Inside the mind of a young person

Most animals are born relatively complete: a newborn gazelle, for example, is running within a couple of hours of birth. Not so for humans: for us, birth is very much just the beginning.

“In a newborn baby’s brain, many cells haven’t gotten where they need to go,” explains Professor David Rowitch, Head of Cambridge’s Department of Paediatrics. “We think this ‘commuting’ process is vulnerable to adverse events. A lack of oxygen or infection, for example, might block cell movement and derail the schedule of brain circuit formation.”

He and colleagues have shown that neurons travel extensively in the brain as part of this schedule – which makes this a vulnerable time for developing infants. Take a preterm infant born after six, rather than nine, months in the womb. It will spend its early life in a neonatal intensive care unit and has a higher risk of having medical and neurological complications. Such an infant, says Rowitch, is also at risk of mental health problems in later life.

“Because these are not kids who are genetically predisposed to mental health conditions, something must have happened to them early in their life that made them at high risk – that’s an important clue.”

What that ‘something’ is may relate to Rowitch’s own research on the preterm brain – and particularly its ‘building blocks’, cells known as neurons and glia.

‘Glia’ literally means ‘glue’, a rather nondescript term – an indication, he says, of how their importance has been overlooked by neuroscientists. Yet it’s becoming increasingly clear that glia are essential to brain development, in assembling neural circuits and in helping brain centres communicate with each other and the body. Crucially, glia provide myelin to insulate the nerve tracts during development. Rowitch, whose work is supported by the Wellcome Trust, European Research Council, National Institute for Health Research and National Institutes of Health (USA), believes that abnormal glial function plays an important role in the development of neurological, cognitive and mental health problems later in life.

He explains that if these circuits need to balance each other, and there is an adverse event like preterm birth, then suddenly there will be an imbalance in the brain. “Migration of neurons is a relatively late process in the human brain, so problems that affect the newborn may be sufficient to explain long-term problems such as cerebral palsy and cognitive and mental health problems. It could also provide clues to disorders like autism.”

But bridging the diagnosis and treatment of physical changes in the developing brain to the diagnosis and treatment of mental health disorders faces a challenge, he says. “While the majority of mental health problems manifest in children, teens and young adults, the norm for healthcare is that physical and mental health are treated separately, usually at entirely different clinics.”

This seems particularly disjointed when one considers children with eating disorders or those with chronic diseases, who are particularly vulnerable to depression. While there is increasing evidence that genetic factors can increase a child’s vulnerability to mental health conditions, this is clearly not the whole story.

Rowitch and NHS colleagues believe the time is now to bridge the divide between physical and mental health. A vision being developed for a new Children’s Hospital on the Cambridge Biomedical Campus integrates both facets and develops a holistic approach to healthcare.

This would mean that a child with an eating disorder, for example, would be seen by both psychiatric and medical specialists, and a child with a chronic disease would see a psychiatrist, providing early detection and intervention for mental health.

“We need to move away from silos,” Rowitch says. “And this is where Cambridge, with strengths across the board from genomics to complex medical care, child and adolescent psychiatry, is perfectly positioned to lead by example.

“It has been said that it is easier to build strong children than to repair broken men,” he adds, quoting the words of 19th-century American abolitionist and ex-slave Frederick Douglass. “If our vision can be realised, then Cambridge could help ensure there are fewer ‘broken’ men and women to repair in future.”

The education system is awash with labels: pupils are dyslexic, have attention deficit hyperactivity disorder (ADHD), or have a particular ‘learning style’. Sometimes, like these latter labels - visual, auditory or kinaesthetic learners – they have found common currency and yet are based on no credible evidence.

These styles are “nonsense”, says Dr Duncan Astle from the Medical Research Council (MRC) Cognition and Brain Sciences Unit in Cambridge. “Children will tell you they have a preferred learning style, but they’re no better in their preferred style. In fact, there are probably some dangers to telling a child that they’re a kinaesthetic learner or whatever, because then when you try teaching them in a different format, they think ‘What’s the point in paying attention? This isn’t in my preferred style.’”

Other labels, particularly those based on clinical diagnoses – dyslexia, dyspraxia, ADHD, for example – can be helpful in ensuring a child receives specialist support. But diagnosis is a “thorny issue”, Astle says. These conditions are complex, their causes poorly understood, and children will often meet the diagnostic criteria for multiple disorders. This makes studying them, and hence developing effective interventions, challenging: one child’s ADHD may be very different from another’s. As Astle says: “The labels don’t fully characterise what the child struggles with.”

Together with colleagues Susan Gathercole and Joni Holmes at the Centre for Attention Learning and Memory, Astle sees hundreds of children who have been referred by health and education professionals for problems in attention, memory, language or poor school progress.

Rather than grouping them together according to a clinical diagnosis, the team applied machine learning to identify children with common cognitive problems. They found that the children could be split into four broad cognitive profiles: children with verbal cognition problems (or ‘phonological difficulties’), those with working memory problems, those with more severe problems across the board, and those who do not appear to have any cognitive problems but still struggle at school.

These cognitive profiles may allow for more effective ways of supporting the children, says Astle. He gives the example of a typical problem that might confront a child with working memory problems.

“If you spend time in a primary school, you soon learn that if you can’t follow a list of instructions, you’re stuffed. ‘Hang your coat up, go to the table, pick up a card and a green pen, and come and sit in front of me.’ Even copying things down from the board will be very slow and error prone if you can only hold one or two letters in mind at a time.”

Problems with working memory can soon spill over to other aspects of learning, so if a teacher can limit the number of instructions or the amount of copying from the board, for example, then this could benefit the child’s overall learning and development.

Astle’s team has been looking at whether ‘brain training’ could help these children. The researchers showed that just 40 minutes of training per day focused on working memory led to improvements – and to changes in brain connectivity – although the benefits were limited.

“They get better at the thing they’re training on and closely adjacent skills, but the kids who undergo this kind of training don’t spontaneously get better at maths or start experiencing fewer symptoms of ADHD,” he says.

Brain training is becoming an increasingly popular way to help children overcome their learning difficulties. Professor Usha Goswami from the Centre for Neuroscience in Education is working on a game that could help children with dyslexia, for example.

One way of getting to the root cause of learning disorders could be to identify infants at greatest risk and to see how their brains develop in the first few months – or even days – after birth. This is not without its challenges, as Professor Mark Johnson, Head of Psychology, knows too well.

Johnson joined Cambridge recently from Birkbeck, University of London, where he pioneered research into infants’ and toddlers’ brains at the world-renowned Babylab. He is now turning his attention to an even earlier stage, the period from immediately before birth to the first few months after.

“Most people will agree that the biggest change in environment that the brain has in its lifetime is birth,” he says, “going from being a baby in the womb to being outside within a couple of hours, in a world with human beings, lights and everything. It’s clearly a very dramatic event for the brain.”

In collaboration with Professor Topun Austin at the Rosie Hospital in Cambridge, and building on earlier work by Professor Simon Baron-Cohen at the Autism Research Centre, Johnson plans to use the latest prenatal MRI and ultrasound techniques to study the behaviour of the baby in the womb. It’s been clear for a while that the fetus has a “behavioural repertoire”, he says. A recent study, for example, showed that a fetus will follow a light source shone onto the mother’s abdomen.

Once the babies have been born, he hopes to observe their brain development over their first few days in the outside world. Babies’ skulls are relatively thin and translucent. By shining infrared light on a newborn’s head, it’s possible to observe subtle changes in the colour of the blood, which becomes bluer as activity (and hence oxygen) levels in a brain region fall, and redder when they increase. Using this technique, known as near-infrared spectroscopy, Johnson wants to validate initial data that suggests there are dramatic changes in brain function over the first few days.

His research has already shown how certain brain regions ‘tune up’ during infancy, such as the area that in adults has been shown to process faces.

“In infants, those same regions respond to faces, but they also respond to other complex objects,” he says. “Over time, they become selectively interested in faces. This could be one of the processes that goes awry in autism, where the part of the brain that responds to social stimuli has not been properly tuned.”

This is unlikely to be the whole story, however. Johnson points out that there are also other, more generalised problems in autism, such as subtle motor delays and problems with visual and auditory perception, which then manifest in social challenges later in life.

Johnson believes that these later manifestations may arise from the autistic child’s inability to process complex information. “If you’re a 12-month-old, the most complex aspect of the external world is other human beings. They’re unpredictable, they’re dynamic, they make sounds, they smell. It’s a massive challenge to understand the social world, which might explain why autistic children prefer stimuli that are repetitive or more predictable.”

He agrees with Astle that understanding and measuring brain function is better than applying labels. When trialling interventions to help ameliorate some of the traits of these conditions, brain measures are better than clinical tools at predicting outcome.

This move away from broad labels and towards a more nuanced approach is reflected in the latest edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which has moved towards ‘dimensions’ of symptoms of autism rather than categories (the term ‘Asperger’s’ is now classified within the Autism Spectrum, for example).

“In the past, we’ve been overly reliant on biomedical models,” Johnson says. “People tend to think of autism and ADHD as diseases, when they in fact describe a series of behaviours. It’s not right to think of them in the same way as, say, the flu.”

As humans, we like labels: they help us categorise and simplify the world around us. We may not be able to dispense with labels like autism and dyslexia anytime soon, but if science is teaching us anything, it’s to look beyond the label and remember that behind it lies a unique – and complex – individual.