Causal brain connectivity: Brain stimulation combined with optically pumped magnetometers

The core aim of this proposal is to implement a novel technique to assess the connectivity in the human brain by developing optically pumped magnetometers (OPMs) that can be combined with transcranial magnetic stimulation (TMS). This allows us to assess brain connectivity by stimulating one region and measuring the response in another region. The approach holds the promise of providing capabilities needed for understanding the brain as a network and to investigate brain connectivity in cognition and disorders.

Currently there is strong enthusiasm for OPMs. This new type of sensor has the potential of revolutionizing human electrophysiology. In particular OPMs allow us to measure small magnetic fields from neuronal currents in the brain, which so far is usually done using conventional SQUID-based magnetoencephalography (MEG). The disadvantages of conventional MEG are that 1) the sensors rely on cooling by liquid Helium which is highly expensive and 2) the sensors cannot work with brain stimulation. OPMs solve both concerns but need to be further developed to be integrated with brain stimulation.

Brain stimulation using TMS is used to activate a given brain region by delivering a brief but strong magnetic pulse. The technique can also be used to stimulate one brain region and measure the response in connected regions. This has recently been attempted by combining TMS with electroencephalography (EEG); however, the resulting signals are spatially blurred and therefore difficult to interpret. Combining TMS with OPMs holds the promise of better identifying the regions responding to a specific perturbation. As such it will allow us to measure connectivity in the brain and quantify how this connectivity is modulated in a task specific manner. Furthermore, the technique can be used to assess connectivity changes associated with brain injuries and neurological disorders.

Specifically, we will develop a new type of OPMs that can be used together with TMS. These new sensors will be benchmarked against conventional MEG sensors. Subsequently we will test the OPMs together with TMS. This will first be done using phantom recordings and subsequently tested in humans performing various tasks hypothesized to modulate brain connectivity. Within this proposal we are aiming at using up to 5 sensors. Therefore, B-conn will provide the stepping-stone for developing a whole-head OPM-MEG system with ~100 sensors in collaboration with commercial and academic partners. The longer-term goal is to develop an integrated stimulus-response system that can be used in clinical settings for diagnostic purposes by quantifying alterations in brain connectivity associated with communication delays and strengths. Examples are traumatic brain injury and neurodegenerative diseases.

The goal is to assemble compact all-optical optically pumped magnetometers employing the nonlinear magneto-optical rotation to measure the field. We will build on the existing OPM developed at UoB. Sensor's head will be non-magnetic. To minimize the undesired effects that TMS pulses might have on the OPM, the laser, modulator, detection and control units will be placed outside the shielded room and modulated light will be delivered using optical fibres. The OPM and stimulation coil will be integrated using 3D-printed subject specific headcasts designed based on MRI scans. It will incorporate multiple slots for the sensor to simulate multichannel MEG recordings. The TMS pulse/OPM readout sequence will be time synchronized employing advanced computer control system and time delays to minimize the "dead-time" of the sensor. All artefacts of the TMS coils will be reduced by adding extra electronics to the coil driver. OPMs will be benchmarked against Neuromag MEG by measuring and quantifying the brain response using a standard spatial attention paradigm. We will record evoked and oscillatory response to the visual stimulus. Finally, we will conduct a set of experiments where we stimulate one region of the brain with TMS and measure the response over cortex using the OPMs. We will stimulate the frontal-eye field (FEF), which is known to project to the visual cortex via the dorsal longitudinal fasciculus. This proof-of-principle experiment will allow us to establish that the stimulation works and can elicit an evoked response over longer distances. We will quantify the visual evoked and oscillatory responses to the TMS pulse of the FEF. We will employ visuospatial attention tasks in which attention mediated via the FEF is known to modulate evoked and oscillatory visual responses. We will perturb this modulation as measured by the OPMs by stimulating the FEF during the allocation of spatial attention, expecting to observe a reduced modulation of the alpha band activity.

Mapping structural and functional connectivity of the human connectome is an emerging and expanding field that is experiencing an impressive exponential grow in impact. For instance The Human Connectome Project sponsored by NIH has the ambition to map the neural connections in human brain in their entirety which is an enormous task given that there are about 100 billions neurons and 10000 connections. Important experimental contributions towards investigation of neural connections are still challenging and this project will have a substantial impact on the expanding national and international academic community working on the topic. We will provide an innovative and powerful platform which will allow to focally excite one part of the brain and measure the response in another part with great precision. For the first time, we will be able to directly assess connectivity in the brain in a causal manner and to investigate how this connectivity changes when different brain networks are engaged in different tasks.

Moreover, development of miniaturized all-optical optically pumped magnetometers, one of the key elements in this project, is among the building blocks of next generation technologies. This research programme has been conceived to fill the gap in the promising and exciting field of magnetoencephalography with quantum sensors. MEG with OPMs is already becoming a popular and rapidly growing field of research, however, we are still lacking sensors able to work together with various stimulators, especially TMS pulses. Our novel experimental methods will have a substantial impact on the field of neuroscience due to the unprecedented combination of brain stimulation and MEG.

The proposed project will not only deepen our understanding of human brain and connectome but also will establish how abnormal connectivity changes with cognitive and neurological problems, thus moving forward the frontiers for future medical diagnostics technologies. The developed integrated stimulus-measurement system will be a novel tool, which can establish new methodologies for a drug-free non-invasive treatment of brain disorders by closed-loop brain stimulation. B-conn will create a baseline of neuroscience knowledge of an effective bio-stimulation. It could represent the starting point of a new technology that might have an important impact in the industry and society in a decade.

By exploring a new branch of research, we will consolidate existing knowledge and add a new edge to optical magnetometry concepts, educating a large number of researchers and students via involvement in the work, seminars and workshops. This project will identify new challenges for the community interested in optical magnetometers and quantum sensors. Overcoming them will allow to lay the foundations of a new manner of managing quantum devices and combining them with a conventional neuroscience and medical techniques. By realizing its objectives, this project will thus make a substantive impact in our understanding of human brain, with immediate benefits for the broadest neuroscience and medical community. The project goals and tasks illustrated herein make this project potentially relevant both for industrial applications in quantum technologies and medical applications.