Developing novel neuroimaging approaches to investigate the neural antecedents of tics and brain correlates of premonitory urges in Tourette syndrome

Tourette syndrome (TS) is a neurological condition of childhood onset that is characterised by motor and vocal tics. Many (~90%) people with TS report that their tics are preceded by a 'premonitory urge' (PU) that is described as uncomfortable bodily sensations that is experienced as a strong urge-to-tic. People who experience PU often report that they would not exhibit tics if they did not experience PU. For these reasons, we consider it timely and highly important to investigate the brain mechanisms that give rise to the urge to tic in TS using brain imaging techniques such as functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG).

Unfortunately, scanning individuals with TS using conventional fMRI and MEG methods is extremely difficult due to their unwanted movements, which often lead to a very high (50-75%) loss of data. This problem is exacerbated if the individual is actually required to express their tic while being scanned (i.e., in conventional fMRI analyses it is necessary that tics actually occur so that the time course of the brain activity associated with producing the tic can be modelled). However, most TS patients can suppress their tics quite effectively: although tic suppression is associated with increasing levels of discomfort which is experienced as a strong urge-to-tic. This suggests that we might successfully scan many TS patients if we asked them to suppress their tics throughout the period they were being scanned.

The objective of this project is to develop new approaches to imaging PU and the neural antecedents of tics in TS. One approach is based upon an alternative, data-driven, framework for the analysis of functional magnetic resonance imaging (fMRI) data, termed 'Multi-echo Sparse Paradigm Free Mapping' (ME-SPFM), in which we obtain fMRI measurements associated with PU that occur in TS without the necessity for tic expression. Using this approach, we will accurately and reliably identify functional brain activity that is associated with the occurrence of PU in circumstances where tics are effectively suppressed (i.e. there is no tic to use as an external timing event).

The second approach involves our using an entirely novel form of wearable MEG device, developed at the University of Nottingham. MEG is a non-invasive brain imaging technique that has advantages over fMRI: not least it allows the measurement of ongoing brain activity at the millisecond scale. Using this device will allow us to record brain activity associated with PU, and the brain activity that precedes a tic, in patients with TS even when they are executing large head or body movements. A key focus of the MEG studies that we will carry out are that they will allow us to investigate how transiently-synchronising brain networks are assembled linking brain regions associated with the experience of the urge-for-action with brain networks involved in the initiation of action. Once again, these analyses will be conducted using novel, state-of-the-art, data-driven approaches to investigating changes in functional connectivity between brain areas.

TS is a neurological condition characterised by motor and vocal tics. Many (~90%) individuals with TS report that their tics are preceded by 'premonitory sensory/urge phenomena' (PU) that are described as uncomfortable bodily sensations that precede the execution of a tic and are experienced as a strong urge-to-tic.

We consider it timely and also highly important to investigate the functional anatomy and pathophysiology of the urge to tic in TS using novel neuroimaging approaches that overcome the difficulties associated with trying to study the neural antecedents of movement (tics) in scanning environments in which movement is typically avoided at all costs.

Most TS patients can suppress their tics quite effectively, although tic suppression is associated with increasing levels of discomfort which is experienced as a strong urge-to-tic. This suggests that we might successfully scan many TS patients during tic suppression, however this would make investigating the neural antecedents of tics challenging.

Our solution to this will be to develop:

(a) an approach termed 'Multi-echo Sparse Paradigm Free Mapping' (ME-SPFM) in which we obtain fMRI BOLD measurements associated with PU that occur in TS without the necessity for tic expression. Unlike in conventional fMRI studies, ME-SPFM can detect the onset and spatial distribution of BOLD events in the brain without the need for prior timing information. Using this approach, we will accurately and reliably identify functional brain activity that is associated with the occurrence of PU in circumstances where tics are effectively suppressed (i.e. there is no tic to use as an external timing event).

(b) an approach to imaging the neural antecedents of tics in TS, based upon novel, 'wearable', MEG technology developed at the University of Nottingham. This has the advantage that MEG signals, measured at the millisecond scale, can be reliably recorded - even when an individual is executing large movements

Mental health represents 15% of the disease burden in developed countries and improving young people's mental health is a key challenge and policy objective for the NHS. Tourette syndrome (TS) is a relatively common mental health condition that affects around 1% of children and adolescents and can have a devastating effect on a child's cognitive, emotional, social and educational development, and impact negatively on the child's immediate family and caregivers.

Neurodevelopmental disorders such as TS carry a substantial societal and economic cost. For ADHD (which is highly co-morbid with TS) the cost in England and Wales of initial specialist assessment is estimated to be £23 million annually; with medication costs for this disorder estimated to exceed £78 million. Similar economic estimates for conditions such as TS are not currently available.

Impact on Stakeholder Groups:
Our research programme has been developed in collaboration with the UK-wide charity for TS -- Tourettes Action (TA) -- and is based on research priorities identified by TS patients and their families. One such priority is to understand the pathophysiology of tics and the role played by premonitory urges (PU) in the generation of tics. Another is to use this knowledge to develop safe, effective, non-invasive neuromodulation approaches that can promote the remission of tics and the suppression of PU, and would, ideally, be suitable for home administration. We will seek to disseminate our findings widely to the membership of TA and other stakeholder groups and deliver regular updates through public engagement lectures organised by the TA for health professional and other stakeholder groups.

Impact on Public Understanding:
TS is a very widely misunderstood disorder and, despite the fact that it causes so much misery to patients and their families, is often not taken particularly seriously by the media and by some members of general public. We will seek to widely disseminate our findings describing the neural antecedents of tics and the neural correlates of PU in TS through regular updates through the University of Nottingham media centre. To date our work has led to numerous articles, interviews and programmes in the written press, radio and TV (e.g., BBC Inside Out 2019; BBC The One Show, 2019).

Impact on UK Industry:
A key aim of our research programme is to contribute to the development of safe, effective, non-invasive neuromodulatory devices that can promote or enhance brain alterations that lead to the remission of tics during early adulthood and would be suitable for home administration. This has been identified by patient groups and their families as a very high priority goal for our research efforts. The focus of the current grant is on understanding the pathophysiology of tics and the brain correlates premonitory urges (PU) in TS.

The NIHR Healthcare Technology Co-operative (HTC) for Mental Health & Neurodevelopmental Disorders (MindTech) is hosted by the University of Nottingham and was established and funded to provide a national resource to facilitate collaboration between industry, academics, clinicians and service users to develop and evaluate new technologies that support assessment, monitoring and therapy in mental health and neurodevelopmental disorders. Through MindTech we will work with industrial partners, clinicians and patient groups to contribute our findings to the development of neuromodulation devices that would be suitable for administration within the clinic and within the home. Our research findings will be particularly relevant to this goal and updates on our findings will be regularly communicated to interested parties through meetings and workshops organised via MindTech, and through MindTech web-based and social media communications.