Neural dynamics of response inhibition and gambling across the lifespan

Response inhibition or 'impulse control' is a hallmark of flexible and intelligent behavior, required whenever a thought or action must be stopped or slowed. Without inhibition, many everyday behaviors would be impossible, such as driving a motor vehicle or engaging in normal social interactions. The importance of inhibition is highlighted by the fact that patients with psychiatric conditions or brain damage often present with life-changing deficits of inhibitory control, including severe addictions. Furthermore, as we advance into middle-age and beyond, response inhibition is one of several cognitive functions that witnesses a steadily decline.

The current scientific consensus is that response inhibition in humans is supported by the frontal lobe, but precisely how this large area mediates our cognition and behaviour is deeply mysterious. The aim of this project is to enrich understanding of how the brain inhibits behaviour, with the goal of working toward a deeper understanding of the ageing process and new therapies for addiction. To achieve this, the project will combine a series of different human neuroscience techniques, including methods for stimulating the brain and for measuring the physiology and chemistry of complex brain networks.

Part A of the project investigates how specific brain regions in the human frontal lobe might control other brain regions to support response inhibition. In particular, it is possible that inhibitory control requires frontal brain regions to exert 'remote control' over more primitive areas that respond to emotion or coordinate motor output. To observe directly how these long-range brain connections support inhibition, we will measure brain activity using magnetic resonance imaging (MRI) while simultaneously stimulating parts of the frontal lobe with transcranial magnetic stimulation (TMS). We will also test how these brain connections are altered by normal ageing.

Part B focuses on understanding links between response inhibition and risk-taking behavior, specifically gambling. Our recent research shows that expecting to stop a simple motor response, or being trained to stop simple responses, can reduce risk-taking when gambling. These effects may be likened to building an inhibitory "muscle" that, once trained, can more effectively resist urges. In Part B we will again use TMS and MRI to study why motor response inhibition influences gambling decisions, how different brain systems are affected, and how these processes evolve with age. We will also use a technique called magnetic resonance spectroscopy to test how training in response inhibition influences brain chemistry.

Overall, this project promises to reveal new insights into the complex brain processes that enable response inhibition, with future implications for addiction therapy. Gambling addiction is a severe public health concern, affecting at least 100 million people worldwide. A simple method for training response inhibition may provide a complementary new therapy for reducing this burden, but first we must understand how response inhibition is linked to higher-level systems that oversee risky decision-making. The studies in our project will provide a crucial step forward in this direction, yielding new insights into the basic neuroscience of response inhibition while furthering understanding of this potential new therapy.

The overarching aim of this research project is to advance understanding of how the human brain controls inhibitory decision-making, with a view toward developing a deeper understanding of ageing, and furthering new interventions in the treatment of pathological gambling and related addictions.

Part A will employ concurrent transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) to determine how the prefrontal cortex inhibits actions via connections with key subcortical structures, including the basal ganglia. We will also test how fronto-subcortical interactions are influenced by normal ageing.

Part B will explore the neural mechanisms underpinning our recent discovery that inhibitory motor demands can cause a powerful and long-lasting reduction in risk-taking during gambling. In particular, we will employ fMRI, concurrent TMS-fMRI, and magnetic resonance spectroscopy (MRS) - in combination with behavioural tasks that combine motor inhibition and gambling - to uncover the neurophysiological and neurochemical systems that link decision-making at different levels of cognitive control. As in Part A, we will also study the extent to which the relationship between motor inhibition and gambling behaviour differs between younger and older adults.

Overall, this project seeks to reveal new insights into neural mechanisms of response inhibition, with implications for understanding the neurobiology of ageing and the development of new therapeutic pathways for addiction.

This project is basic cognitive neuroscience, investigating the neural mechanisms that support cognitive control in the healthy human brain. The potential impact of our work can be summarised as follows:

1. Academic impact. Few centres worldwide have the facilities and expertise to support simultaneous transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI), and to our knowledge, Cardiff University is the only centre in the world with a published track record in both TMS-fMRI and in vivo magnetic resonance spectroscopy (MRS). The application of these cutting-edge methods, combined with our focus on advancing the methodology via our academic-industrial partnership with Magstim, has the potential to significantly advance the knowledge economy of Wales, and of the UK more broadly. The success of this project, including the application of TMS-MRI, will provide a strategic edge for Cardiff University in attracting the best cognitive neuroscience researchers from around the world. This project will also facilitate the ongoing training and development of two research staff in advanced TMS, MRI, and MRS methodologies.

2. Economic impact. As basic research, our project carries no direct economic benefits. However, the proposed studies involving concurrent TMS-MRI are likely to produce new technical innovations, some of which may be relevant to our ongoing academic-industrial collaboration with Welsh neuromedical company, Magstim. We will monitor carefully for potential spin-off projects and discuss with both the University and Magstim whether such advances could be exploited in the private sector. In the longer term, our project has a potential health-economic impact by advancing understanding of how ageing alters the brain and cognition, consistent with the BBSRC strategic priority "Ageing research: lifelong health and wellbeing".

3. Social impact. We are committed to effective public engagement activities, including exhibitions, public lectures, public tours of CUBRIC facilities, and interactions with the media. These activities are aimed not only at increasing public understanding of neuroscience and psychology, but to also raise aspirations in secondary students to pursue a career in science. Understanding the basic neuroscience of human cognitive control may have also implications for the diagnosis and management of cognitive deficits that accompany brain injury, disease, and healthy ageing. Such clinical benefits are beyond the scope of this project, but have the potential to positively impact health and well being in the longer term.