Paolo Mazzone

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.

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.

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.

The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex

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.

The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation

Abstract. Descending corticospinal volleys were recorded from a bipolar electrode inserted into the cervical epidural space of four conscious human subjects after monophasic transcranial magnetic stimulation over the motor cortex with a figure-of-eight coil. We examined the effect of reversing the direction of the induced current in the brain from the usual posterior-anterior (PA) direction to an anterior-posterior (AP) direction. The volleys were compared with D waves evoked by anodal electrical stimulation (two subjects) or medio-lateral magnetic stimulation (two subjects). As reported previously, PA stimulation preferentially recruited I1 waves, with later I waves appearing at higher stimulus intensities. AP stimulation tended to recruit later I waves (I3 waves) in one of the subjects, but, in the other three, I1 or D waves were seen. Unexpectedly, the descending volleys evoked by AP stimulation often had slightly different peak latencies and/or longer duration than those seen after PA stimulation. In addition the relationship between the size of the descending volleys and the subsequent EMG response was often different for AP and PA stimulation. These findings suggest that AP stimulation does not simply activate a subset of the sites activated by PA stimulation. Some sites or neurones that are relatively inaccessible to PA stimulation may be the low-threshold targets of AP stimulation.

Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex.

Abstract Under certain conditions, EMG responses evoked by pairs of transcranial magnetic stimuli over the motor cortex are larger than the sum of the responses to each stimulus given alone. This occurs with interstimulus intervals of around 1.3, 2.5 and 4.3 ms and could be due to interaction between the responses to each stimulus at either the cortex or spinal cord. We recorded the descending volleys set up by such pairs of stimuli from the cervical epidural space of five patients implanted with chronic stimulators for pain control. Interstimulus intervals of 1, 1.2, 1.4 and 2 ms were used to investigate the first peak of facilitation. Enhanced EMG responses occurred after pairs of stimuli at 1, 1.2 and 1.4 ms, and these were accompanied by larger and more numerous descending volleys than expected from the sum of each stimulus alone. We conclude that facilitatory interaction between the stimuli can occur within the cerebral cortex. This may involve elements that produce repetitive I-wave activity in response to a single stimulus.