Sven Bestmann

Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits

Recent studies indicate that the cortical effects of transcranial magnetic stimulation (TMS) may not be localized to the site of stimulation, but spread to other distant areas. Using echo‐planar imaging with blood‐oxygenation‐level‐dependent (BOLD) contrast at 3 Tesla, we measured MRI signal changes in cortical and subcortical motor regions during high‐frequency (3.125 Hz) repetitive TMS (rTMS) of the left sensorimotor cortex (M1/S1) at intensities above and below the active motor threshold in healthy humans. The supra‐ and subthreshold nature of the TMS pulses was confirmed by simultaneous electromyographic monitoring of a hand muscle. Suprathreshold rTMS activated a network of primary and secondary cortical motor regions including M1/S1, supplementary motor area, dorsal premotor cortex, cingulate motor area, the putamen and thalamus. Subthreshold rTMS elicited no MRI‐detectable activity in the stimulated M1/S1, but otherwise led to a similar activation pattern as obtained for suprathreshold stimulation though at reduced intensity. In addition, we observed activations within the auditory system, including the transverse and superior temporal gyrus, inferior colliculus and medial geniculate nucleus. The present findings support the notion that re‐afferent feedback from evoked movements represents the dominant input to the motor system via M1 during suprathreshold stimulation. The BOLD MRI changes in motor areas distant from the site of subthreshold stimulation are likely to originate from altered synaptic transmissions due to induced excitability changes in M1/S1. They reflect the capability of rTMS to target both local and remote brain regions as tightly connected constituents of a cortical and subcortical network.

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy.

Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for ≤1 h when applied over the primary motor cortex (M1) in humans. Here we use magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx). cTBS to the left M1 led to an increase in GABA compared with stimulation at a control site without significant change in Glx. This direct evidence for increased GABAergic interneuronal activity is framed in terms of a new hypothesis regarding mechanisms underlying cTBS.

Subthreshold high-frequency TMS of human primary motor cortex modulates interconnected frontal motor areas as detected by interleaved fMRI-TMS

To elucidate changes in human brain activity evoked by repetitive transcranial magnetic stimulation (rTMS), sub- and suprathreshold rTMS (4 Hz, 10 s) over the left primary sensorimotor cortex (M1/S1) was interleaved with blood-oxygenation-level-dependent (BOLD) echo-planar imaging of primary and secondary motor areas. Suprathreshold rTMS over left M1/S1 caused marked increases in BOLD signal in the stimulated area and SMA-proper in seven of eight subjects. By contrast, we found no change in BOLD signal in the stimulated M1/S1, when rTMS was given at intensities that were subthreshold for inducing motor responses in the contralateral hand. However, five of eight subjects showed consistent increases in BOLD MRI signal in the SMA-proper and, to a lesser extent, in bilateral lateral premotor cortex (LPMC) during subthreshold rTMS. A decrease in BOLD MRI signal was found in contralateral (right) M1/S1 in 6/8 subjects across all conditions. No significant changes were observed in the pre-SMA. The results support the notion that BOLD MRI responses to suprathreshold rTMS over M1/S1 are dominated by neuronal activity related to reafferent processing of TMS-induced hand movements. At subthreshold intensity, a short train of high-frequency rTMS seems to predominantly modulate activity of corticocortical connections which link the stimulated area with remote frontal premotor areas.

BOLD MRI responses to repetitive TMS over human dorsal premotor cortex

Functional magnetic resonance imaging (fMRI) studies in humans have hitherto failed to demonstrate activity changes in the direct vicinity of transcranial magnetic stimulation (TMS) that cannot be attributed to re-afferent somatosensory feedback or a spread of excitation. In order to investigate the underlying activity changes at the site of stimulation as well as in remote connected regions, we applied short trains of high-intensity (110% of resting motor threshold) and low-intensity (90% of active motor threshold) repetitive TMS (rTMS; 3 Hz, 10 s duration) over the presumed location of the left dorsal premotor cortex (PMd) during fMRI. Signal increases in the direct vicinity of the stimulated PMd were observed during rTMS at 110% RMT. However, positive BOLD MRI responses were observed with rTMS at both 90% and 110% RMT in connected brain regions such as right PMd, bilateral PMv, supplementary motor area, somatosensory cortex, cingulate motor area, left posterior temporal lobe, cerebellum, and caudate nucleus. Responses were generally smaller during low-intensity rTMS. The results indicate that short trains of TMS can modify local hemodynamics in the absence of overt motor responses. In addition, premotor rTMS cannot only effectively stimulate cortico-cortical but also cortico-subcortical connections even at low stimulation intensities.

Functional MRI of cortical activations induced by transcranial magnetic stimulation (TMS)

The effects of repetitive transcranial magnetic stimulation (rTMS) on human brain activity and associated hemodynamics were investigated by blood-oxygenation-level-dependent (BOLD) MRI using echo-planar imaging at 2.0 T. Apart from bilateral activation of the auditory cortex by the audible rTMS discharges (23 bursts, 1 s duration, 10 Hz, 10–20 s interstimulus intervals), BOLD responses were restricted to cortical representations of actual finger movements performed either voluntarily or evoked by suprathreshold rTMS of the motor cortex. Neither subthreshold rTMS of the motor cortex nor suprathreshold rTMS of the lateral premotor cortex induced a detectable BOLD response. These findings suggest that neuronal depolarization as induced by rTMS modulates the spiking output of a brain area but does not automatically alter cerebral blood flow and oxygenation. The observation of BOLD MRI activations probably reflects the afferent intracortical processing of real movements.

On the synchronization of transcranial magnetic stimulation and functional echo‐planar imaging

To minimize artifacts in echo‐planar imaging (EPI) of human brain function introduced by simultaneous transcranial magnetic stimulation (TMS).

rTMS over the cerebellum can increase corticospinal excitability through a spinal mechanism involving activation of peripheral nerve fibres

OBJECTIVES Single-pulse transcranial magnetic stimulation (TMS) over the cerebellum affects corticospinal excitability by a cerebellar and a peripheral mechanism. We have investigated whether any of the long-lasting effects of repetitive TMS (rTMS) over cerebellum can also be attributed to peripheral effects. METHODS Five hundred conditioning stimuli at 1 Hz were given over either the right cerebellum using a double-cone coil, or over the right posterior neck using a figure-8-coil. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the right and left hand and forearm muscles. Hoffman reflexes (H-reflex) were also obtained in the right flexor carpi radialis muscle. RESULTS rTMS over either the right cerebellum or the right posterior neck significantly facilitated MEPs in hand and forearm muscles in the right but not in the left arm (n=8) for up to 30 min after the end of the train. rTMS (1 Hz) of the right neck area increased the amplitude of the H-reflex (n=5). CONCLUSIONS Much of the persisting effects of rTMS over the cerebellum on corticospinal excitability appear to be mediated through stimulation of peripheral rather than central structures. Moreover, the results show that rTMS over peripheral areas can cause long-lasting changes in spinal reflexes.

Inhibitory interactions between pairs of subthreshold conditioning stimuli in the human motor cortex

OBJECTIVE These experiments examined short interval paired-pulse paradigms for intracortical inhibition (ICI) and facilitation (ICF). We tested whether pairs of subthreshold conditioning stimuli interact, and whether they showed rapid periodicity similar to that observed in subthreshold I-wave interaction. METHODS Transcranial magnetic stimulation (TMS) was given over left M1 to evoke a motor-evoked potential (MEP) of approximately 1 mV peak-to-peak amplitude in the contralateral first dorsal interosseous (FDI) muscle. Each test shock (TS) was preceded by single or paired subthreshold conditioning stimuli (CS(1) and CS(2)) at short interstimulus intervals (ISIs 1-15 ms). Intensities of CS were set just below thresholds for intracortical inhibition (ICI) or intracortical facilitation (ICF). RESULTS Each CS(single) alone had no effect on the test MEP, but with two CS, clear inhibition was elicited at certain intervals. With a CS(2)-TS interval of 2 ms, maximum suppression occurred if CS(1) was applied 1-2.5 ms before CS(2). This inhibitory effect tapered off gradually as the CS(2)-CS(1) interval was increased up to 13 ms. When facilitation was present with a CS(single)-TS interval of 10 ms, a small but non-significant extra-facilitation occurred at ISIs between CS(2) and CS(1) of 6-15 ms. CONCLUSIONS Two subthreshold conditioning stimuli facilitate inhibition that lacks the rapid periodicity typical of I-wave interaction. The data would be compatible with a model in which synaptic inputs converge on a common inhibitory interneurone.

Interleaving TMS with functional MRI: now that it is technically feasible how should it be used?

Department of Neurology, Christian-Albrechts-University, Niemannsweg 147, D-24105 Kiel, Germany Brain Imaging Institute Hamburg-Kiel-Lubeck at Hamburg University Hospital, Hamburg, Germany Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College London, London, UK Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fur biophysikalische Chemie, Goettingen, Germany

Cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change in speech

Neuroimaging studies suggest that the cerebellum might play a role in both speech perception and speech perceptual learning. However, it remains unclear what this role is: does the cerebellum help shape the perceptual decision, or does it contribute to the timing of perceptual decisions? To test this, we used transcranial direct current stimulation (tDCS) in combination with a speech perception task. Participants experienced a series of speech perceptual tests designed to measure and then manipulate (via training) their perception of a phonetic contrast. One group received cerebellar tDCS during speech perceptual learning, and a different group received sham tDCS during the same task. Both groups showed similar learning-related changes in speech perception that transferred to a different phonetic contrast. For both trained and untrained speech perceptual decisions, cerebellar tDCS significantly increased the time it took participants to indicate their decisions with a keyboard press. By analyzing perceptual responses made by both hands, we present evidence that cerebellar tDCS disrupted the timing of perceptual decisions, while leaving the eventual decision unaltered. In support of this conclusion, we use the drift diffusion model to decompose the data into processes that determine the outcome of perceptual decision-making and those that do not. The modeling suggests that cerebellar tDCS disrupted processes unrelated to decision-making. Taken together, the empirical data and modeling demonstrate that right cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change. The results provide initial evidence in healthy humans that the cerebellum critically contributes to speech timing in the perceptual domain.