Assessing the mechanisms of brain plasticity by transcranial magnetic stimulation

Abstract

Transcranial magnetic stimulation (TMS) is a non-invasive technique for focal brain stimulation based on electromagnetic induction where a fluctuating magnetic field induces a small intracranial electric current in the brain. For more than 35 years, TMS has shown promise in the diagnosis and treatment of neurological and psychiatric disorders in adults. In this review, we provide a brief introduction to the TMS technique with a focus on repetitive TMS (rTMS) protocols, particularly theta-burst stimulation (TBS), and relevant rTMS-derived metrics of brain plasticity. We then discuss the TMS-EEG technique, the use of neuronavigation in TMS, the neural substrate of TBS measures of plasticity, the inter- and intraindividual variability of those measures, effects of age and genetic factors on TBS aftereffects, and then summarize alterations of TMS-TBS measures of plasticity in major neurological and psychiatric disorders including autism spectrum disorder, schizophrenia, depression, traumatic brain injury, Alzheimer's disease, and diabetes. Finally, we discuss the translational studies of TMS-TBS measures of plasticity and their therapeutic implications.

Fig. 1. Common metrics of applying TMS to motor cortex.

a Resting motor threshold (rMT) for the APB muscle is calculated by identifying the minimum stimulus strength, measured in percent machine output (% MO), that evokes an MEP of a fixed amplitude (typically ≥50 μV) in the APB at rest in a majority of trials. Stimulus strength is indicated in the left panel, with resulting MEPs shown in the right panel, where red arrows indicate the time of stimulation and percent stimulator output is proportional to the arrow length. b ppTMS paradigms where a subthreshold conditioning stimulus (short red vertical line) followed by a suprathreshold test stimulus (longer red vertical line). At short interstimulus-intervals (ISIs) (1–5 ms) short interval intracortical inhibition (SICI) is seen with inhibition of the test MEP by the antecedent conditioning stimulus. At longer ISIs (10–20 ms), test MEP amplitude is enhanced relative to the control MEP, such that ICF is seen. c Still longer ISIs (50–300 ms) are applied with two suprathreshold stimuli in LICI protocols where the MEP resultant from the test stimulus is predictably lower in amplitude than the preceding MEP resulting from the conditioning stimulus. ICF intracortical facilitation, ISI interstimulus interval, LICI long-interval intracortical inhibition, ppTMS paired-pulse transcranial magnetic stimulation, rTMS repetitive transcranial magnetic stimulation, spTMS single-pulse transcranial magnetic stimulation (adapted from ref. [333]).

Fig. 2. cTBS and iTBS measures of plasticity.

Evaluation of corticospinal excitability by comparing MEPs recorded from the peripheral muscle in response to a single pulse to M1. TBS involves applying triplet pulses at 50 Hz repeated at intervals of 200 ms. MEPs are recorded at baseline and following either cTBS or iTBS, providing an index of local cortical plasticity. Following iTBS, MEPs typically show increased amplitude for ~30 min, whereas cTBS induces a suppression MEPs for approximately the same amount of time [93]. Post-TBS enhancement or suppression of cortical activity is considered an index of LTP- or LTD-like mechanism of plasticity in the targeted brain area. Applying paired pulses to M1 at an ISI of either 3 or 100 ms can be used to evaluate intracortical inhibition. cTBS continuous theta-burst stimulation, ISI interstimulus interval, iTB intermittent theta-burst stimulation, LTD long-term depression, LTP long-term potentiation, M1 primary motor cortex, MEP motor evoked potential, TBS theta-burst stimulation (adapted from ref. [106]).

Fig. 3. Neurophysiological effects of plasticity-inducing TMS protocols.

a Epidural volleys recorded at baseline (black trace) and after excitatory (red traces) and inhibitory (green traces) plasticity protocols. Each trace is the average of the responses to 10–25 TMS pulses. 5 Hz rTMS increases the amplitude of the proximal D wave and all I waves. Paired associative stimulation at a 25 ms ISI (PAS25) selectively facilitates the late I waves without changing the I1 wave. cTBS leads to suppression of the amplitude of the I1 wave. 1 Hz rTMS causes a selective suppression of late I waves with no change in the I1 wave. b Corticospinal volleys and MEPs evoked by single TMS pulses in baseline conditions and after iTBS. Each trace is the average of 20 sweeps. Three descending waves can be observed in the epidural recording. iTBS facilitates the amplitude of I2 and I3 waves without affecting the amplitude of the I1 wave. The amplitude of MEP is slightly (but, in this case, nonsignificantly) increased following iTBS. c It is proposed that 5 Hz subthreshold rTMS suppresses the excitability of superficial inhibitory circuits, including superficial (L1) cortical neurons, and that most of the protocols (iTBS, PAS25, PAS10, 1 Hz rTMS, TDCS) modulate bursting neurons of layer 2 and 3 (L2/L3) that project upon PTNs and generate the late I waves. It is proposed that cTBS selectively suppresses the excitability of monosynaptic connections to PTNs. 5 Hz rTMS may produce its excitatory effects by enhancing the excitability of PTNs. cTBS continuous theta-burst stimulation, ISI interstimulus interval, iTBS intermittent theta-burst stimulation, MEP motor evoked potential, PAS paired associative stimulation, PTNs pyramidal tract neurons, rTMS repetitive transcranial magnetic stimulation. TDCS transcranial direct current stimulation (adapted from refs. [123, 128]).

Fig. 4. Translational TMS studies in rats.

a TMS-MMG setup. An unanesthetized rat is restrained on a platform with 4 straps with minimal discomfort. A figure-of-8 TMS coil is centered over the dorsal scalp at the interaural line. The MMG is obtained by two 3-axis accelerometers on each ventral surface of the foot while the rat is under brief isoflurane anesthesia before placement into the restraint. b Representative data during spTMS (left) or ppTMS (right) obtained with ISIs of 50, 100, and 200 ms in rats. ppTMS traces show long-interval intracortical inhibition of the test-evoked MMG. Arrow indicates the onset of the test stimulus. c Examples of MEP changes following sham stimulation, iTBS, and cTBS in anesthetized rats. Representative MEP traces following TBS show no obvious change after sham stimulation, whereas MEP traces show increased amplitude after iTBS and reduced amplitude after cTBS. cTBS continuous theta-burst stimulation, ISI interstimulus interval, iTBS intermittent theta-burst stimulation, MEP motor evoked potential, MMG mechanomyogram, ppTMS paired-pulse transcranial magnetic stimulation, spTMS single-pulse transcranial magnetic stimulation, TMS transcranial magnetic stimulation (adapted from refs. [243, 285]).

Fig. 5. Antidepressant response to repetitive transcranial magnetic stimulation is associated with functional connectivity (FC) between the stimulation site and the subgenual cingulate cortex (SGC) across different cohorts.

The intrinsic spontaneous activity of the SGC (a) can be compared with that of other regions of the brain to identify regions of strong positively or negatively correlated FC. The dorsolateral prefrontal cortex (DLPFC) (b) includes regions of positive (red) and negative (blue) FC with the SGC. Stronger negative FC with the SGC occurs at more anterolateral sites. c Illustration of negative (anticorrelated) time course between the DLPFC (green) and SGC (red). d, e Greater treatment outcome (% change in clinical score) was associated with more negative SGC FC at the individual DLPFC stimulation site across Boston (d) and Melbourne (e) cohorts. For the Boston cohort, the green and red circles in (d) highlight individual participants with good and poor clinical outcomes, corresponding to circled cortical sites of negative and positive SGC FC, respectively, displayed in (b). BDI Beck Depression Inventory, BOLD blood oxygen–level dependent, HCP Human Connectome Project, MADRS Montgomery–Åsberg Depression Rating Scale (adapted from ref. [334]).

Fig. 6. Precision neurostimulation.

The stimulation can be adapted to individual patient needs by achieving specificity in the key elements of dosing (spatial, temporal, and contextual). Spatial precision can be achieved through individual imaging-guided targeting, electric field modeling, and focal or multifocal coils/electrodes. Temporal precision can be achieved by optimizing the pulse waveform, frequency, and train characteristics and by coupling it to endogenous oscillations via closed-loop techniques. Contextual precision can be achieved by controlling brain state during stimulation via online cognitive task performance, synchronizing to endogenous neural oscillations, or combination therapies such as simultaneous brain stimulation and pharmacotherapy (adapted from ref. [335]).