Getting to the nub of the issue with NIBS and Tourette Syndrome

Posted on 31 January 2018

Research Manager at Tourettes Action, Dr Seonaid Anderson features in prestigious publication, The Psychologist, interviewing Tourette Syndrome research pioneer, Professor Stephen Jackson on the benefits of using non-invasive brain stimulation to treat TS. You can read the full unedited article here.

With Brain Awareness Week (BAW) in March each year (12-18^th March 2018) this global campaign aims to increase public awareness of the progress and benefits of brain research. Using the momentum of this initiative, research charity Tourettes Action has the chance to engage patients, the public and professionals in the misunderstood condition Tourette Syndrome. This Q & A highlights the flow of communication between research charity, scientist and the patient in this overview of research into the potential use of non-invasive brain stimulation for Tourette Syndrome.

Tourette Syndrome (TS) is an inherited neurological condition. It affects one school child in every hundred and is more common amongst boys. Over 300,000 children and adults are living with TS in the UK. The key features are tics – involuntary sounds and movements, which must be present for at least 12 months to meet the diagnostic criteria. Over 85% of people with TS will also experience co-occurring conditions and features which might include Attention Deficit Hyperactivity Disorder (ADHD), Obsessive Compulsive Disorder (OCD), and Anxiety.

TS is often misunderstood as a condition which makes people swear, or say socially inappropriate things. Although it is true that 'coprolalia' – the clinical term for involuntary swearing – is a symptom of TS, it only affects a minority of people. 90% of people with TS do not have coprolalia.

Q & A with Professor Stephen Jackson                                                                    

 

Professor Stephen Jackson & Dr Seonaid Anderson	Tourettes Action research manager Dr Seonaid Anderson wanted to find out more about a potential non-drug treatment for TS and interviewed Professor Stephen Jackson from the University of Nottingham to ask some questions….

 

SA: Professor Jackson how long have you been involved in Tourette Syndrome research?

SJ: I have been researching human sensorimotor function (i.e., how sensory information is used to plan and control movements), including neurological movement disorders, for over 25 years, but my focus on Tourette syndrome really started around 10 years ago. Now it is my primary research interest and a topic that fascinates me.

SA: What are the research areas you are interested in?

SJ: My research is guided by two primary objectives, both of which stem from discussions with people with Tourette syndrome and their families. The first objective is to develop a means of predicting clinical and behavioural outcomes in Tourette syndrome. Around two thirds of individuals who experience debilitating tics as children will have mild tics, or their tics will have remitted, by early adulthood. However, the remaining third will experience persistent tics in adulthood. My research uses brain imaging and brain stimulation techniques to understand how tics become controlled or remit during the course of adolescence. The second objective is to develop safe and effective non-drug treatments for TS that can ideally be used within the home to suppress tics. Currently our focus is on evaluating whether non-invasive brain stimulation [NIBS] techniques can be used to reliably suppress tics.

SA: People with TS would be interested in hearing more about treatments for TS.  I understand that you have published research about a neurotransmitter called GABA playing a role in TS? Can you tell us a little more about this? Is there potential for this to lead to a new treatment in the future?

SJ: Tourette syndrome has been associated with alterations in the balance of excitatory and inhibitory influences within key brain networks and in particular with alterations in the operation of the neurotransmitter GABA. GABA is the main inhibitory neurotransmitter in the brain and contributes to almost all brain functions. The role of GABA neurons (brain cells) is to reduce the activity of neurons to which they make contact. As GABA neurons make contact with very many neighbouring cells they play a key role in controlling the activity (excitation) within brain networks. Currently we think that hyper-activity in the brain's motor networks give rise to the occurrence of tics.  We recently investigated whether alterations in GABA concentration contributed to the occurrence of tics in Tourette syndrome using a brain scanning technique call magnetic resonance spectroscopy. Our results showed something really very new and exciting. We found that concentrations of GABA within the supplementary motor area [SMA] - a region strongly associated with the generation of motor tics - were increased in individuals with TS and associated with decreased motor excitability. Furthermore, GABA concentrations within the SMA were associated with motor tic severity. Together these results indicate that localised alterations in GABA may contribute to the suppression of tics in Tourette syndrome and suggest an important direction for new approaches to treatment.

SA: We have heard of a new potential treatment called - Repetitive transcranial magnetic stimulation (TMS)?

From the literature we have a definition of TMS 'Transcranial magnetic stimulation is a non-invasive method of brain stimulation in which an electric coil is used to induce a magnetic field over the scalp. This induces circular electrical (eddy) currents in the brain that in turn cause stimulation of neurons and muscle activity. Repeated stimulation with short bursts of high-frequency stimulation has been applied for the treatment of movement disorders in humans' (Hollis et al, 2016).

SJ: Transcranial magnetic stimulation [TMS] is one particular type of non-invasive brain stimulation [NIBS]. NIBS techniques have been shown previously to alter cortical excitability for a sustained period after stimulation has stopped. Furthermore, NIBS is known to alter levels of GABA and glutamate (the primary excitatory neurotransmitter in the brain) following stimulation. These findings suggest that NIBS may form the basis for new non-drug treatments for Tourette syndrome that are safe and effective in suppressing tics.

NIBS equipment. Photos courtesy of University of Nottingham 2017.

SA: It looks as though this has already been used for TS? From the literature it would appear so.  'The use of rTMS has mainly been focused on application to Parkinson's disease but it has also been used for dystonia and TS' (Hollis et al, 2016).

SJ: Repetitive TMS [rTMS] involves delivering a series of magnetic pulses to a specific brain area. When rTMS is used therapeutically it may be delivered daily for several days or even weeks. A number of studies have now been conducted to evaluate whether rTMS can have beneficial effects in Tourette syndrome. These studies suggest that rTMS can lead to a significant reduction in tics that can be observed for several months after stimulation has ceased.

SA: A potential treatment? My understanding from this research was that an important result was found from this that new brain stimulation techniques, such as TDCS, can be used to increase or decrease GABA in targeted areas of the cortex? It sounds as though potentially young people with TS could 'train' their brains to help them gain control over their tics?

SJ: NIBS may be used directly to alter cortical excitability and thus suppress tics, or else it may be used to enhance the effects of other treatments. Specifically, NIBS techniques have been shown previously to enhance motor learning. It is likely that delivering NIBS as an adjunct to other forms of therapy (e.g., habit-reversal therapy) may enhance the effectiveness of therapy. Our research programme at the NIHR-funded Nottingham Biomedical Research Centre is focused specifically on investigating a wide range of NIBS techniques, and evaluating their potential as effective treatments for the clinical symptoms of Tourette syndrome and co-occurring disorders.

 

Figure reproduced from Zrenner C, Belardinelli P, Müller-Dahlhaus F and Ziemann U (2016) Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops. Front. Cell. Neurosci. 10:92. doi: 10.3389/fncel.2016.00092

SA: What stage is this at?

SJ: Our work is still at an early stage. We are currently evaluating a wide range of NIBS approaches with the aim of identifying those that have the most potential as effective therapies. We have already identified some approaches that , while effective, are unlikely to develop into useful therapies long-term, and others that show great promise. We are also looking at evaluating the effectiveness of peripheral electrical stimulation (similar to the TENS machines used to treat chronic pain conditions). Once we have identified a few approaches that we feel have potential, we will then begin a series of studies to evaluate their clinical effectiveness.

SA: Are there people in the UK with TS using these machines in this way?

'There is no robust evidence to suggest that the physical interventions reviewed [deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), intravenous (iv.) immunoglobulin, botulinum toxin and acupuncture] are sufficiently effective and safe to be considered as treatments for tics in children and young people with TS' (Hollis et al, 2016).

SJ: Although NIBS is being used in the UK to treat a number of conditions such as depression, chronic pain, and to promote recovery of function after stroke, I am not aware of NIBS being used to treat Tourette syndrome as yet. However, I think this will happen before too long.

SA: Availability? Is this available to people, can they ask for these machines on the NHS – how would you envisage this working? People going to clinic for this type of treatment? Using it at home?

SJ: Some forms of NIBS such as rTMS can only be used within a hospital or University setting and are unlikely to be suitable for self-administration. Other forms of NIBS, such as transcranial electrical stimulation [tES] have the potential to be used within the home. In fact we have recently completed two placebo-controlled single case studies in which we conducted a trial of the effectiveness of home administration of tES for Tourette syndrome. The findings from this study were really promising and demonstrated a reduction in tic severity and premonitory urges after active stimulation compared to placebo stimulation. We hope to run further such studies in the near future and will be looking for volunteer families in due course.

SA: Any dangers/concerns using this technique? 'Very high intensity rTMS can induce seizures and guidelines recommend limits on the maximum stimulation intensity. The intensity of stimulation is often determined relative to a person's resting motor threshold (minimum intensity needed to cause a response in the target muscle) reducing intensity settings to safe limits' (Hollis et al, 2016).

I understand that physical treatments (like rTMS) are used rarely in children and young people except in exceptional circumstances?

SJ: TMS and rTMS are used routinely all over the world and are extremely safe provided that they are used properly and operated within agreed limits. These safety limits are widely known and strictly adhered to. TMS and rTMS can be used safely with children and adolescents. Other forms of NIBS such as tES are extremely safe and carry little or no known risk of seizure. For this reason they have the potential to be developed for use outside of the clinic.

 

Patients perspective

Keen to get the patients perspective, I contacted Ben Parfitt who was involved in a research project about TCDS at the University of Nottingham.

'I was diagnosed about 6 years old, I'm 18 now. I've got multiple motor and vocal tics all the time. When my Dad told me about the research I was chuffed and I thought it was brilliant as I had tried everything so far'.

The University of Nottingham invited Ben to be part of a blind, sham-controlled case study of the beneficial effects of tDCS. Ben and his father Neil were trained in how to apply the electrodes and operate the tDCS system (this is completely pre-programmed by the researchers at the University of Nottingham and cannot be altered or misused so it is deemed appropriate for home use). 

Ben described how the research started 'I had a brain scan at the University of Nottingham and then the treatment of once a day for 20 minutes with the machine at home. It wasn't painful but it did tingle a little, in a good way like you were being tickled. It took a couple of days for the treatment to kick in, just the way medication does'.

Ben was stimulated each day for 20 mins (in his own home) for 10 consecutive days and we are obtaining video of his tics every other day. After a 7 day washout period a second 10 day period of stimulation was carried out. One of these was a sham stimulation (is not active and is used like a placebo) and one was active stimulation. Ben, Neil and those people measuring tics from the videos were all blind to this (they didn't know when the stimulation was real or a sham).

Ben describes how the research continued 'we went back to University of Nottingham and they made some adjustments and changed the settings and then there was a bigger difference and all my tics reduced. It was brilliant. At first I felt a little nausea and dizzy but very soon, after about 5 days it was gone. That was the only side effect, but they warned me this might happen'. In terms of how he was after the research had finished 'I had a year of doing it (the research), I finished in May (2016) and now the tics have gone back to how they used to be. But since being involved in the research and instead of going to school in my last year I had home tuition and have an apprenticeship now.  I feel much better now and once I had been involved in the research my attitude changed. I was out and about and went to the gym and didn't let it stop me from living my life'.

SA: Would this treatment be an alternative to medication/behavioural therapy or used in conjunction with them? 'It is unknown if rTMS is an effective treatment for tics in adults with severe TS. Hollis et al (2016) found that there was no evidence available for the use of rTMS in children and young people with TS.

SJ: The meta-analysis you refer to has strict rules about what kinds of studies can be included. There have now been a number of open label studies that indicate that NIBS is successful in reducing tics in TS. NIBS can be used as a stand-alone treatment aimed at reducing tics or in conjunction with other therapies where it might be used to enhance or accelerate the effects of therapy.

SA: What do you think is the future direction of this research?

Hollis et al (2016) state that 'currently, there is no clear evidence that rTMS is an effective treatment for tics and the predominance of crossover trials with the potential for carry-over effects makes it difficult to drawn any firm conclusions. Future parallel trials may provide better evidence on which to base judgements. Although rTMS is a less invasive a procedure than DBS, there remains uncertainty over its safety and suitability for use in children and young people'.

SJ: I think that research into the potential benefits of NIBS for treating neurodevelopmental conditions is currently at a very exciting stage. Current research has examined only a very limited set of NIBS approaches. One future direction will be to explore a much wider range of NIBS techniques. We might also need to re-think how we evaluate the effectiveness of potential therapies. At the moment the randomised-controlled trial (RCT) is viewed as the 'Gold Standard', however this may not be ideal.  One of the striking features of many therapies is that the success rate is often close to 50-60%. Does this mean that the therapy hasn't worked for 40-50% of participants, or is it that the therapy was not optimal for those individuals? A key objective for many groups is to develop therapies that are tailored to individual patients. In my view, a future direction for NIBS research will be to deliver stimulation with much more precision that is tailored to an individual's physiology. In the case of Tourette syndrome, it would be advantageous to deliver NIBS precisely when and where it was needed: i.e., whenever an individual is about to tic.

 

References:

1. Hollis C; Pennant M; Cuenca J; Glazebrook C; Kendall T; Whittington C; Stockton S; Larsson L; Bunton P; Dobson S; Groom M; Hedderly T; Heyman I; Jackson GM; Jackson S; Murphy T; Rickards H; Robertson M; Stern J (2016). Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis. Health Technology Assessment, No. 20.4
2. Draper, A., Stephenson, M.C., Jackson, G.M, Pepes, S., Morgan, P.S., Morris. P.G. & Jackson, S.R.  Increased GABA contributes to enhanced control over motor excitability in Tourette syndrome. Current Biology 2014 Oct 6; 24(19): 2343–2347.
3. Kim SY, Stephenson MC, Morris PG, Jackson SR (2014). tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: A 7 T magnetic resonance spectroscopy study. NeuroImage 9: 237-243.

Thanks to Professor Stephen Jackson and Ben & Neil Parfitt.

Professor Stephen Jackson is a Professor of Cognitive Neuroscience at the University of Nottingham and acknowledges the financial support of the NIHR Nottingham Biomedical Research Centre

Dr Seonaid Anderson, Tourettes Action research manager

Tourettes Actionwww.tourettes-action.org.ukis the leading support and research charity for people with Tourette Syndrome and their families.  Helpdesk: 0300 777 8427. Email: help@tourettes-action.org.uk

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