Periodic Reporting for period 2 - ConnectToBrain (Connecting to the Networks of the Human Brain) Reporting period: 2021-03-01 to 2022-08-31 Summary of the context and overall objectives of the project Non-invasive modulation of the brain with transcranial magnetic stimulation (TMS) has demonstrated good results and has been approved widely for clinical use and insurance coverage. However, with the current technology, the locus (position in the brain) of the stimulation can only be changed slowly and real-time information of the electrical brain-state is not taken into account, limiting the therapies, in practice, to a single brain site and open-loop stimulation. The goal in the multinational and multidisciplinary ConnectToBrain project is to develop and prepare for wide clinical use a transformative multi-locus closed-loop TMS technique. The synergistic project consists of three main areas of development:1) Multilocus TMS (mTMS) coil array, power and control electronics, and user interface, the array covering most of the cortical mantle and allowing real-time high-precision control over the locus, direction, intensity, and timing of the stimulation pulses.2) Real-time analysis of brain activity and connectivity by using functional information from high-density electroencephalography (EEG) and anatomical information from magnetic resonance imaging for brain-state-dependent and closed-loop stimulation.3) Demonstration of feasibility, safety, and efficacy of the developed techniques and methods, and their therapeutic utility in dysfunctional brain networks in brain disorders such as Alzheimer’s disease and motor stroke.An illustration of the future system is presented in Fig. 1. By the end of the project, we expect to have developed new technology capable of correcting dysfunctional brain networks in several brain disorders with better therapeutic efficacy than current state-of-the-art techniques and the potential to induce a major paradigm shift in therapeutic neuromodulation. If successful and widely transferred for clinical use, ConnectToBrain will eventually lead to a substantial reduction in the suffering and economic burden caused by several brain disorders. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The corona crisis slowed down most aspects of the work, including instrument development and the planned researcher exchange; almost all travel was cancelled, which also contributed to the difficulty of working together. However, there was steady and satisfactory progress in all tasks described in the grant agreement; preparations were made to allow quick action immediately after normal working conditions would be restored.At AALTO, we have experimented with the previously built 2-coil TMS device to help develop closed-loop algorithms for ConnectToBrain multi-coil systems. The planned 5-coil prototype at Aalto has been built, has undergone technical tests and is currently used in preliminary human experiments. The prototype for Tübingen, with novel features, including compatibility for hospital use, was further delayed due to corona, the somewhat unexpected complications related to regulatory requirements (including safety measures and documentation) when installing it in a German hospital, and more recently, by very long waiting times for some key electronic components. The instrument was installed in Tübingen in October 2022. We have worked also on the 12-channel design and on solutions for TMS-compatible EEG and algorithms and cap design for reducing TMS-related artifacts in EEG. Because of technical difficulties with our experimental MEG–MRI system, the correction of which will require a new round of SQUID sensor fabrication in a separate and independent project, we have not yet started attempts to measure tissue conductivities with ultra-low-field MRI. Overall, the technical development proved far more challenging and broad that initially anticipated. As a consequence, we had to hire more people to the hardware and software group to speed up the project. The original plan to concentrate most of the design and prototyping (electronics, software architecture and transducers) work to the first 3 years of the project became even more focused to the first years.At EKUT, we have completed proposed experiments on brain-state-dependent stimulation in simple 2-node networks in healthy subjects. We confirmed our hypothesis that effective connectivity between the primary motor cortices of the two hemispheres as tested by dual-coil interhemispheric short-interval inhibition is most strongly expressed if the two TMS pulses are applied when the sensorimotor µ-rhythm in the two hemispheres is synchronized. We have completed experiments to test the Communication Through Coherence theory, one of the central neurobiological hypotheses of the ConnectToBrain project, by repetitively stimulating the primary motor cortices of the two hemispheres at specific phase relations of the ongoing µ-rhythm. Unfortunately, the findings overall were non-significant. In particular, it could not be demonstrated that repetitive stimulation of the two primary motor cortices while in-phase with respect to µ-rhythm phase resulted in more efficient change of interhemispheric effective connectivity compared to out-of-phase or random phase stimulation. This does not disprove the Communication Through Coherence theory, and we are currently working out, why the experiments were negative. In addition, we have completed several more studies that elaborate on principles of signal-to-noise ratio for real-time estimation of the phase in EEG-recorded oscillations, and on causal decoding of EEG data for estimation of cortical excitability at the individual level. We have extended the application of real-time analysis of EEG for brain-state-dependent transcranial magnetic stimulation from µ-rhythm of motor cortex to the alpha- and theta-rhythms of prefrontal cortex. This is crucial preparatory work that will allow the planned targeting of the working memory network where the prefrontal cortex as one major hub. The results of these studies are pivotal for further usage and software development in our brain-state-dependent stimulation approaches. Furthermore, we have designed a proof-of-principle experiment for the first application of closed-loop transcranial magnetic stimulation in humans and have successfully started closed-loop experiments. We have performed extensive simulation studies to demonstrate the feasibility of deep learning algorithms to support the automated optimized determination of µ-rhythm phase for inducing long-term potentiation-like plasticity of the connection between the supplementary motor area and primary motor cortex in healthy individual subjects. We have started the real experiments with conventional TMS instrumentation, and will continue these experiments in late 2022 or early 2023 in a validation experiment by using the 5-channel mTMS device that has been developed at AALTO and arrived at EKUT on October 10, 2022. These experiments follow a request of the ConnectToBrain Scientific Advisory Board. The closed-loop approach is considered essential for the success of the ConnectToBrain project. At UdA, we have worked towards establishing algorithms to assess whole brain connectivity in real time from EEG data. To this aim, the real-time performance of algorithms widely used for functional connectivity analysis have been assessed. We have demonstrated that, to achieve a reliable connectivity estimate in real-time, a data analysis window of about 5 cycles is sufficient for the majority of the tested connectivity metrics. Using data acquired at EKUT, we investigated the relationship between functional connectivity in the motor network and Motor Evoked Potential (MEP) amplitude. We demonstrated that mu rhythm connectivity in the motor network in the time period preceding left primary motor cortex (M1) stimulation modulates MEP amplitude. On the same data, we were able to identify transient brain states lasting few hundreds of milliseconds with a specific spatial, temporal and spectral fingerprint and variable relation to MEP amplitude. Finally, using motor cortex stimulation data from the Aalto 2-coil mTMS system, we assessed connectivity modulation before and after stimulation of the left Supplementary Motor Area (SMA) showing that functional connectivity between SMA and left and right M1s is enhanced by the stimulation. Overall, the results of these studies are crucial for the assessment of the role of connectivity in brain-state-dependent stimulation at multiple sites by mTMS.At AALTO, we organized the BrainSTIM 2020 conference in May 2020 and 8th Science Factory: TMS–EEG Summer School and Workshop in September 2022. These meetings were very successful. In addition, all three sites together have presented special scientific sessions on the ConnectToBrain theme, for instance, in the Basic and Clinical Multimodal Imaging Conference (“BaCI”, virtual, October 2021), in the Brain Stimulation Conference (Charleston, SC, USA, December 2021), in 32nd International Congress of Clinical Neurophysiology (Geneva, CH, September 2022), and 22nd International Biomagnetism Conference (Birmingham, UK, August–September 2022). Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) We have already progressed beyond the state of the art in three major ways.1) We have constructed a multi-locus TMS device, with 5 overlapping coils: one round, two figure-of-eight, two cloverleaf-shaped. When these coils are activated simultaneously, a focal electric field in the brain can be produced. By adjusting the relative intensities of the 5 coil currents, the focal point of stimulation in the cortex can be electronically defined; these stimulation points can be changed in less than a millisecond, allowing spatially distributed sequences of TMS pulses that were not possible before. This work has involved the design of the coils, power electronics, control electronics, navigation, patient support systems, software architecture and user interface design, all of which include novel features that will allow safe and efficient use of the technology.2) We have developed algorithms for analyzing electromyography (EMG) and electroencephalography (EEG) data for brain-state-dependent closed-loop brain stimulation. We have developed algorithms to predict the phase of EEG-recorded oscillations at sensor and source levels in real time, in order to deliver TMS pulses at desired phases of the oscillatory activity. We have also developed algorithms that clean noise and artifacts from the EEG signal, in particular eye-movement and TMS-evoked muscle artifacts. Furthermore, we have developed algorithms for determining time-dependent changes of functional connectivity in the brain based on EEG; this will allow one to perform closed-loop stimulation based on connectivity information. Moreover, we have developed closed-loop rTMS based on deep reinforced learning algorithms to enchance connectivity in nodes of the motor network.3) We have demonstrated with existing one-coil technology that TMS efficacy for induction of long-term plasticity in motor cortex can be enhanced by triggering the pulses at the right phase of alpha-frequency EEG signals. We have demonstrated with the existing two-coil device that one can find motor representation areas without moving the transducer and with a much smaller number of pulses than with traditional methods.By the end of the project, we expect to have developed new technology capable of correcting dysfunctional brain networks in several brain disorders with better therapeutic efficacy than current state-of-the-art techniques and the potential to induce a major paradigm shift in therapeutic neuromodulation. If successful and widely transferred for clinical use, ConnectToBrain will eventually lead to a substantial reduction in the suffering and economic burden caused by brain disorders. Fig. 1: Illustration of the feedback-controlled multi-locus transcranial magnetic stimulation system
