Ying-Zu Huang

Theta Burst Stimulation of the Human Motor Cortex

It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.

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.

Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex

We used transcranial magnetic stimulation (TMS) in a paired pulse protocol to investigate interhemispheric interactions between the right dorsal premotor (dPM) and left primary motor cortex (M1) using interstimulus intervals of 4, 6, 8, 10, 12, 16 and 20 ms in ten healthy subjects. A conditioning stimulus over right dPM at an intensity of either 90 or 110% resting motor threshold (RMT) suppressed motor‐evoked potentials (MEPs) evoked in the first dorsal interosseous (FDI) muscle by stimulation of left M1. Maximum effects occurred for interstimulus intervals (ISIs) of 8–10 ms. There was no effect if the conditioning stimulus was applied 2.5 cm lateral, anterior or medial to dPM. The effect differed from previously described M1 interhemispheric inhibition in that the threshold for the latter was greater than 90% RMT, whereas stimulation of the dPM at the same intensity led to significant inhibition. In addition, voluntary contraction of the left FDI (i.e. contralateral to the conditioning TMS) enhanced interhemispheric inhibition from right M1 but had no effect on the inhibition from right dPM. Finally, conditioning to right dPM at 90% RMT reduced short‐interval intracortical inhibition (SICI; at ISI = 2 ms) in left M1 whilst there was no effect if the conditioning stimulus was applied to right M1. We conclude that conditioning TMS over dPM has effects that differ from the previous pattern of interhemispheric inhibition described between bilateral M1s. This may reflect the existence of commissural fibres between dPM and contralateral M1 that may play a role in bimanual coordination.

The effect of short-duration bursts of high-frequency, low-intensity transcranial magnetic stimulation on the human motor cortex.

OBJECTIVE To explore the effect of applying a short burst of high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human motor cortex as a preparatory investigation before attempting theta burst stimulation in humans. METHODS Five or 15 pulses of 50 Hz rTMS were given at 50-80% active motor threshold (AMT). The time course of changes in motor-evoked potential (MEP) size and short interval intracortical inhibition (SICI) were evaluated from 20 to 300 ms after the end of each burst in the relaxed first dorsal interosseous muscle of 15 healthy volunteers. RESULTS No subjects noted any adverse effects. MEPs were enhanced and SICIs were reduced at 20 ms after a burst of either 5 or 15 pulses at 70 or 80% AMT, but not at 50% AMT. Subsequent experiments used a 5 pulse burst at 80% AMT. The threshold for producing SICI increased from 60 to 80% AMT when tested 10 or 20 ms after the end of the burst. MEPs were enhanced for 100 ms, whereas SICI was reduced for 200-300 ms. CONCLUSIONS A short burst of low-intensity 50 Hz rTMS over the hand motor area transiently increases MEP amplitude with a longer lasting decrease in SICI. SIGNIFICANCE This means that it may be possible in future experiments to apply theta burst conditioning safely to the human cortex.

Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers

A mutation in the DYT1 gene causes dominantly inherited childhood‐onset primary dystonia, but intriguingly, only 30 to 40% of those who carry the mutation ever develop symptoms. We have used the unique model provided by this group of patients to investigate the hypothesis that abnormalities in brain plasticity underlie the pathophysiology of primary dystonia. We recruited 8 DYT1 gene carriers with dystonia, 6 DYT1 gene carriers without dystonia, 6 patients with sporadic primary dystonia (torticollis), and 10 healthy control subjects. Groups were age‐matched. We compared the effect in these groups of subjects of repetitive transcranial magnetic stimulation (rTMS) delivered to the motor cortex, by assessing changes in corticospinal excitability following rTMS. rTMS was given in the form of theta burst stimulation (TBS) using the inhibitory protocol “cTBS” (total of 300 pulses in 50‐Hz bursts given every 5Hz). DYT1 gene carriers with dystonia and subjects with torticollis had a significantly prolonged response to rTMS in comparison with healthy subjects. In contrast, DYT1 gene carriers without dystonia had no significant response to rTMS. These data demonstrate an excessive response to an experimental “plasticity probing protocol” in subjects with dystonia, but a lack of response in genetically susceptible individuals who have not developed dystonia. These preliminary data suggest that the propensity to undergo plastic change may affect the development of symptoms in genetically susceptible individuals and that this may be an important mechanism in the pathogenesis of primary dystonia in general.

The theoretical model of theta burst form of repetitive transcranial magnetic stimulation

OBJECTIVE Theta burst stimulation, a form of repetitive transcranial magnetic stimulation, can induce lasting changes in corticospinal excitability that are thought to involve long-term potentiation/depression (LTD/LTD)-like effects on cortical synapses. The pattern of delivery of TBS is crucial in determining the direction of change in synaptic efficiency. Previously we explained this by postulating (1) that a single burst of stimulation induces a mixture of excitatory and inhibitory effects and (2) those effects may cascade to produce long-lasting effects. Here we formalise those ideas into a simple mathematical model. METHODS The model is based on a simplified description of the glutamatergic synapse in which post-synaptic Ca(2+) entry initiates processes leading to different amount of potentiation and depression of synaptic transmission. The final effect on the synapse results from summation of the two effects. RESULTS The model using these assumptions can fit reported data. Metaplastic effects of voluntary contraction on the response to TBS can be incorporated by changing time constants in the model. CONCLUSIONS The pattern-dependent after-effects and interactions with voluntary contraction can be successfully modelled by using reasonable assumptions about known cellular mechanisms of plasticity. SIGNIFICANCE The model could provide insight into development of new plasticity induction protocols using TMS.

Abnormal bidirectional plasticity-like effects in Parkinson’s disease

Levodopa-induced dyskinesia is a major complication of long-term dopamine replacement therapy for Parkinsons disease that becomes increasingly problematic in advanced Parkinsons disease. Although the cause of levodopa-induced dyskinesias is still unclear, recent work in animal models of the corticostriatal system has suggested that levodopa-induced dyskinesias might result from abnormal control of synaptic plasticity. In the present study, we aimed to explore control of plasticity in patients with Parkinsons disease with and without levodopa-induced dyskinesias by taking advantage of a newly developed protocol that tests depotentiation of pre-existing long-term potentiation-like synaptic facilitation. Long-term potentiation-like plasticity and its reversibility were studied in the motor cortex of 10 healthy subjects, 10 patients with Parkinsons disease and levodopa-induced dyskinesias, who took half of the regular dose of levodopa and 10 patients with Parkinsons disease without levodopa-induced dyskinesias, who took either half or the full dose of levodopa. Patients with Parkinsons disease without levodopa-induced dyskinesias had normal long-term potentiation- and depotentiation-like effects when they took their full dose of levodopa, but there was no long-term potentiation-like effect when they were on half dose of levodopa. In contrast, patients with levodopa-induced dyskinesias could be successfully potentiated when they were on half their usual dose of levodopa; however, they were unresponsive to the depotentiation protocol. The results suggest that depotentiation is abnormal in the motor cortex of patients with Parkinsons disease with levodopa-induced dyskinesias and that their long-term potentiation-like plasticity is more readily affected by administration of levodopa than their clinical symptoms.

Effects of theta burst stimulation protocols on phosphene threshold

OBJECTIVE We investigated the effects on occipital cortex, of two newly developed methods of repetitive transcranial magnetic stimulation (rTMS): continuous and intermittent theta burst stimulation (cTBS and iTBS), that lead to long lasting changes in excitability when applied over primary motor cortex. METHODS Phosphene threshold to a single TMS pulse was measured before and after application of either continuous or intermittent theta burst stimulation (cTBS/iTBS; 600 total pulses at 80% phosphene threshold). RESULTS In our cohort, cTBS increased phosphene threshold by an average of 10%. In contrast, iTBS, which transiently increases motor cortex excitability, had no effect on phosphene threshold. CONCLUSIONS cTBS can be applied successfully to non-motor areas of cortex, but iTBS may need modification to produce maximal effects. SIGNIFICANCE cTBS maybe a new useful tool in disorders characterized by an abnormal state of activity of the visual cortex.

The effect of continuous theta burst stimulation over premotor cortex on circuits in primary motor cortex and spinal cord

OBJECTIVE To understand the effect of continuous theta burst stimulation (cTBS) given to the premotor area, we studied the circuits within the primary motor cortex and spinal cord after cTBS over the dorsal premotor area (PMd). METHODS Three sets of parameters, including corticospinal excitability, short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) and forearm reciprocal inhibition (RI) were tested. RESULTS Paralleling the effects of cTBS applied directly to the primary motor cortex, cTBS over the left PMd suppressed corticospinal excitability as measured by the change in the size of MEPs evoked by single pulse TMS over primary motor cortex. Premotor cTBS appeared to have a longer lasting, but no more powerful effect on corticospinal excitability than motor cTBS, however, unlike motor cTBS it had no effect on SICI or ICF. Finally, although premotor cTBS had no effect on spinal H-reflexes, it did reduce the third phase of RI between forearm extensor and flexor muscles. CONCLUSIONS Premotor cTBS is a quick and useful way of modulating excitability in cortical and possibly subcortical motor circuits. SIGNIFICANCE Premotor cTBS can be used as an alternative to regular rTMS to evaluate cortical function, motor behaviours and the response to disease therapy.

Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects

BACKGROUND/OBJECTIVES Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.