University of Manchester Research: Update

In Autumn 2023, Nerve Tumours UK supported PhD projects carried out at the University of Manchester and Birkbeck College, University of London, under the supervision of Dr Shruti Garg and Dr Fong Kuan Wong. 

MOTOR AND NEURAL BIOMARKERS OF ATYPICAL DEVELOPMENT IN NEUROFIBROMATOSIS TYPE 1: A LONGITUDINAL INVESTIGATION

Children with NF1 are more likely to have conditions such as Autism Spectrum Condition (ASC) and attention deficit hyperactivity disorder (ADHD), which can impact how they learn, move, and interact with the world. However, because NF1 affects the brain in unique ways, the characteristics of ASC and ADHD in children with NF1 may differ from those seen in the general population. In fact, we do not even know exactly how they differ or why NF1 is linked to these conditions in the first place— its underlying biology is complex, with many contributing factors. Understanding these differences is crucial. By identifying how ADHD presents in children with NF1 compared to those with ADHD alone, we can identify early signs and create tailored support strategies for children with NF1 who also have ADHD.

My project is part of a larger study called the Early Development in Neurofibromatosis (EDEN) study, a collaboration between the University of Manchester and Birkbeck, University of London. EDEN aims to identify early signs of cognitive and behavioural differences in NF1 within the first three years of life. My research is supervised by a team of expert clinicians and academics in the field of neurodevelopment comprised of Dr Shruti Garg, Dr Szilvia Linnert, Professor Jonathan Green, Dr Jannath Begum Ali and Professor Emily Jones.

My research focuses on comparing early motor activity in infants with NF1 to infants with a family history of ADHD alone. My project will use data from motion-tracking devices called accelerometers, standardized motor assessments conducted in the lab, and parent reports.

Additionally, I will examine early brain activity related to movement using a method called electroencephalography (EEG). This technique involves placing a cap of sensors on the scalp to measure brain activity while infants observe different stimuli, providing an understanding of the brain mechanisms underlying motor development.

By understanding early differences in motor activity, we hope to build a clearer picture of how NF1 shapes neurodevelopment and behaviour. This knowledge will help us develop early diagnosis and treatment strategies, ensuring that children with NF1 receive timely and appropriate support tailored to their unique needs.

Sadali Wanniarachchi's PhD led project “Motorskills Development in Infants” is being carried out in collaboration with the University of Manchester, and Birkbeck College, University of London.

Many children with NF1 struggle with their fine and gross motor skills. Handwriting and certain tasks such as using cutlery or even kicking a football can be difficult for some children.

Her project studies how motor skills develop in children, from when they are infants until they turn 3 years old.

HOW ARE CELLS IN THE BRAIN DIFFERENT IN NF1?

The brain is composed of approximately 86 billion brain cells or neurons which can be categorised as excitatory and inhibitory. Imagine your brain is like a big, exciting football game:

• Excitatory neurons are like the players who are always ready to run, kick, and play the game. When these neurons are active, they send signals to other parts of the body, helping you think, move, and do things, just like when players run after the ball and try to score a goal.
• Inhibitory neurons are like the referee who blows the whistle when the game gets too rough or when the players need to stop for a break. These neurons help slow things down and make sure everything stays in control, so things don’t get too wild.

So, excitatory neurons are the ones getting everyone excited and moving, and inhibitory neurons are the ones making sure the game stays fair and doesn’t get too crazy. Together, they keep everything working smoothly in your brain. However, in NF1 these inhibitory neurons are over-activated, and they send out excessive ‘stop’ signals. This contributes to an overall drop in the signals in the brain which leads to neurological symptoms such as learning difficulties, attention deficit hyperactive disorder (ADHD) and memory problems.

Most individuals with NF1 have learning difficulties and sleep disturbances. Although seemingly unrelated, both these symptoms are linked by association with dysfunction in the inhibitory cells. Our work utilises a mouse model to mimic the interneuron dysfunction in NF1 to uncover how and why inhibitory neurons behave different in NF1. We also aim to understand how the dysfunction leads to learning disabilities and sleep disturbances in NF1 at a cellular level. I am a second year MRC DTP-CASE PhD student at the University of Manchester in partnership with Nerve Tumours UK. My project, under the supervision of Fong Kuan Wong, Mino Belle and Shruti Garg, focuses on understanding cell-level differences in inhibitory neurons in the brain in NF1.

How does our work feed back to the community? By understanding how and why inhibitory neurons behave differently in NF1, our work can fill critical gaps in our understanding of the cellular mechanisms underlying the condition. Our research could guide the development of new therapies or interventions that specifically address the dysfunction in inhibitory neurons. These therapies could help regulate the "stop" signals that are excessively sent out by the inhibitory cells, potentially restoring a healthier balance in the brain. This could result in improved learning and sleep quality for individuals with NF1. Along with NTUK, our findings can be communicated to healthcare professionals, and the public creating awareness of NF1's neurological impacts and help them better navigate the challenges posed by the condition.