), with the maximum effect occurring at 5-10 min after the end of stimulation. The present results show that cTBS preferentially decreases the amplitude of the corticospinal I1 wave, with approximately the same time course. This is consistent with a cortical origin of the effect on the MEP. However, other protocols that lead to MEP suppression, such as short-interval intracortical inhibition, are characterized by reduced excitability of late I waves (particularly I3), suggesting that cTBS suppresses MEPs through different mechanisms, such as long-term depression in excitatory synaptic connections.

Low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex results in lasting changes of excitatory neurotransmission. We investigated the effects of suprathreshold 1 Hz rTMS on brain derived neurotrophic factor (BDNF) plasma levels in 10 healthy subjects and effects of either 1 Hz or 20 Hz rTMS in four amyotrophic lateral sclerosis (ALS) patients. BDNF levels were progressively decreased by 1 Hz rTMS in healthy subjects; there was no effect of 1 Hz rTMS on BDNF plasma levels in ALS patients, an effect probably due to the loss of motor cortex pyramidal cells. High frequency rTMS determined a transitory decrease in BDNF plasma levels. Cumulatively these findings suggest that rTMS might influence the BDNF production by interfering with neuronal activity.

The effects of repetitive transcranial magnetic stimulation (rTMS; 20 stimuli at 5 Hz at 120% resting motor threshold intensity using a biphasic stimulus pulse) on the excitability of human motor cortex were investigated in two patients who had an electrode implanted into the cervical epidural space. The corticospinal D wave increased in amplitude with successive stimuli, and reached a maximum after three or five pulses. At this stage, the amplitude of the I waves was unchanged, but after a further 10 stimuli an additional I wave was recruited. Both effects were still evident 2 min after the end of the rTMS. The effects are compatible with a short-term increase in cortical excitability during suprathreshold rTMS.