Real-time fMRI Neurofeedback as a novel neurotherapy for children with ADHD

The study aims to test a novel, non-pharmacological, brain-based therapy for ADHD. Attention Deficit/ Hyperactivity Disorder (ADHD) is one of the most prevalent childhood disorders, typified by poor attention and poor self-control. The last 2 decades of brain imaging have shown that ADHD children have problems with engaging the right inferior frontal cortex (rIFC), which is a key region for self-control and attention. ADHD children are treated typically with stimulant medication which we have shown enhances the activation of this normally underactivated region, bringing it to normal functioning levels. However, stimulants seem to have no longer-term effects, are associated with side effects and not tolerated by all patients. Non-pharmacological treatments are preferred by parents, patients and clinicians, but are not very efficient. In this study we want to test a new treatment that targets a key deficient brain activity in ADHD by teaching ADHD children to self-up-regulate the activity of the rIFC. We hypothesise that this treatment will be efficient because it targets the key brain abnormality that is causing the behavioural problems. We plan to achieve this by using functional magnetic resonance imaging Neurofeedback (fMRI-NF). In fMRI-NF the brain activity of the participant is connected to a videogame. Every time the child increases or decreases brain activity in the target region of the brain (i.e. rIFC) this will drive the gameplay in the videogame. This way the child learns to enhance the activity of certain brain regions by trial and error in a playful way by playing the videogame with their own brain activity. fMRI-NF therefore trains patients to achieve volitional self-control over brain activation. NF using a cheaper method, using electrophysiology (EEG-NF), has been shown to have moderate but relatively long-term efficiency in improving ADHD symptoms of up to 2 years. However, it has been shown that fMRI-NF effects are significantly faster and can target deep cortical regions that are affected in ADHD such as rIFC that cannot be targeted with EEG-NF. rtfMRI-NF studies have been promising in other disorders in remediating key neurofunctional deficit and associated behaviours. Our own pilot feasibility rt-fMRI-NF study showed that 31 ADHD children learned to progressively enhance the activity of their rIFC within 11 sessions of 8 min of fMRI-NF. Furthermore, they managed to do this even without the feedback at the end of the training which shows that the learning effect can be sustained without the scanner. The self-upregulation of rIFC was furthermore associated with reduced severity of their ADHD problems, with better performance on cognitive tests of attention and self-control and with better brain activity in rIFC during tests of self-control. We also showed that the improvement of their behavioural symptoms were maintained 11 months after the treatment. The findings of this first pilot study to test fMRI-NF in ADHD children were therefore very promising. However, we did not include a control condition and hence cannot rule out a placebo effect. We therefore plan a larger and more definite study to prove the concept that children with ADHD can learn to self-upregulate brain activity in the rIFC in 14 sessions of 8.5 minutes of rtfMRI-NF. For this purpose, we will recruit 100 children with ADHD and randomise them between an experimental group (NF of rIFC) and a "sham" (placebo) control group (they will receive "non-real" feedback from another participant), to test whether this new brain treatment will improve ADHD behaviour, as well as brain activity and performance on tests of attention and self-control. The aim is to develop a novel, side-effect free, non-pharmacological, and longer-lasting treatment for ADHD that is based on neuroscience evidence remediating the key brain abnormality of ADHD children that is underlying their poor self-control and poor attention.

The aim is to test the efficacy of a novel, non-pharmacological, neural-correlate focussed therapy for ADHD with no side-effects, expected to be welcomed by patients, parents and professionals. Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent childhood disorders, typified by poor attention and self-control. One of the most consistent and disorder-specific neurofunctional biomarkers is the underactivation of right inferior prefrontal cortex (rIFC), which is upregulated with psychostimulants, the benchmark treatment for ADHD. However, longer-term efficacy of stimulant medication has not been shown, it is associated with side effects and is not indicated for all patients. Non-pharmacological treatments are preferred, but have modest efficacy. We hypothesise that Neurofeedback (NF) that teaches patients to achieve volitional self-control over the key rIFC dysfunction region is likely to be successful. NF using electrophysiology has shown moderate but relatively long-term efficacy in improving ADHD symptoms. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) effects are significantly faster and can target deep (sub)cortical regions that are impaired in ADHD such as rIFC. rtfMRI-NF has been promising in other disorders in remediating key neurofunctional substrates and associated behaviours. Our pilot feasibility rtfMRI-NF study showed that ADHD children can learn to self-regulate rIFC within 11 sessions of 8.5min each with significant transfer effects which is associated with improved clinical symptoms and inhibitory rIFC activation. However, placebo effects cannot be ruled out as we did not include a sham control condition. We therefore plan a larger and more definite data-driven proof of concept study to test the efficacy of a novel neurotherapy for ADHD consisting of rtfMRI-NF of rIFC in 100 children with ADHD, randomised into active and sham control groups, on improving ADHD behaviour, brain function and cognition.

Clinical users: If successful and replicated, in the long-term this research will lead to the improvement of health and quality of life of ADHD patients by developing a novel non-pharmacological treatment for ADHD with no side effects, much preferred by parents, patients and clinicians. Although rtfMRI-NF is expensive, the learning effects have been shown to be relatively fast compared to EEG-NF, requiring only a few sessions of 30min in adults. In our pilot study we showed a learning effect in ADHD children after 6 sessions of 8.5 min fMRI-NF. In addition, we showed significant transfer effects (upregulation without the NF), which were associated with clinical improvements after the training and which persisted for a mean of 11 months. If effects can be achieved in relatively few sessions and are longer lasting than stimulant effects, then ultimately, the neurotherapy may be more cost-effective given that pharmacological treatment typically needs to be given for years, despite losing efficacy over time. In addition, once we have established the proof of concept of rtfMRI-NF as an efficacious neurotherapy for ADHD and have understood the underlying cortical and subcortical mechanisms of action, which can only be tested in fMRI, we will then be able to test the treatment of hemodynamic self-regulation using cheaper methods such as near-infrared spectroscopy NF (NIRS-NF).
Academic users: Academic users will benefit from the study's experience and software development. Other users will want to pioneer our rtfMRI-NF methods for children in other developmental neuropsychiatric, neurological or medical pathologies. We will make the methods available to other users via collaborations.
Private sector: According to business intelligence provider GBI Research, the ADHD therapeutics market value will rise from $6.9 billion in 2013 to $9.9 billion by 2020, due to broadening diagnostic criteria. The company's latest report states that this increase represents a Compound Annual Growth Rate of 5.3% and relates to 8 major markets (including US and UK). ADHD prevalence is predicted to rise steadily across the major markets, from approximately 15 million cases in 2013 to just over 18 million by 2020. The benchmark treatment for ADHD is stimulant medication which has increased dramatically (over 76 fold) over the last decade. However, recent meta-analyses have questioned the short- and longer-term efficacy. Consequently, alternative treatment development for ADHD is already a huge market for the private sector, with many companies offering EEG-NF, brain stimulation, cognitive training, nutritional interventions, etc, despite relatively little evidence for their efficacy. This project will develop an innovative neurotherapy for ADHD patients. If efficacious in fMRI, it could be easily transferred to the cheaper method of NIRS-NF. We envisage that commercial companies will be interested to develop rt-fMRI-NF or NIRS-NF software and hardware, similar to the now expanding market of EEG-NF software and hardware, for example by German manufacturers in collaboration with researchers (i.e., Neuroconn equipment; http://www.neuroconn.de/produkte_neurofeedback_en). MRI scanner manufacturers are also increasingly interested in using their devices for therapeutic, as well as diagnostic and prognostic purposes.
Public sector: The NHS (and international healthcare systems) would benefit in the long-term by this research and subsequent replications that would establish rt-fMRI-NF or NIRS-NF as a neurotherapy for ADHD. Further, it could lead to similar studies and the introduction of similar methods for the healthcare of other psychiatric and medical patients. This has potential to improve the effectiveness of healthcare services.
Transferrable skills: Researchers will develop analytic, statistical, communication and writing skills, team work, and dealing with difficult patients. They will learn analyses of cognitive, clinical and fMRI data.