Antonio Oliviero

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

Magnetic transcranial stimulation at intensities below active motor threshold activates intracortical inhibitory circuits

Abstract A magnetic transcranial conditioning stimulus given over the motor cortex at intensities below threshold for obtaining electromyographical (EMG) responses in active hand muscles can suppress responses evoked in the same muscles at rest by a suprathreshold magnetic test stimulus given 1–5 ms later. In order to define the mechanism of this inhibitory effect, we recorded descending volleys produced by single and paired magnetic transcranial stimulation of motor cortex through high cervical, epidural electrodes implanted for pain relief in two conscious subjects with no abnormality of the central nervous system. The conditioning stimulus evoked no recognisable descending activity in the spinal cord, whilst the test stimulus evoked 3–4 waves of activity (I-waves). Conditioning stimulation suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus. Inhibition of the descending spinal volleys was most pronounced at ISI 1 ms and had disappeared by ISI 5 ms. It was evident for all components following the I1-wave, while the I1-wave itself was not inhibited at all. We conclude that a small conditioning magnetic stimulus can suppress the excitability of human motor cortex, probably by activating local cortico-cortical inhibitory circuits.

Short latency inhibition of human hand motor cortex by somatosensory input from the hand

1 EMG responses evoked in hand muscles by transcranial stimulation over the motor cortex were conditioned by a single motor threshold electrical stimulus to the median nerve at the wrist in a total of ten healthy subjects and in five patients who had electrodes implanted chronically into the cervical epidural space. 2 The median nerve stimulus suppressed responses evoked by transcranial magnetic stimulation (TMS) in relaxed or active muscle. The minimum interval between the stimuli at which this occurred was 19 ms. A similar effect was seen if electrical stimulation was applied to the digital nerves of the first two fingers. 3 Median or digital nerve stimulation could suppress the responses evoked in active muscle by transcranial electrical stimulation over the motor cortex, but the effect was much less than with magnetic stimulation. 4 During contraction without TMS, both types of conditioning stimuli evoked a cutaneomuscular reflex that began with a short period of inhibition. This started about 5 ms after the inhibition of responses evoked by TMS. 5 Recordings in the patients showed that median nerve stimulation reduced the size and number of descending corticospinal volleys evoked by magnetic stimulation. 6 We conclude that mixed or cutaneous input from the hand can suppress the excitability of the motor cortex at short latency. This suppression may contribute to the initial inhibition of the cutaneomuscular reflex. Reduced spinal excitability in this period could account for the mild inhibition of responses to electrical brain stimulation.

A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans.

OBJECTIVES The present experiments were designed to compare the understanding of the transcranial electric and magnetic stimulation of the human motorcortex. METHODS The spinal volleys evoked by single transcranial magnetic or electric stimulation over the cerebral motor cortex were recorded from a bipolar electrode inserted into the cervical epidural space of two conscious human subjects. These volleys were termed D- and I waves, according to their latency. Magnetic stimulation was performed with a figure-of-eight coil held over the right motor cortex at the optimum scalp position, in order to elicit motor responses in the contralateral FDI using two different orientations over the motor strip. The induced current flowed either in a postero-anterior or in a latero-medial direction. RESULTS At active motor threshold intensity, the electric anodal stimulation evoked pure D activity. At this intensity, magnetic stimulation with the induced current flowing in a posterior-anterior direction evoked pure I1 activity. When a latero-medial induced current was used, magnetic stimulation evoked both D and I1 activity. Using electric anodal stimulation, at a stimulus intensity of 9% of the stimulator output above the active motor threshold (corresponding approximately to 1.5 active motor threshold), a small I1 wave appeared only in subject 1. Using magnetic stimulation with a posterior-anterior induced current, at a stimulus intensity of 21% of maximum stimulator output above the active motor threshold (corresponding approximately to 1.8 times threshold in subject 1 and to two times threshold in subject 2), a small D wave appeared in subject 1 but not in subject 2. CONCLUSIONS Present results demonstrate that, in conscious humans at threshold intensities, electric stimulation evokes D waves and magnetic stimulation (with a posterior-anterior induced current) evokes I waves, while magnetic stimulation (with a latero-medial induced current) evokes both activities.

Effects of voluntary contraction on descending volleys evoked by transcranial stimulation in conscious humans

1 The spinal volleys evoked by single transcranial magnetic or electric stimulation over the cerebral motor cortex were recorded from a bipolar electrode inserted into the cervical epidural space of three conscious human subjects. These volleys were termed direct (D) and indirect (I) waves according to their latency. 2 We measured the size and number of volleys elicited by magnetic stimulation at various intensities with subjects at rest and during 20 or 100 % maximum contraction of the contralateral first dorsal interosseous muscle (FDI). Surface EMG activity was also recorded. 3 Electrical stimulation evoked a D‐wave volley. Magnetic stimulation at intensities up to about 15 % of stimulator output above threshold evoked only I‐waves. At higher intensities, a D‐wave could be seen in two of the three subjects. 4 At all intensities tested, voluntary contraction increased the number and size of the I‐waves, particularly during maximum contractions. However, there was only a small effect on the threshold for evoking descending activity. Voluntary contraction produced large changes in the size of EMG responses recorded from FDI. 5 Because the recorded epidural activity is destined for muscles other than the FDI, it is impossible to say to what extent increased activity contributes to voluntary facilitation of EMG responses. Indeed, our results suggest that the main factor responsible for enhancing EMG responses in the transition from rest to activity is likely to be increased excitability of spinal motoneurones, rather than increases in the corticospinal volley. The latter may be more important in producing EMG facilitation at different levels of voluntary contraction.

Inhibition of motor system excitability at cortical and spinal level by tonic muscle pain

OBJECTIVE To assess whether the motor system excitability can be modified by experimental tonic pain induced either in muscles or in subcutis. METHODS Transcranial magnetic stimulation of the left primary motor cortex was used to record motor evoked potentials (MEPs) from the right abductor digiti minimi (ADM) muscle. Recordings were made before, during and after experimental pain induced by (1) injection of hypertonic (5%) saline into the right ADM, the right first dorsal interosseum (FDI) and the left ADM muscles, and (2) injection of hypertonic saline in the subcutaneous region of the right ADM. Both MEPs and H-reflex were recorded also from the right flexor carpi radialis (FCR) before, during and after muscle pain. RESULTS MEPs recorded from the ADM muscle were significantly reduced in amplitude during pain induced in the right ADM and right FDI muscles, but not during pain in the left ADM muscle or during subcutaneous pain. This inhibitory effect was observed during the peak-pain and persisted also after the disappearance of the pain sensation. In the FCR muscle, the MEP inhibition was observed during the peak-pain, while a significant reduction of the H-reflexs amplitude was observed starting 1 min after the peak-pain. CONCLUSIONS Tonic muscle pain can inhibit the motor system. The motor cortex inhibition observed at an early phase is followed by a reduction of the excitability of both cortical and spinal motoneurones.

Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex

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.

Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation.

Abstract Electromyographic (EMG) responses evoked in hand muscles by a magnetic test stimulus over the motor cortex can be suppressed if a conditioning stimulus is applied to the opposite hemisphere 6–30 ms earlier. In order to define the mechanism and the site of action of this inhibitory phenomenon, we recorded descending volleys produced by the test stimulus through high cervical, epidural electrodes implanted for pain relief in three conscious subjects. These could be compared with simultaneously recorded EMG responses in hand muscles. When the test stimulus was given on its own it evoked three waves of activity (I-waves) in the spinal cord, and a small EMG response in the hand. A prior conditioning stimulus to the other hemisphere suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus when the interstimulus interval was greater than 6 ms. In the spinal recordings, the effect was most marked for the last I-wave (I3), whereas the second I2-wave was only slightly inhibited, and the first I-wave (I1) was not inhibited at all. We conclude that transcranial stimulation over the lateral part of the motor cortex of one hemisphere can suppress the excitability of the contralateral motor cortex.

Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson's disease.

The pattern of neuronal discharge within the basal ganglia is disturbed in Parkinsons disease (PD). In particular, there is a tendency for neuronal elements to synchronise at around 20 Hz in the absence of dopaminergic treatment, whereas this activity can be replaced by spontaneous synchronisation at much higher frequencies (>70 Hz) following dopaminergic treatment [J. Neurosci. 21 (2001) 1033; Brain 126 (2003) 2153]. In two PD patients (3 sides), we show that stimulating the subthalamic area at around 20 Hz exacerbates synchronisation at similar frequencies in the globus pallidus interna, the major output structure of the human basal ganglia. In contrast, stimulating the subthalamic area at >70 Hz suppresses pallidal activity at about 20 Hz. Clinically, stimulation of the subthalamic area at similar high frequencies reverses parkinsonism and forms the basis of therapeutic deep brain stimulation in PD. The results point to a possible common mechanism by which both dopaminergic treatment associated synchronisation of subthalamic activity at very high frequency and synchronisation imposed by therapeutic stimulation of the subthalamic area inhibit an abnormal and potentially deleterious synchronisation of basal ganglia output at around 20 Hz. If this activity is unchecked by synchronisation at higher frequency, then pathological 20-Hz oscillations may cascade through the basal ganglia, increasing at subsequent levels of processing.