fMRI-compatible TMS stimulation equipment for concurrent brain stimulation and measurement

One of the great mysteries of our time is how human cognition - our ability to perceive, think, remember, reason, imagine and feel - arises from our brain physiology. Non-invasive brain imaging techniques like functional magnetic resonance imaging (fMRI) allow us to observe the brain in action, examining how blood flow to different parts of the brain changes when participants perform task. This has been important for understanding which brain regions are involved in different tasks, and advanced analysis methods now also allow us to examine the types of stimulus and task distinctions that activity in these brain regions encodes. However, the inference from fMRI is limited in an important way: we cannot tell whether the activity we observe is causally involved in generating thought and behaviour. For example, if a particular brain region is active when a stimulus is shown, this region may be necessary for perception of that stimulus (i.e. the task could not be done without it), or it may just reflect superfluous activation (e.g. a copy of information) that is not critical for perception. Using traditional techniques, we cannot examine whether activity in one brain region is causally linked to activity in another, or whether activity in any brain region is actually necessary for behaviour.

The proposed research uses transcranial magnetic stimulation (TMS) concurrent with fMRI to overcome this limitation. TMS is an established technique which temporarily perturbs activity in a targeted brain region. If TMS to a brain region changes performance on a cognitive task, we know that the brain region must be causally involved. Typically, the inference stops there. However, this is again limited because we cannot observe the hidden effects that the TMS is having on local and distant brain regions, meaning that we cannot unpick the mechanisms by which performance was affected.

We propose to invest in new cutting-edge TMS machinery that can be used simultaneously with fMRI, so that we can perturb activity in a targeted brain region with TMS and simultaneously read of the effects of the perturbation throughout the brain, while also recording any changes in behaviour. This will allow us to trace the local and distant, immediate and sustained physiological effects of the TMS stimulation, and thus to link neural activity in the targeted brain region with information processing throughout the brain, and behaviour. In this way we will finally begin to understand the causal role of different brain regions in giving rise to thought and action. This is a critical insight that has been missing from the majority of previous brain imaging studies.

This proposal brings together experts in neuroimaging and cognition from across the University of Cambridge in the Departments of Psychology, Psychiatry and the MRC Cognition and Brain Sciences unit, in a new cross-departmental collaboration that will transform the University to a centre of excellence in this field and bring the UK to the forefront of research into the causal biological mechanisms underpinning cognition. We will use the technology to discover the casual biological mechanisms underpinning a wide range of cognitive processes, including how we pay attention, perceive the visual world, understand speech, derive meaning of concepts, learn, and remember. Contributing to a global endeavour to understand the human brain, this will significantly enhance the UK research base in the physiology of cognition, provide outstanding training opportunities for PhD students and early career researchers, and advance our understanding of brain function with implications for human health and well-being including healthy ageing.

Human neuroscience needs a step-change in its ability to link biology (brain activation, neurotransmitters, etc) formally and causally to cognitive function. Most current methods (e.g. functional magnetic resonance imaging, fMRI) are inherently correlational, leaving a dire need for an alternative experimental approach.
Transcranial Magnetic Stimulation (TMS) offers a well-established way to influence local brain function and test the causal relationship between brain and behaviour. However, TMS is critically limited in that it does not reveal the neural effects of stimulation, so yields incomplete understanding of the biological mechanisms at play.
A solution is provided by concurrent TMS-MRI. TMS pulses are delivered while a participant performs a task in an MRI scanner: we perturb activity in a target brain region and immediately record the effects of stimulation. This has many advantages. Most importantly, because we observe both local and downstream effects, we can causally relate verifiable perturbation of a targeted brain region to physiological changes elsewhere in the brain and to behaviour. Using single pulses of TMS, we can also target the brain region at specific timepoints, giving temporal resolution that is not available with sequential TMS-followed-by-fMRI approaches, and we can intermingle TMS and control trials, improving experimental control.
There is a pressing need to enhance the UK research-base in this method. We propose to purchase the UK's first integrated TMS stimulation and MR receiver coils, delivering greater flexibility in coil positioning, better signal to noise ratio, and compatibility with advanced fMRI acquisition techniques. Housed in our well-supported research-dedicated facility at the University of Cambridge, and employed to examine fundamental aspects of perception, attention, learning, memory, and emotion in human health, it will provide the opportunity for major advances in understanding the physiology of human cognition.

This novel equipment system designed to allow concurrent TMS-MRI will be, in the configuration we propose, the first of its kind in the UK. Our proposal is designed as a multi-user facility for scientists in Cambridge and also the UK more broadly. As such it is not possible to detail the pathways to impact for all projects that will utilise the system.

The Case for Support does, though, outline some exemplar projects including pathways to impact. At a broad, strategic level there are three kinds of impact plan:

1. Collaboration for equipment manufacturers: As noted above and in the Case for Support, this equipment for concurrent TMS-MRI is the first of its kind in the UK. We have already initiated strategic discussions with the manufacturer, Magventure, to form a strategic relationship in terms of working in partnership to explore the capabilities of the technology, to improve future iterations of the system and data acquisition and to become a host institution. These discussions are at an early stage. Assuming that these progress positively we will engage with the University of Cambridge's IP partners (Cambridge Enterprise Ltd) to formalise agreements on any IP, etc. that may arise from the collaboration.

2. Clinical translation: All exemplar projects noted in the Case for Support are focussed on the basic science of examining the neurobiology of numerous sensory, motor and higher cognitive functions. Many of them note, in addition, that there is considerable potential for broader impact, particularly in the clinical neuroscience disciplines (e.g., neurology, neuropsychology, psychiatry and clinical psychology) and allied health professions (e.g., speech and language therapy). These pathways to impact all reflect the unique ability of the concurrent TMS-MRI to measure the impact and broader responses to stimulation. This has the potential to be used as an experimental model of clinical populations - for example, to explore the intrinsic compensatory mechanisms that may support recovery of function after brain damage. In addition, the system should allow for a proper parameterisation of stimulation protocols. To date, clinical use of TMS and other forms of neurostimulation is based on custom-and-practice with minimal research-led guidance. Formal examination of stimulation protocols and design offer a major shift in clinical practice towards neurobiological and neuroscience led interventions.

3. Education translation: the explorations into the neurobiological bases of memory formation, language learning and speech perception are highly relevant to educators. Contemporary education policy and methods are increasingly calling on neuroscience findings to inform practice with regard to optimal learning methods and strategies.

Methods for translation:
The investigators including in this application and their host departments all have a very strong track record for translation of research into clinical and educational contexts. This is achieved through multiple methods. First, the applying departments are inherently multi-disciplinary in nature containing basic scientists, education practitioners and clinically active staff. This allows for immediate and direct translation of the basic science and also reverse translation. Secondly, numerous staff are either clinically-qualified or clinically active. The three departments work together to support a wide range of clinical and educational special interest groups which bring educators and clinicians together with the basic scientists to review and plan the next translational steps. All departments have a strong track record in translating science for the benefit of education policy and practice, clinical translation, clinical trials and clinical guidelines. These multiple, proven pathways will be used to secure impact and translation.