Axel Thielscher

Simultaneous PET-MRI: a new approach for functional and morphological imaging

Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.

Motor thresholds in humans: a transcranial magnetic stimulation study comparing different pulse waveforms, current directions and stimulator types

OBJECTIVES To evaluate the stimulation effectiveness of different magnetic stimulator devices with respect to pulse waveform and current direction in the motor cortex. METHODS In 8 normal subjects we determined motor thresholds of transcranial magnetic stimulation in a small hand muscle. We used focal figure-of-eight coils of 3 common stimulators (Dantec Magpro, Magstim 200 and Magstim Rapid) and systematically varied current direction (postero-anterior versus antero-posterior, perpendicular to the central sulcus) as well as pulse waveform (monophasic versus biphasic). The coil position was kept constant with a stereotactic positioning device. RESULTS Motor thresholds varied consistently with changing stimulus parameters, despite substantial interindividual variability. By normalizing the values with respect to the square root of the energy of the capacitors in the different stimulators, we found a homogeneous pattern of threshold variations. The normalized Magstim threshold values were consistently higher than the normalized Dantec thresholds by a factor of 1.3. For both stimulator types the monophasic pulse was more effective if the current passed the motor cortex in a postero-anterior direction rather than antero-posterior. In contrast, the biphasic pulse was weaker with the first upstroke in the postero-anterior direction. We calculated mean factors for transforming the intensity values of a particular configuration into that of another configuration by normalizing the different threshold values of each individual subject to his lowest threshold value. CONCLUSIONS Our transformation factors allow us to compare stimulation intensities from studies using different devices and pulse forms. The effectiveness of stimulation as a function of waveform and current direction follows the same pattern as in a peripheral nerve preparation (J Physiol (Lond) 513 (1998) 571).

Impact of the gyral geometry on the electric field induced by transcranial magnetic stimulation

The spatial extent of the effects of transcranial magnetic stimulation (TMS) on neural tissue is only coarsely understood. One key problem is the realistic calculation of the electric field induced in the brain, which proves difficult due to the complex gyral folding pattern that results in an inhomogeneous conductivity distribution within the skull. We used the finite element method (FEM) together with a high-resolution volume mesh of the human head to better characterize the field induced in cortical gray matter (GM). The volume mesh was constructed from T1-weighted structural magnetic resonance images to allow for an anatomically accurate modeling of the gyrification pattern. Five tissue types were taken into account, corresponding to skin, skull, cerebrospinal fluid (CSF) including the ventricles as well as cortical gray and white matter. We characterized the effect of the current direction on the electric field distribution in GM. Importantly, the field strength in GM was increased by up to 51% when the induced currents were perpendicular to the local gyrus orientation. This effect was mainly restricted to the gyral crowns and lips, but did not extend into the sulcal walls. As a result, the focality of the fields induced in GM was increased. This enhancement effect might in part underlie the dependency of stimulation thresholds on coil orientation, as commonly observed in TMS motor cortex studies. In contrast to the clear-cut effects of the gyrification pattern on the induced field strength, current directions were predominantly influenced by the CSF-skull boundary.

Electric field properties of two commercial figure-8 coils in TMS: calculation of focality and efficiency

OBJECTIVE To compare two commonly used TMS coils, namely the Medtronic MC-B70 double coil and the Magstim 70 mm double coil, with respect to their electric field distributions induced on the cortex. METHODS Electric field properties are calculated on a hemisphere representing the cortex using a spherical head model. The coil designs are characterised using several parameters, such as focality, efficiency and stimulation depth. RESULTS Medtronic and Magstim coils exhibit similar focality values and stimulation depths, despite very different coil designs. However, the Medtronic coil is about 1.2 times more efficient compared to the Magstim coil. This difference corresponds to different motor and visual phosphene thresholds obtained in previous physiological studies, thereby validating the chosen coil modelling approach. Focality of the Medtronic coil changed less with varying coil-cortex distance compared to the Magstim coil, whereas both coils exhibited similar dependencies on changes in cortex radius. CONCLUSIONS The similar values for focality and stimulation depth indicate that both coil types should evoke similar physiological effects when adjusting for the different efficiencies. The different physiological thresholds of the two coils can be traced back to differences in coil design. Ideally, focality should depend neither on coil-cortex distance nor on cortex radius in order to allow for an inter-subject comparability. In particular, in motor mapping experiments the size of the resulting maps is affected by these two parameters. Consequently, they are at least partially the cause of the variability across subjects seen in these experiments.

The navigation of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a new method for investigating cortical information processing and for investigating therapeutic applications in psychiatry and neurology. A common problem of most studies in this field regards the localization of the magnetic coil with respect to the cortex. This article reviews the currently used methods and proposes a neuronavigational approach. The method of neuronavigated TMS is described and discussed in detail. It is used to guide the magnetic coil on an individual basis to a structurally or functionally predetermined cortical area while monitoring the location of the coil in relation to the subjects head in real time. Possible applications of TMS in combination with functional neuroimaging in clinical research within a cognitive neuroscience framework are discussed. Future applications of TMS should take individual anatomy into account, and neuronavigation provides the means to do so.

Electric field calculations in brain stimulation based on finite elements: An optimized processing pipeline for the generation and usage of accurate individual head models

The need for realistic electric field calculations in human noninvasive brain stimulation is undisputed to more accurately determine the affected brain areas. However, using numerical techniques such as the finite element method (FEM) is methodologically complex, starting with the creation of accurate head models to the integration of the models in the numerical calculations. These problems substantially limit a more widespread application of numerical methods in brain stimulation up to now. We introduce an optimized processing pipeline allowing for the automatic generation of individualized high‐quality head models from magnetic resonance images and their usage in subsequent field calculations based on the FEM. The pipeline starts by extracting the borders between skin, skull, cerebrospinal fluid, gray and white matter. The quality of the resulting surfaces is subsequently improved, allowing for the creation of tetrahedral volume head meshes that can finally be used in the numerical calculations. The pipeline integrates and extends established (and mainly free) software for neuroimaging, computer graphics, and FEM calculations into one easy‐to‐use solution. We demonstrate the successful usage of the pipeline in six subjects, including field calculations for transcranial magnetic stimulation and transcranial direct current stimulation. The quality of the head volume meshes is validated both in terms of capturing the underlying anatomy and of the well‐shapedness of the mesh elements. The latter is crucial to guarantee the numerical robustness of the FEM calculations. The pipeline will be released as open‐source, allowing for the first time to perform realistic field calculations at an acceptable methodological complexity and moderate costs. Hum Brain Mapp, 2013.

Linking Physics with Physiology in TMS: A Sphere Field Model to Determine the Cortical Stimulation Site in TMS

A fundamental problem of transcranial magnetic stimulation (TMS) is determining the site and size of the stimulated cortical area. In the motor system, the most common procedure for this is motor mapping. The obtained two-dimensional distribution of coil positions with associated muscle responses is used to calculate a center of gravity on the skull. However, even in motor mapping the exact stimulation site on the cortex is not known and only rough estimates of its size are possible. We report a new method which combines physiological measurements with a physical model used to predict the electric field induced by the TMS coil. In four subjects motor responses in a small hand muscle were mapped with 9-13 stimulation sites at the head perpendicular to the central sulcus in order to keep the induced current direction constant in a given cortical region of interest. Input-output functions from these head locations were used to determine stimulator intensities that elicit half-maximal muscle responses. Based on these stimulator intensities the field distribution on the individual cortical surface was calculated as rendered from anatomical MR data. The region on the cortical surface in which the different stimulation sites produced the same electric field strength (minimal variance, 4.2 +/- 0.8%.) was determined as the most likely stimulation site on the cortex. In all subjects, it was located at the lateral part of the hand knob in the motor cortex. Comparisons of model calculations with the solutions obtained in this manner reveal that the stimulated cortex area innervating the target muscle is substantially smaller than the size of the electric field induced by the coil. Our results help to resolve fundamental questions raised by motor mapping studies as well as motor threshold measurements.

How the brain tissue shapes the electric field induced by transcranial magnetic stimulation

In transcranial magnetic stimulation (TMS), knowledge of the distribution of the induced electric field is fundamental for a better understanding of the position and extent of the stimulated brain region. However, the different tissue types and the varying fibre orientation in the brain tissue result in an inhomogeneous and anisotropic conductivity distribution and distort the electric field in a non-trivial way. Here, the field induced by a figure-8 coil is characterized in detail using finite element calculations and a geometrically accurate model of an individual head combined with high-resolution diffusion-weighted imaging for conductivity mapping. It is demonstrated that the field strength is significantly enhanced when the currents run approximately perpendicular to the local gyral orientation. Importantly, the spatial distribution of this effect differs distinctly between gray matter (GM) and white matter (WM): While the field in GM is selectively enhanced at the gyral crowns and lips, high field strengths can still occur rather deep in WM. Taking the anisotropy of brain tissue into account tends to further boost this effect in WM, but not in GM. Spatial variations in the WM anisotropy affect the local field strength in a systematic way and result in localized increases of up to 40% (on average ~7% for coil orientations perpendicular to the underlying gyri). We suggest that these effects might create hot spots in WM that might contribute to the excitation of WM structures by TMS. However, our results also demonstrate the necessity of using realistic nerve models in the future to allow for more definitive conclusions.

Neural Correlates of Perceptual Choice and Decision Making during Fear–Disgust Discrimination

In the present study, we tested the hypothesis that brain activation would reflect perceptual choices. To probe this question, we used functional magnetic resonance imaging (fMRI) during a challenging fear–disgust, two-choice discrimination task. We investigated how moment-to-moment fluctuations in fMRI signals were correlated with perceptual choice by computing a choice probability index that quantified how well behavioral choice could be predicted by single-trial fMRI amplitude. Our analyses revealed that reporting a neutral face as “fearful” was associated with activation in a broad network of brain regions that process emotionally arousing stimuli, whereas reporting a neutral face as “disgusted” was associated with activation in a focused set of sites that included the putamen and anterior insula. Responses predictive of perceptual reports were not only observed at the group level but also at the single-subject level. Thus, voxel-by-voxel fluctuations in fMRI amplitude for an individual participant could be used to reliably predict the perceptual choice of individual trials for that subject. In addition to the investigation of choice, we also isolated the neural correlates of decision making per se by using reaction time as an index of decision processes. Overall, our findings revealed that brain responses dynamically shifted according to perceptual choices. In addition, the neural correlates of decision making involved at least the anterior cingulate cortex, middle frontal gyrus, and inferior frontal gyrus/insula, consistent with recent proposals that decisions may emerge from distributed processes.

Disrupting Parietal Function Prolongs Dominance Durations in Binocular Rivalry

Human brain imaging studies of bistable perceptual phenomena revealed that frontal and parietal areas are activated during perceptual switches between the two conflicting percepts. However, these studies do not provide information about causality, i.e., whether activity reports a consequence or a cause of the perceptual change. Here we used functional magnetic resonance imaging to individually localize four parietal regions involved in perceptual switches during binocular rivalry in 15 subjects and subsequently disturbed their neural processing and that of a control site using 2 Hz repetitive transcranial magnetic stimulation (TMS) during binocular rivalry. We found that TMS over one of the sites, the right intraparietal sulcus (IPS), prolonged the periods of stable percepts. Additionally, the more lateralized the blood oxygen level-dependent signal was in IPS, the more lateralized the TMS effects were. Lateralization varied considerably across subjects, with a right-hemispheric bias. Control replay experiments rule out nonspecific effects of TMS on task performance, reaction times, or eye blinks. Our results thus demonstrate a causal, destabilizing, and individually lateralized effect of normal IPS function on perceptual continuity in rivalry. This is in accord with a role of IPS in perceptual selection, relating its role in rivalrous perception to that in attention.