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

Abstract

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.

Figures

Figure 1. Corticospinal volleys and motor evoked potentials evoked by single pulse magnetic stimulation in baseline conditions and after right motor cortex intermittent theta burst stimulation (iTBS) in subjects 1 after stimulation of the ipsilateral (left panel) and contralateral (right panel) hemisphere

Each trace is the average of 20 sweeps. A, magnetic stimulation evokes three descending waves. The latency of the earliest (I1) wave is indicated by the vertical line. After iTBS, a further I-wave is recruited (I4), the size of the I2 and I3 waves is increased (F1,18 = 26.53, P < 0.000), and the amplitude of the I1 wave is unchanged (F1,18 = 0.606, P = 0.446). The amplitude of MEP is significantly increased after iTBS (F1,18 = 30.1, P < 0.0001). B, magnetic stimulation evokes three descending waves. After iTBS, the size of the latest (I3) wave is decreased (F1,18 = 7.116, P = 0.016), the amplitude of the I1 wave is unchanged (F1,18 = 4.08, P = 0.058), and the amplitude of MEP is decreased (F1,18 = 14.254, P = 0.001).

Figure 2. Corticospinal volleys and motor evoked potentials evoked by single pulse magnetic stimulation in baseline conditions and after right motor cortex intermittent theta burst stimulation (iTBS) in subject 2

Each trace is the average of 20 sweeps. Magnetic stimulation evokes three descending waves. After iTBS, the size of the I2 and I3 waves is increased (F1,18 = 5.9, P = 0.026), and the amplitude of the I1 wave is unchanged (F1,18 = 2.4, P = 0.138). The amplitude of MEP is slightly increased after iTBS, but the change is not significant (F1,18 = 0.57, P = 0.459).

Figure 3. Corticospinal volleys and motor evoked potentials evoked by single pulse magnetic stimulation in baseline conditions and after right motor cortex intermittent theta burst stimulation (iTBS) in subjects 3 after stimulation of the ipsilateral (left panel) and contralateral (right panel) hemisphere

Each trace is the average of 20 sweeps. A, magnetic stimulation evokes three descending waves. The latency of the earliest (I1) wave is indicated by the vertical line. After iTBS, the size of the I2 and I3 waves is increased (F1,18 = 9.04, P = 0.008), the amplitude of the I1 wave is unchanged (F1,18 = 0.137, P = 0.716). The amplitude of MEP is significantly increased after iTBS (F1,18 = 6.35, P = 0.021). B, magnetic stimulation evokes several descending waves. After iTBS, the size of the later waves is significantly decreased (F1,18 = 10.74, P = 0.004), and the amplitude of the I1 wave is unchanged (F1,18 = 1.3, P = 0.268). The amplitude of MEP is decreased after iTBS, but the change is not significant (F1,18 = 0.59, P = 0.453).

Figure 4. Bar graphs showing grand mean amplitudes of the I1 wave, of the later I-waves (the sum of the amplitudes of waves following I1) and of motor evoked potentials in baseline conditions and after iTBS in the three subjects studied

The amplitude of later I-waves is increased by about 46% after iTBS, and the amplitude of MEPs is increased by about 90% after iTBS.

Figure 5. Mean increase in MEP amplitude of the stimulated and contralateral hemisphere after iTBS in groups of control subjects of different ages

The facilitation of MEPs (in stimulated hemisphere) is larger in younger control subjects (groups I aged 20–40 and II aged 41–60 years) than in older subjects (group III aged 61–80 years) (facilitation of MEPs: group I 96.4 ± 112% (s.d.), group II 80 ± 105%, and group III 36.3 ± 46.9%), but the difference is not significant (F2,15 = 0.67, P = 0.528). Inhibition of MEPs (in contralateral hemisphere) is similar in younger and older subjects (F2,15 = 1.246, P = 0.316).