A novel dual-site transcranial magnetic stimulation paradigm to probe fast facilitatory inputs from ipsilateral dorsal premotor cortex to primary motor cortex
Introduction
The dorsal premotor cortex (PMd) is critically involved in the selection, preparation and execution of voluntary actions (Cisek and Kalaska, 2005, Grafton et al., 1998, Hoshi and Tanji, 2004, Picard and Strick, 2001). It is located just anterior to the primary motor cortex hand area (M1HAND) (Picard and Strick, 2001) and has direct cortico-cortical connections to ipsilateral (Dum and Strick, 2005) and contralateral M1HAND (Marconi et al., 2003). In monkeys, cortical microstimulation in PMd elicits short-latency responses of pyramidal neurons in ipsilateral M1HAND with early (mean latency: 2.3 ms) excitatory responses followed by inhibition (Tokuno and Nambu, 2000).
In recent years, several groups have used dual-site transcranial magnetic stimulation (dsTMS) to study functional connectivity between the PMd and M1HAND in the intact human brain (Baumer et al., 2006, Boorman et al., 2007, Civardi et al., 2001, Davare et al., 2008, Mochizuki et al., 2004, O'Shea et al., 2007). Such dsTMS approaches were first introduced by Ferbert et al. and consist of a suprathreshold test stimulus (TS) applied to the M1HAND that produces a motor evoked potential (MEP) in a contralateral hand muscle (Ferbert et al., 1992). The TS over M1HAND is given either in isolation or after a conditioning stimulus (CS) delivered via a second coil over a remote frontal area. The conditioning effects of the CS on the MEP amplitude relative to the MEP amplitude evoked by the TS alone provide a physiological assay of the facilitatory or inhibitory impact of the remote cortical area on excitability in M1HAND at millisecond resolution.
So far, dsTMS studies have predominantly focussed on inter-hemispheric interactions between the PMd and contralateral M1HAND because the size of the stimulating coils precluded simultaneous targeting of ipsilateral PMd and M1HAND. These dsTMS studies revealed facilitatory and inhibitory inter-hemispheric PMd to M1HAND interactions which critically depended on the timing and intensity of the CS as well as the motor state (Baumer et al., 2006, Boorman et al., 2007, O'Shea et al., 2007). In these experiments, the CS was applied several milliseconds before the TS to give sufficient time for neural excitation evoked in PMd to spread to the contralateral M1HAND, presumably via transcallosal connections.
Here we used a new dsTMS paradigm to non-invasively probe intra-hemispheric PMd to M1HAND connectivity with dsTMS in the intact human brain. The dsTMS paradigm integrated two novel features: First, we used specifically designed minicoils which enabled us to concurrently target the left PMd and left M1HAND. Second, we used very short pulse intervals and reversed the temporal order of stimulation, applying the TS over M1HAND 0.8 to 2.0 ms before the CS over the left PMd. We have recently shown that dsTMS with the CS following shortly after the TS can be used to probe short-latency PMd to M1HAND facilitation, presumably by targeting intracortical circuits in M1HAND involved in the generation of indirect corticospinal volleys (Groppa et al., 2012b). In contrast to the studies mentioned above, where TS followed the CS, we changed the order of CS and TS with the TS preceding the CS. We reasoned that this new CS–TS paradigm might shed light into the temporal filtering or refractory properties of the involved cortical areas.
By applying dsTMS at rest and during movement selection, we were able to trace changes in intra-hemispheric PMd to M1HAND facilitation in the context of response selection based on arbitrary cues. In addition, we employed diffusion tensor imaging (DTI) to test whether the context-dependent changes in intra-hemispheric PMd to M1HAND facilitation during conditional response selection correlate with DTI-based measures of microstructural integrity. We derived quantitative measurements of fractional anisotropy (FA), as well as axial and radial diffusivity. These parameters characterise the properties of water diffusion in each voxel and are sensitive to the degree of myelination and axonal density (Beaulieu, 2002). Previous DTI studies have identified distinct tracts where these microstructural measures correlate with inter-individual variations in visuomotor response selection (Madsen et al., 2011, Tuch et al., 2005) or variations in inter-hemispheric PMd to M1HAND interaction (Boorman et al., 2007). We expected to find structural correlation in the juxtacortical white matter connecting the cortical nodes of the described functional network.
Section snippets
Subjects
Thirty-three healthy right-handed subjects (11 males) aged between 21 and 28 years (mean age 24 ± 2.5 years) with no history of neurological or psychiatric disorder or head injury participated in the study. All subjects gave their written informed consent. The study was approved by the Ethics committee of the University of Kiel and conformed to the declaration of Helsinki for human rights.
Dual-site transcranial magnetic stimulation
In all experiments the same dsTMS procedure was applied (Fig. 1A). In contrast to conventional paired-pulse TMS
Results
All participants tolerated the experimental procedures without major side effects. All values are given as mean ± standard deviation, if not indicated otherwise.
Discussion
Here we used a novel dsTMS paradigm to characterise ipsilateral PMd–M1HAND connectivity in the intact human brain both, at rest and during engagement of the involved cortical areas in a motor task. Our results confirm the presence of a short latency facilitatory pathway linking left PMd and M1HAND in humans. The facilitatory premotor-to-motor interaction was present at rest but not during tonic voluntary contraction. When subjects had to select a right or left hand finger movement based on two
Methodological considerations
In this study, the coil geometry did not allow for a flexible positioning of the PMd coil. This is the main reason why we did not used individual peak activations in PMd based on an fMRI localiser to guide the placement of the PMd coil. Further, it is unclear which stimulus intensity is optimal for PMd TMS to evoke maximal PMd to M1 interactions. Therefore, it is conceivable that the effects observed in this study might have been even stronger if it had been possible to adjust the stimulation
Conclusions
Using a novel dsTMS paradigm that uses highly focal coils and very short ISIs with a reversed order of CS and TS we were able to demonstrate a direct short latency facilitatory premotor to motor pathway in the intact left hemisphere of healthy human volunteers. The observed temporal pattern of interaction resembles that of classical I-wave interactions in the human motor system. We also show that such short latency PMd–M1HAND interaction is dynamically expressed depending on the motor state
Acknowledgments
The study was funded by Volkswagenstiftung (Grant number: I/79-932). HRS received additional support by the Bundesministerium für Bildung und Forschung (Grant number: 01GO0511 ‘NeuroImageNord’) and a Grant of Excellence from The Lundbeck Foundation on Mapping, Modulation & Modeling the Control of Actions “ContAct” (Grant number: R59 A5399).
Disclosure: The authors have reported no conflicts of interest.
References (57)
- et al.
Individual differences in white-matter microstructure reflect variation in functional connectivity during choice
Curr. Biol.
(2007) - et al.
Neural correlates of reaching decisions in dorsal premotor cortex: specification of multiple direction choices and final selection of action
Neuron
(2005) - et al.
Transcranial magnetic stimulation can be used to test connections to primary motor areas from frontal and medial cortex in humans
Neuroimage
(2001) - et al.
Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans
Electroencephalogr. Clin. Neurophysiol.
(1998) - et al.
Motor areas in the frontal lobe of the primate
Physiol. Behav.
(2002) - et al.
Longitudinal changes in grey and white matter during adolescence
Neuroimage
(2010) - et al.
A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee
Clin. Neurophysiol.
(2012) - et al.
Functional specialization in dorsal and ventral premotor areas
Prog. Brain Res.
(2004) - et al.
Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor threshold and motor evoked potentials
Neuroimage
(2009) - et al.
Navigated transcranial magnetic stimulation does not decrease the variability of motor-evoked potentials
Brain Stimul.
(2010)
Brain microstructural correlates of visuospatial choice reaction time in children
Neuroimage
Three-dimensional locations and boundaries of motor and premotor cortices as defined by functional brain imaging: a meta-analysis
Neuroimage
A probabilistic atlas of the human brain: theory and rationale for its development the international consortium for brain mapping (ICBM)
Neuroimage
Frontal lobe inputs to primate motor cortex: evidence for four somatotopically organized ‘premotor’ areas
Brain Res.
The refractory period of fast conducting corticospinal tract axons in man and its implications for intraoperative monitoring of motor evoked potentials
Clin. Neurophysiol.
Functionally specific reorganization in human premotor cortex
Neuron
Imaging the premotor areas
Curr. Opin. Neurobiol.
The cortical motor system
Neuron
Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee
Electroencephalogr. Clin. Neurophysiol.
Cerebral dominance for action in the human brain: the selection of actions
Neuropsychologia
Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference
Neuroimage
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
Neuroimage
Visualization of peripheral nerve degeneration and regeneration: monitoring with diffusion tensor tractography
Neuroimage
Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex
Electroencephalogr. Clin. Neurophysiol.
Diffusion MRI of complex neural architecture
Neuron
Physiological basis of motor effects of a transient stimulus to cerebral cortex
Neurosurgery
Magnetic stimulation of human premotor or motor cortex produces interhemispheric facilitation through distinct pathways
J. Physiol.
The basis of anisotropic water diffusion in the nervous system — a technical review
NMR Biomed.
Cited by (59)
Probing intrahemispheric interactions with a novel dual-site TMS setup
2024, Clinical NeurophysiologyPMd and action preparation: bridging insights between TMS and single neuron research
2023, Trends in Cognitive SciencesTranscranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper
2022, Clinical NeurophysiologyCitation Excerpt :Further, dual-site TMS experiments probed PMd-to-M1 interactions and revealed short-latency (1.2 ms) net facilitatory effects of ipsilateral PMd on corticospinal output from M1-HAND (Groppa et al., 2012c). The expression of this ultra-short ipsilateral premotor-to-motor facilitation was modulated by task context, depending on the cued motor response (Groppa et al., 2012c). Hence, dual-site TMS can probe how preparatory motor activity encoded in PMd contributes to motor output generated in M1 during cued motor tasks.
Acute Exercise Modulates the Excitability of Specific Interneurons in Human Motor Cortex
2021, NeuroscienceCitation Excerpt :Recent modelling evidence suggests that AP currents may activate a cortical site within the precentral gyrus that is more anterior than that activated with PA currents (Aberra et al., 2020). Similarly, it is hypothesized that AP stimulation activates more rostral areas of M1 that receive inputs from the premotor cortex (Groppa et al., 2012; Volz et al., 2015). It has been hypothesized that AP stimulation could activate inputs from the premotor or primary somatosensory cortices (Di Lazzaro et al., 2008, 2012; Volz et al., 2015).
A 3-axis coil design for multichannel TMS arrays
2021, NeuroImage