Design and evaluation of a rodent-specific focal transcranial magnetic stimulation coil with the custom shielding application in rats

Repetitive TMS has been used as an alternative treatment for various neurological disorders. However, most TMS mechanism studies in rodents have been based on the whole brain stimulation, the lack of rodent-specific focal TMS coils restricts the proper translation of human TMS protocols to animal models. In this study, we designed a new shielding device, which was made of high magnetic permeability material, to enhance the spatial focus of animal-use TMS coils. With the finite element method, we analyzed the electromagnetic field of the coil with and without the shielding device. Furthermore, to assess the shielding effect in rodents, we compared the c-fos expression, the ALFF and ReHo values in different groups following a 15 min 5 Hz rTMS paradigm. We found that a smaller focality with an identical core stimulation intensity was achieved in the shielding device. The 1 T magnetic field was reduced from 19.1 mm to 13 mm in diameter, and 7.5 to 5.6 mm in depth. However, the core magnetic field over 1.5 T was almost the same. Meanwhile, the area of electric field was reduced from 4.68 cm2 to 4.19 cm2, and 3.8 mm to 2.6 mm in depth. Similar to this biomimetic data, the c-fos expression, the ALFF and ReHo values showed more limited cortex activation with the use of the shielding device. However, compared to the rTMS group without the shielding application, more subcortical regions, like the striatum (CPu), the hippocampus, the thalamus, and the hypothalamus were also activated in the shielding group. This indicated that more deep stimulation may be achieved by the shielding device. Generally, compared with the commercial rodents’ TMS coil (15 mm in diameter), TMS coils with the shielding device achieved a better focality (~6 mm in diameter) by reducing at least 30% of the magnetic and electric field. This shielding device may provide a useful tool for further TMS studies in rodents, especially for more specific brain area stimulation

Analysis and development of transcranial magnetic stimulation devices

Transcranial magnetic stimulation (TMS) is an emerging technique to stimulate neural tissue non-invasively by inducing electric field in the brain with pulsed high-intensity magnetic field. The advantages of stimulating neural tissue in this way have resulted in the technique being rapidly adopted for research and clinical purposes. Advances in the depth and localization of stimulation that TMS can achieve will allow new applications to be established that could replace surgical alternatives. To evaluate the performance of coils used for TMS it is necessary to understand how electric field is induced in neural tissue. To model this phenomenon, numerical methods and anatomically realistic human head models have been employed to accurately determine where neural stimulation will occur. The results of this analysis reveal the simplified homogeneous head models used in earlier studies are unable to correctly predict the distribution of induced electric field at depth in the brain. This method has subsequently been applied to develop novel coil designs to facilitate stimulation of deep-lying brain regions. Additionally, the mechanical stress experienced by TMS coils has been investigated to support further development of combined neuromodulation and neuroimaging systems

Novel coil designs for different neurological disorders in transcranial magnetic stimulation

Transcranial magnetic stimulation is a non-invasive, safe, painless out-patient treatment for major depressive disorder. In TMS, time varying magnetic field is used to induce electric field, in the region of interest, to stimulate the neurons. Coil design is an important aspect of TMS, as coils are used to navigate the magnetic field in the desired location. The work presented in this dissertation is regarding the use of the coil design development for the application of transcranial magnetic simulation. Two TMS coils namely the Triple Halo Coil and the Quadruple Butterfly Coil were presented, with one aiming for deep brain stimulation and other one for precise stimulation. The magnetic field due to the Triple Halo Coil is 7 times more than circular coil at 10 cm below the head. It can stimulate deep brain regions which are affected in disorders such as Parkinson’s disease and PTSD. The Quadruple Butterfly Coil has reduced volume of stimulation by around 10% at the vertex and dorsolateral prefrontal cortex when compared with the Figure-8 coil. Fifty heterogeneous MRI derived head models were used for the analysis of the induced electric field due to the Quadruple Butterfly Coil and the results were compared with the Figure-8 coil. For both the coils, first computer modelling was done on heterogeneous head models, using a finite element tool and testing using a prototype built by Jali Medicals with the help of an axial Hall probe and a gaussmeter. Furthermore, seven different coils for small animals were presented in this dissertation. These coils had varying electric field with the Slinky coil having the minimum area of stimulation and lowest electric field below 10 mm of the head, while the Animal Halo Coil had maximum area of stimulation and highest electric field at 1 mm below the head. Animal coils are important as animal testing reduces the cost and expedites the research time

Computational Electromagnetic Methods for Transcranial Magnetic Stimulation.

Transcranial magnetic stimulation (TMS) is a noninvasive technique used both as a research tool for cognitive neuroscience and as a FDA approved treatment for depression. During TMS, coils positioned near the scalp generate electric fields and activate targeted brain regions. In this thesis, several computational electromagnetics methods that improve the analysis, design, and uncertainty quantification of TMS systems were developed. Analysis: A new fast direct technique for solving the large and sparse linear system of equations (LSEs) arising from the finite difference (FD) discretization of Maxwell’s quasi-static equations was developed. Following a factorization step, the solver permits computation of TMS fields inside realistic brain models in seconds, allowing for patient-specific real-time usage during TMS. The solver is an alternative to iterative methods for solving FD LSEs, often requiring run-times of minutes. A new integral equation (IE) method for analyzing TMS fields was developed. The human head is highly-heterogeneous and characterized by high-relative permittivities (10^7). IE techniques for analyzing electromagnetic interactions with such media suffer from high-contrast and low-frequency breakdowns. The novel high-permittivity and low-frequency stable internally combined volume-surface IE method developed. The method not only applies to the analysis of high-permittivity objects, but it is also the first IE tool that is stable when analyzing highly-inhomogeneous negative permittivity plasmas. Design: TMS applications call for electric fields to be sharply focused on regions that lie deep inside the brain. Unfortunately, fields generated by present-day Figure-8 coils stimulate relatively large regions near the brain surface. An optimization method for designing single feed TMS coil-arrays capable of producing more localized and deeper stimulation was developed. Results show that the coil-arrays stimulate 2.4 cm into the head while stimulating 3.0 times less volume than Figure-8 coils. Uncertainty quantification (UQ): The location/volume/depth of the stimulated region during TMS is often strongly affected by variability in the position and orientation of TMS coils, as well as anatomical differences between patients. A surrogate model-assisted UQ framework was developed and used to statistically characterize TMS depression therapy. The framework identifies key parameters that strongly affect TMS fields, and partially explains variations in TMS treatment responses.PhDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111459/1/luisgo_1.pd

Optimizing the neuroplastic effects of cathodal transcranial direct current stimulation over the primary motor cortex and transferability to prefrontal cortex

Die Behandlungsmöglichkeiten neurologischer und neuropsychiatrischer Erkrankungen haben sich in den letzten Jahrzehnten deutlich verbessert, sind aber immer noch eingeschränkt. Eine Dysregulation oder Störung der Neuroplastizität ist bei vielen psychischen und Hirnfunktionsstörungen beteiligt. Hier sind nicht-invasive Hirnstimulationstechniken relevant, die die Plastizität des Gehirns modulieren, ohne die physische Integrität des Schädels zu beeinträchtigen. Eine davon, die transkranielle Gleichstromstimulation (tDCS), hat in mehreren klinischen Pilotstudien vielversprechende Ergebnisse zur Verminderung von Symptomen auf der Grundlage von Störungen des Zentralnervensystems gezeigt. Diese Effekte sind jedoch häufig moderat, zeigen eine nichtlineare Dosisabhängigkeit und eine interindividuelle Variabilität. Um die Wirksamkeit dieses Verfahrens zu verbessern, sind länger anhaltende und homogenere Effekte erforderlich. Dies erfordert neuartige, verbesserte Interventionsstrategien. Darüber hinaus wurden die neuromodulatorischen Wirkungen von tDCS auf den primären motorischen Kortex bisher weitgehend als Grundlage für die Anwendung dieser Intervention auf andere Hirnregionen herangezogen, während eine direkte Untersuchung der physiologischen Wirkungen von tDCS auf nichtmotorische Regionen weitgehend fehlt. Die Arbeit zielt darauf ab, diese Herausforderungen durch den Einsatz innovativer neurophysiologischer und mathematischer Techniken anzugehen, um die Wirksamkeit des kathodalen tDCS über dem primären motorischen Kortex zu verbessern, aber auch die Übertragbarkeit der Ergebnisse auf den präfrontalen Kortex zu untersuchen. Zu diesem Zweck titrierten wir im ersten Schritt systematisch kathodale tDCS-Parameter für das humane motorische Kortexmodell mit unterschiedlichen Intensitäten (1, 2 und 3 mA) und Stimulationsdauern (15, 20 und 30 min). Die Ergebnisse zeigten intensitätsabhängige nichtlineare Effekte, bei denen die Stimulation mit 1 mA eine signifikante Verringerung der Amplitude der motorisch evozierten Potentiale (MEP) induzierte, während die Stimulation mit 2 mA zu einer signifikanten Erhöhung der kortikospinalen Erregbarkeit führte. Protokolle mit höherer Stimulationsintensität (insbesondere Stimulation mit 3 mA) induzierten erneut eine signifikante Verringerung der Erregbarkeit, die etwa eineinhalb Stunden nach der Stimulation andauerte, und waren daher effizienter als die anderen Protokolle. Im zweiten Schritt haben wir untersucht, ob wiederholte tDCS-Protokolle mit unterschiedlichen Intervallen die Nacheffekte verlängern können. Wir verglichen die Auswirkungen von Einzelinterventionen mit konventioneller (1 mA für 15 Minuten) und optimierter kathodaler tDCS (3 mA für 20 Minuten) mit den Auswirkungen einer wiederholten Anwendung in Intervallen von 20 Minuten und 24 Stunden auf die Erregbarkeit des primären motorischen Kortex, basierend auf tierexperimentellen Befunden, dass kurze, aber nicht lange Intervalle zwischen einzelnen Interventionen eine langanhaltende Plastizität erzeugen. Die Ergebnisse zeigten, dass die Dauer der Nacheffekte wiederholter konventioneller und optimierter Protokolle mit kurzen Intervallen im Vergleich zu den jeweiligen Einzelinterventionsprotokollen nahezu unverändert blieb. Für das lange Intervall (24 h) veränderte die Stimulation mit dem herkömmlichen Protokoll die jeweiligen Nachwirkungen nicht signifikant, während sie die Wirksamkeit des optimierten Protokolls im Vergleich zu den jeweiligen Einzelinterventionen verringerte. Ein wichtiges Ergebnis der ersten Studie waren die beobachteten nichtlinearen intensitätsabhängigen Effekte von tDCS, die eine Erklärung für teilweise heterogene Ergebnisse der kathodalen Stimulation bieten können, allerdings hinsichtlich ihrer neurophysiologischen Grundlagen bisher nur unzureichend untersucht waren. Im dritten Schritt haben wir daher die zugrunde liegenden Mechanismen dieser nonlinearen Effekte untersucht. Da tDCS eine NMDA-Rezeptor-abhängige Neuroplastizität erzeugt, die Kalzium-abhängig ist, kann eine solche Nichtlinearität möglicherweise durch unterschiedliche durch die Intervention induzierte Kalziumkonzentrationen erklärt werden, die die Richtung der Plastizität steuern. Wir verabreichten daher den Kalziumkanalblocker Flunarizin in niedrigen (2,5 mg), mittleren (5 mg) oder hohen (10 mg) Dosierungen vor der kathodalen tDCS des motorischen Kortex mit 3 mA für 20 Minuten. Die Ergebnisse zeigten, dass die durch kathodale tDCS hoher Intensität induzierten inhibitorischen Nachwirkungen bei niedrigen, mittleren bzw. hohen Dosierungen eines Kalziumblockers nicht verändert, verringert oder in eine Erregbarkeitserhöhung modifiziert wurden, was die Kalzium-abhängige Direktionalität von tDCS-induzierter Neuroplastizität bestätigt. Das Ergebnis der ersten und zweiten Studie zeigten eine relevante interindividuelle Variabilität der tDCS-Effekte, die eine weitere Quelle für die begrenzte Wirksamkeit dieser Intervention sein könnte. Jüngste In-vivo-Experimente und Computerstudien am Menschen zeigten, dass das tDCS-induzierte elektrische Feld (EF) stark von der individuellen Anatomie des Gehirns und den Leitfähigkeitseigenschaften des Gewebes abhängt. Die EF-Variabilität könnte daher ein wichtiger Faktor für heterogene Ergebnisse der tDCS sein. Im vierten Schritt, basierend auf neurophysiologischen Daten, die in früheren Studien unserer Gruppe erhoben wurden, die tDCS-induzierte MEP- (induziert durch transkranielle Magnetstimulation (TMS)) und zerebrale Blutfluss-Veränderungen (CBF; gemessen durch funktionelle Magnetresonanztomographie (MRT) über arterielles Spin-Labelling) erfaßten, untersuchten wir den Zusammenhang zwischen einzelnen anatomischen Faktoren, tDCS-induziertem EF und den jeweiligen physiologischen Parametern auf der Ebene des Individuums. Zu diesem Zweck wurde für jeden Teilnehmer ein MRT-basiertes realistisches Kopfmodell entworfen, um 1) anatomische Faktoren zu berechnen und 2) die tDCS- und TMS-induzierten elektrischen Felder (EF) zu simulieren. Anschließend untersuchten wir auf regionaler Ebene, welche einzelnen anatomischen Faktoren die simulierten EFs erklären. Schließlich untersuchten wir, welche spezifischen anatomischen und / oder EF-Faktoren die neurophysiologischen Ergebnisse der tDCS vorhersagten. Die Ergebnisse zeigten, dass von den untersuchten anatomischen Faktoren höhere EF-Werte mit einem geringeren Abstand zwischen Elektrode und Kortex (ECD) und einer geringeren Dicke des Liquor cerebrospinalis (CSF) verbunden waren. Zusätzlich waren CSF-Dicke und ECD negativ korreliert, während EFs positiv mit tDCS-induzierten physiologischen Veränderungen korreliert waren. Schließlich untersuchten wir im fünften Schritt die Übertragbarkeit der durch kathodale tDCS induzierten Neuroplastizität vom motorischen auf den präfrontalen Kortex. Die neurophysiologischen Wirkungen von tDCS auf den primärmotorischen Kortex wurden bereits in einer vielzahl von Studien untersucht. Viel weniger ist jedoch hinsichtlich physiologischer Effekte der tDCS auf nichtmotorische Bereiche wie den präfrontalen Kortex bekannt, der eine wichtige Basis für vielfältige kognitive Funktionen darstellt und dessen Dysfunktionen an neuropsychiatrischen Störungen beteiligt sind. Zu diesem Zweck wurde kathodale tDCS mit niedrigen, mittleren und hohen Dosierungen oder eine Placebo-Stimulation über dem primärmotorischen und dorsolateralen präfrontalen Kortex appliziert. Die Nacheffekte der tDCS wurden mittels TMS-Elektroenzephalographie (EEG) und TMS-MEP auf regionaler Ebene für die Ergebnisparameter TMS-evozierte Potentiale (TEP), TMS-evozierte Oszillationen und MEP-Amplitudenänderungen bewertet. Die Ergebnisse zeigten eine dosisabhängige nichtlineare neurophysiologische Wirkung der tDCS über dem motorischen Kortex, die nicht vollständig auf die Ergebnisse der tDCS über dem präfrontalen tDCS übertragbar war. Niedrige und hohe Dosierungen der tDCS über dem motorischen Kortex reduzierten frühe positive TEP-Peaks und MEP-Amplituden, während eine Erhöhung der Amplituden dieser Potentiale für primärmotorische tDCS mit mittlerer Dosierung beobachtet wurde. Im Gegensatz dazu reduzierte präfrontale tDCS mit niedriger, mittlerer und hoher Dosierung die frühen positiven TEP-Amplituden gleichermaßen. Darüber hinaus wurden für beide kortikalen Bereiche keine tDCS-induzierten neuromodulatorischen Effekte auf späte TEP-Amplituden (mit Ausnahme präfrontaler tDCS mit niedriger Dosierung) oder TMS-evozierte Oszillationen beobachtet. Zusammengenommen hat diese Arbeit unter Verwendung innovativer neurophysiologischer, Computergestützter und bildgebender Verfahren wichtige Aspekte in Bezug auf tDCS-induzierte neuroplastische Effekte untersucht, und liefert neue Erkenntnisse für zukünftige Anwendungen von tDCS in Grundlagen- und klinischen Studien.Major advances have been made in treatment of neurological and neuropsychiatric disorders; they have however still significant limitations. A vast body of evidence shows a dysregulation or disruption of neuroplasticity in mental and brain disorders. Here, non-invasive brain stimulation techniques come into play, which modulate brain plasticity without disrupting the integrity of the skull. One of those, transcranial direct current stimulation (tDCS), has shown promising results in several pilot clinical studies to improve symptoms of central nervous system disorders; but, in general, effects are often moderate, show nonlinear dosage-dependency, and interindividual variability. For improving the efficacy of this tool, more sustained, and homogeneous effects are required. This requires novel, improved intervention strategies. In addition, neuromodulatory effects of tDCS over the primary motor cortex were largely taken as a template so far for the use of this intervention over other brain regions, whereas a direct exploration of the physiological effects of tDCS on non-motor regions is largely missing. The thesis aims to address these challenges, by utilizing advanced neurophysiological and computational techniques, aiming to improve the efficacy of cathodal tDCS over the primary motor cortex, but also to explore the transferability of the results to the prefrontal cortex. To this end, we at the first step systematically titrated cathodal tDCS parameters for the human motor cortex model with different intensities (1, 2, and 3mA) and durations (15, 20 and 30 min). The results revealed intensity-dependent nonlinear effects, in which stimulation with 1 mA induced a significant motor evoked potentials (MEP) amplitude diminution, while stimulation with 2 mA resulted in a significant corticospinal excitability enhancement. Protocols with higher stimulation intensity (specifically stimulation with 3 mA) induced again a significant excitability diminution lasting for about one and half hour after stimulation, and thus were more efficient than the other protocols. At the second step, we explored if repeated tDCS protocols with different intervals can prolong the after-effects. We compared the impact of single interventions of conventional (1mA for 15min) and optimized cathodal tDCS (3mA for 20min) with the effects of repeated application with intervals of 20 min and 24 hours on primary motor cortex excitability, based on the assumption derived from animal models that short, but not long intervals induce late phase plasticity. The results revealed that the duration of after-effects of repeated conventional and optimized protocols with short intervals remained nearly unchanged, as compared to the respective single intervention protocols. For the long interval (24 h), stimulation with the conventional protocol did not significantly alter respective after-effects, while it reduced the efficacy of the optimized protocol, as compared with respective single interventions. One important outcome of the first study were the observed nonlinear intensity-dependent effects of tDCS, which might be an explanation for sometimes heterogeneous outcomes of cathodal stimulation, and are not well explained at the neurophysiological level. At the third step we therefore explored the underlaying mechanisms of this nonlinearity. Since tDCS generates NMDA receptor-dependent neuroplasticity, which has calcium channel properties, such non-linearity can likely be explained by different levels of calcium concentration induced by the intervention, which control for the directionality of plasticity. We therefore administrated the calcium channel blocker flunarizine in low (2.5 mg), medium (5 mg) or high (10 mg) dosages before cathodal motor cortex tDCS of 3mA for 20min. The results revealed that the inhibitory after-effects induced by high intensity cathodal tDCS were unchanged, diminished, or converted to excitability enhancement with low, medium and high dosages of a calcium blocker, respectively, which confirms the calcium-dependent directionality of tDCS-induced neuroplasticity. The outcome of the first and second studies showed also relevant inter-individual variability of tDCS effects, which could be another source of limited efficacy of this intervention. Recent human in-vivo experiments and computational studies indicated that the tDCS-induced electrical field (EF) depends strongly on individual brain anatomy and tissue conductivity properties. EF variability might thus be an important factor for heterogeneous outcomes of tDCS. At the fourth step, based on neurophysiological data obtained in former studies of our group, which explored tDCS-altered MEP (induced by transcranial magnetic stimulation (TMS)) and cerebral blood flow (CBF; measured by functional magnetic resonance imaging (MRI) via arterial spin labeling), we investigated the association between individual anatomical factors and tDCS-induced EF, and the respective physiological outcomes at the level of the individual. To this end, for each participant, a MRI-based realistic head model was designed to 1) calculate anatomical factors and 2) simulate the tDCS- and TMS-induced electrical fields (EF). We then investigated at the regional level which individual anatomical factors explain the simulated EFs. Finally, we explored which specific anatomical and/or EF factors predicted the neurophysiological outcomes of tDCS. The results indicated that, of the included anatomical factors, higher EF values were associated with lower electrode to cortex distance (ECD), and cerebrospinal fluid (CSF) thickness. In addition, CSF thickness, and ECD were negatively correlated, whereas EFs were positively correlated with tDCS-induced physiological changes. Finally, at the fifth step, we explored the transferability of cathodal tDCS-induced neuroplasticity from the motor to the prefrontal cortex. Neurophysiological effects of tDCS have been extensively studied over the primary motor cortex. Much less is however known for its effects over non-motor areas, such as the prefrontal cortex, which is the neuronal foundation for many high-level cognitive functions, and involved in neuropsychiatric disorders. To this end, cathodal tDCS was applied with low, medium, and high dosages, or as sham stimulation, and applied over the primary motor and dorsolateral prefrontal cortex. After-effects of tDCS were evaluated via TMS-electroencephalography (EEG), and TMS-MEP at the regional level, for the outcome parameters TMS-evoked potentials (TEP), TMS-evoked oscillations, and MEP amplitude alterations. The results indicated a dosage-dependent nonlinear neurophysiological effect of motor cortex tDCS, which was not one-to-one transferable to the results of prefrontal tDCS. Low and high dosages of motor cortex tDCS reduced early positive TEP peaks, and MEP amplitudes, while an enhancement was observed for medium dosage motor cortex tDCS (early positive TEP peak and MEP amplitudes). In contrast, prefrontal low, medium and high dosage tDCS uniformly reduced the early positive TEP peak amplitudes. Furthermore, for both cortical areas, tDCS-induced neuromodulatory effects were not observed for late TEP peaks (with the exception of low-dosage prefrontal tDCS), nor TMS-evoked oscillations. Taken together, using advanced neurophysiological, computational and neuroimaging techniques, this thesis has addressed important challenges regarding tDCS-induced neuroplastic effects, and thus provides new insight for future applications of tDCS in basic and clinical studies

Numerical modelling in transcranial magnetic stimulation

Tese de doutoramento, Engenharia Biomédica e Biofísica, Universidade de Lisboa, Faculdade de Ciências, 2009In this work powerful numerical methods were used to study several problems that still remain unsolved in TMS.The first problem that was studied is related to the difficulties that arise when stimulating sub-cortical deep regions with TMS, due to the fact that the induced field rapidly decays and loses focality with depth. This study's approach to overcome this difficulty was to combine ferromagnetic cores with a coil designed to induce an electric field that decays slowly. The efficacy of this approach was tested by using the FEM to calculate the field induced by this coil / core design in a realistically shaped head model. The results show that the core might make this coil even more suited for deep brain stimulation.The second problem that was tackled is related to the lack of knowledge about the dominant mechanisms through which the induced electric field excites neurons in TMS. In this work the electric field along lines, representing trajectories of actual cortical neurons, was calculated using the FEM. The neurons were embedded in a realistically shaped sulcus model, with a figure-8 coil placed above the model. The electric field was then incorporated into the cable equation. The solution of the latter allowed the determination of the site and threshold of activation of the neurons. The results highlight the importance of axonal terminations and bends and tissue heterogeneities on stimulation of neurons.The third problem that was studied concerns TMS of small animals and the lack of knowledge about the optimal geometry, size and orientation of the used coils. This was studied by using the FEM to calculate the electric field induced in a realistically shaped mouse model by several commercially available coils. The results showed that the smaller coils induced fields with higher magnitude, better focality, and smaller decay than the bigger coils.These results highlight the importance of numerical modelling in TMS, either in coil design, determination of basic neurophysiologic mechanisms or optimization of experimental procedures