Calibrated Brain Stimulation by Concurrent TMS/fMRI

Transcranial Magnetic stimulation (TMS) is a non-invasive brain stimulation tool that can be applied to the surface of the brain. It is an officially approved treatment option in the USA for patients suffering from major depressive disorder, particularly for those patients that showed no improvement in their symptoms after standard drug therapy. Despite its great potential, not all of the depressive patients can be successfully treated with this method. The aim of our project is to overcome the two most common sources of problems in magnetic stimulation, namely stimulation of unfavourables brain areas and using too high or too low stimulation dosea. Magnetic stimulation is applied by a magnetic coil placed over the head in a very specific orientation. The beneficial stimulation area for depression treatment is located in a very specific part of left forebrain. Unfortunately, stimulation is very often inefficient because of targeting issues with this specific area or due to motion of the patient during stimulation. Furthermore, the optimal stimulation dose for stimulating the forebrain is currently not known. The adjustment of stimulation intensity is commonly based on observing the reactions of muscles to the stimulation of motion-related brain areas. The relationship between excitability of motor brain areas and excitability of forebrain areas is, however, not known. The goal of this project is to optimize routines for determining stimulation location and optimized doses. Therefore, we are going to use an in-house developed method that allows for the recording of brain images during the direct stimulation of the brain. Using this technique, we have the ability to observe brain activation during stimulation and to furthermore adjust stimulation intensities during stimulation. For that purpose we will use the details from anatomical brain images and other information, including sex, weight, age. Through such optimisations in stimulation targeting and dose we will greatly improve the stimulation treatment outcome. This will reduce the number of patients that are currently not benefitting from magnetic stimulation therapy.

Non-invasive brain stimulation techniques offer promising new therapy options for patients suffering from neurological diseases and psychiatric disorders. Among these techniques, transcranial magnetic stimulation (TMS) is closest to clinical application as it is already approved for treating major depressive disorder in patients that do not sufficiently benefit from pharmacological therapy. A major challenge in applying TMS is, however, the considerable variability in patients' responses to TMS treatment. Combining TMS with functional magnetic resonance imaging (fMRI), a method for obtaining activation and connectivity maps in human brains, can be key in revealing the causes for this variability as it allows assessing the brain activation changes during TMS application. This project was dedicated to improving the challenging combination of TMS and fMRI in order to provide the basis for determining the TMS parameters on the individual patient level. We set up a method for ensuring accurate head motion measurements during the application of TMS in the MR scanner. For this, we developed a novel calibration plate that was designed using extensive computational modelling to ensure maximum coverage while minimising measurement times. This invention allowed assessing the accuracy of distance measurements made with optical neuronavigation hardware in a matter of seconds, covering a range of distances. With this device we not only demonstrated the high accuracy of optical neuronavigation in general, but also validated that this accuracy also holds true inside the MR scanner bore. The second aim of the project focused on determining dose response profiles in individual subjects. In order to achieve this aim, we improved our previously published TMS/fMRI setup where we were using several multiple receive coil arrays positioned around the head. Our results clearly demonstrated that it is possible to measure the dose-response profile in the depression-treatment target area in single study participants. Interestingly, we found that dose responses did not simply increase with higher stimulation intensity as might be expected. In some individuals, we found brain activation decreased when stimulation intensities surpassed certain levels, indicating a mechanism for explaining why some patients do not benefit from TMS therapy. This opens new possibilities for associating actual brain activation levels with treatment success in order to enable early prediction of treatment response based on an initial TMS/fMRI scan. Even more, the newly developed technique could also shed light on the brain activation level required for optimal TMS treatment success. The final aim of the project targeted a technique for improving the quality of TMS/fMRI studies by compensating for the head motion during the TMS application. Based in the neuronavigation methods developed within this project, we successfully implemented an online motion assessment approach that changes stimulation intensity in real-time to alleviate the effects of changes in coil-to-target distances.