Imaging functional activation of the auditory cortex during focal repetitive transcranial magnetic stimulation of the primary motor cortex in normal subjects

doi:10.1016/S0304-3940(99)00454-1

Neuroscience Letters

Volume 270, Issue 1, 23 July 1999, Pages 37-40

https://doi.org/10.1016/S0304-3940(99)00454-1 Get rights and content

Abstract

Positron emission tomography (PET) during focal repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising approach to study cortical connectivity in awake humans. However, the noise caused by the discharging magnetic coil might have confounding effects on the rTMS-related cortical activation pattern. In twelve healthy volunteers, 18-fluoro-2-deoxy-d-glucose (¹⁸FDG) PET was employed to visualize the functional activation of the primary auditory cortex (PAC) during 2 Hz rTMS of the left primary sensorimotor hand area. Magnetic stimuli (1800) were applied at an intensity of 140% of motor resting threshold during the uptake period of ¹⁸FDG. Though all subjects wore earplugs, rTMS-related noise induced a consistent bilateral increase of regional glucose utilization in the PAC (P<0.05, corrected). Thus, rTMS-related acoustic input needs to be taken into account in combined rTMS/PET studies.

Section snippets

Acknowledgements

The authors would like to thank Mrs. G. Dzewas and Mrs. C. Kruschke for their assistance during PET acquisition, and the staff of the Radiochemistry Section for their reliable supply of the radiopharmaceuticals. This study was supported by the Wilhelm Sander Stiftung, Munich, Germany and the SFB 462, Deutsche Forschungsgemeinschaft.

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Combined TMS-neuroimaging studies can pinpoint brain activity changes that are elicited by sensory effects of TMS. In addition to its transcranial mode of action, TMS excites the brain through afferent neuronal channels activated by concurrent auditory and somatosensory stimulation (Bestmann et al., 2004; Siebner et al., 1999). TMS causes peripheral stimulation of the central nervous system through multiple channels, including peripheral receptors and peripheral myelinated axons.
Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.
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This is illustrated by intensity-dependent increases of BOLD response in voxels located within the primary auditory cortex (Bohning et al., 1999) and also by widespread cortical and subcortical activity in the auditory system cortex when TMS is applied to M1 (Bestmann et al., 2004). Similar observations have been made with other imaging modalities and appear to persist despite auditory protection (Siebner et al., 1999). For fMRI-TMS of the motor cortex, another confounding effect is caused by re-afferent somatosensory activation due to the evoked motor response, when using suprathreshold stimulation intensities.
This chapter summarizes how brain imaging can be used in combination with non-invasive transcranial stimulation to probe and induce neuroplasticity in the human brain. We aim to give a conceptual account and highlight exemplary studies. We showcase the scientific and clinical potentials of studies focusing on the combination of transcranial magnetic stimulation (TMS) with Magnetic Resonance Imaging (MRI) or Magnetic Resonance Spectroscopy (MRS). MRI and MRS can be used before brain stimulation to identify target networks and loci but also to inform individual dosing. After a brain stimulation session, MRI and MRS can be used to pinpoint how the stimulation protocol alters brain function, structure, or metabolism and relate these after-effects to behavioral and clinical outcomes. Complementing these “offline” approaches, TMS can also be applied “online” during MRI or MRS to delineate how stimulation acutely engages the stimulated brain regions and networks. In this case, it is critical to account for confounds introduced by off-target stimulation of peripheral structures of the nervous system that may not only confound MR-based readouts but also induce neuroplastic phenomena.
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Later it was also shown that rCBF also increases in M1 during subthreshold rTMS, linearly scaling with stimulation frequency from 1 to 5 Hz (Siebner et al., 2001) and outlasting the stimulation period (Takano et al., 2004). Also 18-fluoro-2-deoxy-d-glucose (18FDG) PET has been used to measure glucose metabolism during 2 Hz rTMS, demonstrating for the first time an TMS click sound induced activation of the primary auditory cortex (Siebner et al., 1999b). While also 11C raclopride PET has been used to show extracellular dopamine concentration in the caudate nucleus following 10 Hz rTMS (Strafella et al., 2001), no concurrent PET-TMS studies have been conducted with these kind of ligands up to date.
The experimental manipulation of neural activity by neurostimulation techniques overcomes the inherent limitations of correlative recordings, enabling the researcher to investigate causal brain-behavior relationships. But only when stimulation and recordings are combined, the direct impact of the stimulation on neural activity can be evaluated. In humans, this can be achieved non-invasively through the concurrent combination of transcranial magnetic stimulation (TMS) with functional magnetic resonance imaging (fMRI). Concurrent TMS-fMRI allows the assessment of the neurovascular responses evoked by TMS with excellent spatial resolution and full-brain coverage. This enables the functional mapping of both local and remote network effects of TMS in cortical as well as deep subcortical structures, offering unique opportunities for basic research and clinical applications. The purpose of this review is to introduce the reader to this powerful tool. We will introduce the technical challenges and state-of-the art solutions and provide a comprehensive overview of the existing literature and the available experimental approaches. We will highlight the unique insights that can be gained from concurrent TMS-fMRI, including the state-dependent assessment of neural responsiveness and inter-regional effective connectivity, the demonstration of functional target engagement, and the systematic evaluation of stimulation parameters. We will also discuss how concurrent TMS-fMRI during a behavioral task can help to link behavioral TMS effects to changes in neural network activity and to identify peripheral co-stimulation confounds. Finally, we will review the use of concurrent TMS-fMRI for developing TMS treatments of psychiatric and neurological disorders and suggest future improvements for further advancing the application of concurrent TMS-fMRI.
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It is noteworthy that the left STG cluster that increased RSFC with the right PPC seed is close to Heschl's gyrus where early cortical auditory processing occurs (Tzourio et al., 1997). This change in RSFC cannot be attributed to the TMS auditory artifact (Siebner et al., 1999), since the connectivity change was unilateral, whereas the auditory artifact is binaural and the direction of change was not identical in the PPC and vertex conditions where the auditory stimulation was comparable. Despite our aim to investigate the effect of inhibitory TMS over the PPC at the group level, we recognize the importance of idiosyncrasies in functional brain organization (Lynch et al., 2019).
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In a crossover experiment in healthy individuals, we delivered continuous theta burst TMS to the right PPC and vertex as control condition. We hypothesized that PPC inhibitory stimulation would result in a rightward visuospatial bias, decrease frontoparietal RSFC, and increase the PPC RSFC with the attentional network in the left hemisphere. We also expected that individual differences in fractional anisotropy (FA) of the frontoparietal network and the callosal pathway between the PPCs would account for variability of the TMS-induced RSFC changes.
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Imaging functional activation of the auditory cortex during focal repetitive transcranial magnetic stimulation of the primary motor cortex in normal subjects

Abstract

Section snippets

Acknowledgements

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Hearing loss from the acoustic artifact of the coil used in extracranial magnetic stimulation

Neurology

Imaging intra-cerebral connectivity by PET during TMS

NeuroReport

Anatomic standardization: linear scaling and nonlinear warping of functional brain images

J. Nucl. Med.

No evidence for hearing loss in humans due to transcranial magnetic stimulation

Neurology

Simple reaction time to focal transcranial magnetic stimulation

Brain

Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of human creebral cortex

J. Neurosci.