Neuroscience and Mental Health UCL School of Life and Medical Sciences Creating knowledge, achieving impact 3 PREFACE

UCL’s School of Life and Medical Cluster (GMEC) for which we lead in Sciences encompasses arguably the the field of rare diseases. Our growing greatest concentration of biomedical collaboration with our science and population health neighbours, the School of expertise in Europe. Our performance Hygiene and Tropical Medicine, is in the UK’s last Research Assessment fuelling exciting developments in Exercise was outstanding, and for most genetic epidemiology and pathogen key measures the School comfortably research. tops UK league tables. The breadth and quality of our In part because of UCL’s size and research creates almost unique organisational complexity, the scale opportunities. Our recent merger with of the School’s achievements is not the London School of Pharmacy adds always apparent. This publication, to our capacity in drug development, one of four, seeks to address this. formulation and adoption. Our highly Our recent reorganisation, with the productive links to the health service, Basic Life Sciences: creation of four new Faculties, has through UCL Partners, provides 1 ‘Discovery’ research, from been designed to create a more access to unmatched clinical expertise molecules to ecosystems. coherent structure, of which the and large patient groups. We are Faculty of Life Sciences, headed by fortunate to be partners in three Translation and the Dean, Professor Mary Collins, National Institute for Health Research 2 Experimental Medicine: is a clear example. But the School’s (NIHR) Biomedical Research Centres restructuring has also placed great and a new NIHR Biomedical Research Driving translation to emphasis on cross-Faculty interactions Unit in dementia. benefit patients’ health and interdisciplinary research – and and well-being. The School’s academic environment indeed on interactions with UCL is one in which intellectual curiosity departments outside the School. can prosper, while a high priority is and Such interdisciplinary endeavour is 3 also given to the practical application Mental Health: promoted through ‘Domains’, inclusive of knowledge to improve health and The science of the brain strategically led fluid networks. This quality of life. This can take many and nervous system, approach allows us to connect all forms, including commercialisation from to social our activities related to fundamental of new products as well as developing interactions. research, promoting collaboration and and informing health and social the sharing of expertise, platforms and policy, and engaging with important resources. Professor Michael Duchen Population Health: stakeholders, including the public. 4 and Dr Paola Oliveri are chairs of the Protecting and improving Basic Life Sciences Domain. This publication, one of four (see the health of populations, right), showcases some of the UK and globally. UCL is acutely aware that scientific outstanding research in translation advance of real relevance to society and experimental medicine being is not only aided by an interdisciplinary carried out within the School and with approach but also through collaborators across UCL and our collaborative strategic alliances with NHS partners, in London, nationally other research-intensive institutions and internationally. It is impossible to with complementary strengths. be comprehensive, but the stories give Our founding partner status in the new a flavour of the breadth, quality and engages us in impact of the School’s research in this what will be the European powerhouse area. Looking forward, our aims are of biomedical research expertise. to enhance and expand our research Our links with our London Academic to ensure we remain a global leader, Health Science Centre partners also and to see more people benefit from include our joint engagement together the groundbreaking research being with the Medical Research Council in carried out across the School. a new imaging company, Imanova, and our commitment to the London Life Sciences Concordat. Wider linkage Sir John Tooke to the London and South East super- Vice-Provost (Health) and cluster is secured by our involvement Head of the UCL School of Life in the Global Medical Excellence and Medical Sciences. CONTENTS

Overview: The grandest challenge 2 Understanding the brain and nervous is the most challenging problem in the whole of biology.

Section 1: Signals and signalling 4 Neurotransmitters and their receptors lie at the heart of efforts to understand nervous system function.

Section 2: All join together 10

The complex functions of the nervous system reflect the coordinated activity of networks of cells. Feature: Making sense: The neuroscience of sensory perception 18

Section 3: The inner world 20 The secrets of the most complex structure in the Universe – the human brain – are gradually being revealed. Feature: Making connections: The Sainsbury–Wellcome Centre 28

Section 4: Decline and fall 30 Loss of underlies a range of devastating diseases affecting mental and physical capacities.

Feature: Neurodegeneration: A path towards earlier intervention 38

Section 5: Brains and behaviour 40 The brain both shapes and is shaped by social interactions.

UCL institutes, support services, partners, funding and sponsors. 46

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 1 The grandest challenge: Neuroscience and Mental Health Understanding the brain and nervous system is perhaps the most challenging problem in the whole of biology – but the rewards could be substantial.

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The brain has been Others favour a ‘top down’ described as the most perspective, examining Mental health conditions are predicted to have complex structure in the regional brain structure and the greatest health burden globally by 2020. known Universe, and function through imaging understanding how it techniques such as magnetic common – their economic while imaging techniques works is one of the greatest resonance imaging (MRI) costs presenting an are providing a more challenges facing science. and functional MRI, alongside enormous challenge to refined view of the nervous Even simple numerical ‘tractography’ – mapping already hard-pressed system damage associated descriptions boggle the the connections between families and healthcare with neurodegenerative mind: 100 billion neurons; regions. Furthermore, there is systems. conditions. 1000 trillion ; 1000 growing interest in the ‘social km of wiring connections. brain’, recognition of the fact Many conditions remain Neuroscience may also From the mundane matter that humans are uniquely poorly served by modern be able to provide a of moving from A to B to the social animals and much medicine. Chronic pain is deeper understanding of most profound philosophical brain activity is devoted to poorly controlled, regain of neuropsychiatric conditions. questions – ‘who am I?’ – managing relationships with function after nerve injury Psychiatry, unlike most the brain lies at the heart others. is rarely successful, and disease areas, continues of human existence and pharmacological treatments to depend primarily on As well as the intellectual consciousness. for psychiatric conditions, categorisation by symptoms. challenge of understanding despite some successes, are The diagnostic criteria for Neuroscientists are chipping nervous system function, far from perfect. Treatment many conditions remain away at the function of the neuroscience has the options are similarly limited opaque and controversial, brain, approaching the potential to make a profound for neurodegenerative and generally bear little challenge from multiple impact on health. Diseases diseases, and other relationship to objective directions. Some are studying affecting the nervous system conditions linked to damage pathological measures the molecular properties of already impose an enormous to brain tissue such as stroke or reflective of genetic key nervous system proteins, burden on individuals, and multiple sclerosis. causes. There is thus a particularly the receptors society and our health great need to develop On the other hand, there of neurotransmitters. This infrastructure, and their a better understanding are reasons to be optimistic. work is leading to a greatly impact is likely to increase of disease mechanisms Advances in a wide range increased understanding still further. Mental health – a challenge likely to of areas are providing of how neurons operate conditions are predicted require insight at multiple new insight into disease and signal transmission is to have the greatest health levels of organisation, processes and novel leads controlled. Other teams are burden globally by 2020. genetic, molecular, for new interventions. examining how the activities As populations age, cellular, neurological and Genetic studies are revealing of neurons are integrated neurodegenerative conditions neuropsychological. in microcircuits and larger such as Alzheimer’s disease new contributory factors neural networks. will become increasingly for numerous conditions,

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Reaching out

UCL’s neuroscience community is at the forefront in engaging lay audiences.

UCL has a strong commitment to communicate its work to audiences outside the research community, and its neuroscience researchers are among the most active contributors to these efforts. Projects are highly varied, spanning work with the media, including national TV and radio, patient-focused events, science festivals, school visits and public lectures, discussions and s211 Lorem ipsum dolosr sit amet consequat ti tiempolo conferences, and innovative partnerships with bodies such as the British Library and Tate Liverpool. Some events are geared towards patients and their families, such as the Retina Patient Day organised by Professor Robin Ali and Dr Translation is an important Huxley and . Mike Michaelides in the UCL Institute of Ophthalmology. Similarly, aim of UCL’s neuroscience Today’s researchers are the Deafness, Cognition and Language Research Centre (DCAL) research. Also covered maintaining and building maintains exceptionally strong links with the deaf community. in the companion volume on the foundations laid by UCL neuroscientists are frequent contributors to TV and radio on Translation and these luminaries, collectively shows. In a notable recent case, Dr Joe Devlin and Professor Cathy Price scanned Stephen Fry’s brain for his ‘Fry’s Planet Word’ series. Experimental Medicine, UCL creating a community of Numerous Events are held at UCL and partner venues, while researchers are making expertise matched by few UCL’s Professor Mark Lythgoe has a key role as co-director of important contributions other institutions anywhere the highly successful Cheltenham Science Festival. UCL has also across multiple conditions in the world. Their work is organised innovative interdisciplinary public events with the British and types of treatment – revealing fundamental insight Library, ‘Do you Hear What I Hear?’ in 2010 and ‘The Performing Brain – A moving story’ in 2012, each involving more than 20 UCL drug development, gene into the brain and nervous neuroscientists. therapy, stem cell therapy, system, and leading to new Policy-makers and politicians are an important audience, with psychotherapy and approaches to treatment UCL researchers such as Professors , and biomarker development. for diseases of critical Sarah-Jayne Blakemore contributing to the Royal Society’s Brain Implementation is also an importance to physical and Waves project, identifying key issues for society arising from neuroscience research. important priority; key work mental health. More unusually, the Institute of Cognitive Neuroscience appointed in health services research James Wilkes as a poet-in-residence, working with Professor and policy development is Sophie Scott and others, while Dr Michelle de Haan collaborated covered in the companion with Tate Liverpool on an art–science project, ‘Wondermind’, linked volume on Population Health. to Alice in Wonderland. Details of these and many other projects can be found at UCL has housed some www.ucl.ac.uk/neuroscience. of the world’s leading neuroscientists, including Nobel laureates Andrew

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 3 SECTION 1

Signals and signalling

Neurotransmitters and neurotransmitter receptors lie at the heart of efforts to understand nervous system function. They are also key targets in pharmaceutical development.

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In 1936, and Neurotransmitters and the receptors they act Henry Dale (who spent upon have been subject to intense scrutiny. an early part of his career The aims have been both practical – to develop at UCL) received a Nobel new therapeutics – but also intellectual: to Prize for demonstrating understand the function of the nervous system that neurotransmission in terms of its constituent parts. was a chemical rather than electrical phenomenon. This profound discovery that glutamate binding to Professor Cull-Candy and established that the receptors generated several Professor Mark Farrant have extraordinary functions on distinct conductance levels, been particularly interested the nervous system could representing transitions in calcium-permeable be traced to the action of of the same channel1. forms of AMPA receptors, small chemicals transmitting He also discovered that which have been implicated signals across the synapse. certain astrocytes (glial in several neurological Since then, neurotransmitters cells), express similar diseases. Calcium and the receptors they act AMPA receptors2, enabling permeability depends upon have been subject to them to respond rapidly to critically on the presence intense scrutiny. The aims glutamate 3. of the GluA2 subunit. After have been both practical – high-frequency synaptic AMPA receptors play a to develop new therapeutics activity, calcium-permeable critical role in synaptic – but also intellectual: to AMPA receptors are rapidly ‘plasticity’ – changes in the understand the function of replaced by calcium- properties of the synapse the nervous system in terms impermeable receptors – a after a signal has been of its constituent parts. change triggered by calcium transmitted. In effect, the entry through the receptors The principal excitatory synapse ‘remembers’ past neurotransmitter in the CNS activity and subsequently 1 Cull-Candy SG, Usowicz MM. Multiple- is glutamate, which binds to responds more (or less) conductance channels activated by several classes of receptor, vigorously. This effect can excitatory amino acids in cerebellar including NMDA, AMPA and be mediated by changes neurons. Nature. 1987;325(6104):525–8. kainate receptors. As well as 2 Usowicz MM, Gallo V, Cull-Candy in AMPA receptor numbers SG. Multiple conductance channels in characterising NMDA and or the conductance of type-2 cerebellar astrocytes activated by excitatory amino acids. Nature. kainate receptors, Professor single AMPA receptor 1989;339(6223):380–3. Stuart Cull-Candy has channels. Various forms of 3 Silver RA, Traynelis SF, Cull-Candy unravelled many key aspects such plasticity are thought SG. Rapid-time-course miniature of AMPA receptor function. to underlie learning and and evoked excitatory currents at cerebellar synapses in situ. Nature. His early studies revealed memory. 1992;355(6356):163–6.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 5 human tachykinin-1 receptor they are widely distributed gene has been linked to throughout the nervous susceptibility to ADHD7. system. As well as GABA receptor– Until recently, ligand interactions, Professor nicotinic acetylcholine Smart has also examined receptors received less the mechanisms of receptor pharmacological attention trafficking and mobility than glutamate receptors. in the plasma membrane But there is a growing (areas also being studied interest in acetylcholine by Dr Josef Kittler and, for receptors, which have now calcium channels, Professor been implicated in several Annette Dolphin; see neurological conditions and 40large Lorem ipsum dolors sit amet consequat ti tiempolo. companion volume on Basic in cognitive processes. Life Sciences). Control of Much of Professor receptor numbers at the Millar’s research involves channels, creating a form a deeper understanding of synapse, through intracellular collaboration with Eli Lilly, of negative feedback 4. disease processes and new trafficking and membrane which maintains an active More recent work has therapeutic leads. translocation, are clearly programme of research on focused on the influence of important mechanisms of While glutamate and other modulators of acetylcholine newly identified accessory regulation. In mice, interfering excitatory neurotransmitters receptor function. The transmembrane proteins, with phosphorylation of spark the nervous partnership is mutually the ‘TARPs’, on calcium- GABA receptors, for system into life, GABA ( A beneficial. The academic permeable AMPA receptors example, affects intracellular -aminobutyric acid) acts to research generates insight (see page xx). trafficking and ultimately keep it in check. The balance into the basic biology of leads to abnormalities in Another researcher with between excitatory and receptors that may inform spatial memory8. an interest in glutamate inhibitory neurotransmitters drug development, while neurotransmission is Dr keeps the CNS responsive A critical aspect of these the UCL lab gains access Alasdair Gibb. His focus, but not overexcitable, studies is the ability to to industrial resources such however, is the NMDA and any distortions to this visualise the location as chemical libraries. It also receptor, and in particular balance can have a major of receptors in the cell. enables junior researchers its potential involvement in impact on health. Professor Smart’s group has to experience work in a Parkinson’s disease (see pioneered new methods of commercial lab. Professor Trevor Smart’s page xx). His expertise in labelling, introducing binding group is exploring the Professor Millar also recording neural activity, sites for quantum dots structural basis for the works closely with UCL’s mainly in rodent brain slices, and fluorescently labelled neurophysiological effects Department of Chemistry, also leads to numerous snake toxins – significantly of GABA, focusing on where researchers generate collaborations – for example smaller than conventional its receptors and their new agents to test the with Professor Patricia methods such as antibody modulation by chemicals properties of receptors. Salinas, on the impact of Wnt labelling. Receptors can such as neurosteroids. signalling on the strength of now be tracked at single This work has led to a new 4 Liu SQ, Cull-Candy SG. Synaptic synaptic connections5. molecule level in living cells. activity at calcium-permeable AMPA mouse model of anxiety and receptors induces a switch in receptor In collaboration with Dr Guy Dr Gibb is also heavily depression, and a growing subtype. Nature. 2000;405(6785):454– Moss, his group has also 8. involved in teaching at focus on translational work on been working on ultra-high- 5 Ciani L et al. Wnt7a signaling promotes UCL, and has also helped new agents targeting GABA dendritic spine growth and synaptic resolution systems, such as + to organise workshops to receptors (see page xx). strength through Ca² /Calmodulin- ‘hopping mode’ scanning ion dependent protein kinase II. Proc Natl transfer skills and promote Acad Sci USA. 2011;108(26):10732–7. Similarly, Professor Smart’s conductance , to interactions between colleague Dr Clare Stanford image the three-dimensional 6 Yan TC, Hunt SP, Stanford SC. researchers in academia Behavioural and neurochemical is characterising a potential surface of living cells. abnormalities in mice lacking functional and industry. Funded by animal model of attention- Developed with collaborators tachykinin-1 (NK1) receptors: a model of the Medical Research attention deficit hyperactivity disorder. deficit hyperactivity disorder at Imperial College and Neuropharmacology. 2009;57(7- Council and industry, and 8):627–35. (ADHD). The model was in industry, the technique organised through the a serendipitous discovery provides structural detail 7 Yan TC et al. NK1 (TACR1) receptor British Pharmacological gene ‘knockout’ mouse phenotype when Dr Stanford and at nanoscale resolution9. predicts genetic association with ADHD. Society, the workshop aims Professor Stephen Hunt J Psychopharmacol. 2010;24(1):27–38. to encourage a two-way flow Professor Neil Millar’s noticed that the symptoms of 8 Tretter V et al. Deficits in spatial of information between the focus is on nicotinic memory correlate with modified a substance P (tachykinin-1) {gamma}-aminobutyric acid type A two sectors. With industry acetylcholine receptors, receptor knockout mouse receptor tyrosine phosphorylation in the increasingly reluctant to one of the two major classes hippocampus. Proc Natl Acad Sci USA. were strikingly similar to 2009;106(47):20039–44. invest in brain-related of acetylcholine receptor. those of ADHD6. Supporting conditions, academia has a As well as being present at 9 Novak P et al. Nanoscale live-cell its relevance to human imaging using hopping probe ion vital role to play in generating the neuromuscular junction, conductance microscopy. Nature disease, variation in the Methods. 2009;6(4):279–81

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Against the flow Glial cells – essential support for life Key insights are being gained into AMPA receptors, critical The oligodendrocytes that form the insulating myelin players in neuronal function. sheath around CNS neurons play a key role in cognitive function and control of muscle contraction. AMPA receptors, one of the two main receptors activated by glutamate, the nervous system’s principal excitatory Efficient transmission of signals along axons in the CNS depends on neurotransmitter, are fundamental to nervous system function. Of a fatty insulating sheath of myelin, produced by a class of glial cells particular significance is their role in ‘plasticity’, changes that affect known as oligodendrocytes. As the work of Professor David Attwell how strongly a signal is transmitted. Professors Stuart Cull-Candy and colleagues has revealed, oligodendrocytes and their precursor and Mark Farrant have spent many years investigating these cells also respond to neurotransmitters and some are electrically critical membrane proteins, most recently shedding important excitable. These properties remain enigmatic, but they may have light on a family of newly discovered accessory proteins, the so important consequences for health. called ‘stargazin’ family of TARPs (transmembrane AMPA receptor Oligodendrocytes are typically characterised as ‘support’ cells regulatory proteins). for neurons, wrapping axons in myelin sheaths that help to maintain Of particular interest has been the AMPA receptor’s permeability action potential propagation along an axon. Their importance is to calcium. Most AMPA receptors are not permeable to calcium, illustrated by conditions such as multiple sclerosis, cerebral palsy because of the presence of a specific component of the receptor and spinal cord injury, which are associated with loss of the myelin – the GluA2 subunit. Professor Cull-Candy and Professor Farrant sheath. have shown that the absence of GluA2 renders receptors sensitive Central to these conditions is the response of oligodendrocytes, to ‘plugging’ by large positively charged polyamines that occur and their precursor cells, to neurotransmitters, particularly the naturally within nerve cells, restricting ion flow to specific situations. excitatory transmitter glutamate. In low-energy conditions, a Work on AMPA receptors was transformed by the discovery in transporter that normally imports glutamate into neurons and 2005 of a family of proteins that associate with the receptors and oligodendrocytes begins to run in reverse, expelling glutamate. regulate their activity. The first of these proteins, stargazin, was This excess glutamate was known to act on one class of glutamate identified in thestargazer mutant mouse (so named because of its receptor on oligodendrocyte lineage cells (AMPA receptors). distinctive head movements). Stargazin is now known to be part of However, Professor Attwell and colleagues found that white a family of six TARPs that are differentially distributed throughout matter oligodendrocytes and their precursors also express NMDA the brain – and which differ in their influence on AMPA receptor receptors responsive to external glutamate which, unlike NMDA properties, and thus in their effects on neuronal signalling. receptors in neurons, are active even at resting potentials. Professors Cull-Candy and Farrant have found that TARPs Furthermore, contrary to received wisdom, it turns out that such as stargazin significantly reduce the ability of polyamines to some oligodendrocyte precursor cells actually generate an action plug the channel. Furthermore, their research has revealed that a potential after neurotransmitter binding. The significance of this supposedly non-functional member of the TARP family (known as electrical signalling remains to be elucidated, but it may play a role -5) has specific effects at calcium-permeable AMPA receptors in in controlling the development of the cells. glial cells. Unlike other TARPs, these effects are partly inhibitory, Further research on the neurotransmitter receptors involved in reducing ion flow and restricting AMPA receptor expression. controlling myelination during nervous system development, and Abnormal AMPA receptor regulation has been implicated in in triggering demyelination in pathological conditions, will provide several serious neurological and psychiatric disorders. During potential leads for the development of new agents for conditions development, calcium-permeable AMPA receptors are present in such as multiple sclerosis, cerebral palsy and spinal cord injury. oligodendrocyte precursor cells (which give rise to myelin-producing glial cells). Unfortunately, this renders the cells vulnerable to damage Káradóttir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors linked to low oxygen levels, which can ultimately lead to conditions are expressed in oligodendrocytes and activated in ischaemia. Nature. such as cerebral palsy. Professors Cull-Candy and Farrant have 2005;438(7071):1162–6. found that TARPs play a key role in AMPA receptor regulation in Káradóttir R, Hamilton NB, Bakiri Y, Attwell D. Spiking and nonspiking oligodendrocyte precursor cells. Ultimately, a fuller understanding of classes of oligodendrocyte precursor glia in CNS white matter. Nature Neurosci. 2008;11(4):450–6. the dynamics of AMPA receptors, and the influence of TARPs, could inform new efforts in drug discovery and treatment.

Soto D et al. Stargazin attenuates intracellular polyamine block of calcium- permeable AMPA receptors. Nature Neurosci. 2007;10(10):1260–7.

Soto D et al. Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, gamma-5. Nature Neurosci. 2009;12(3):277– 85.

Zonouzi M, Renzi M, Farrant M, Cull-Candy SG. Bidirectional plasticity of calcium-permeable AMPA receptors in oligodendrocyte lineage cells. Nature Neurosci. 2011;14(11):1430 – 8.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 7 Pic to come

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A channel to better pain relief Two’s company Rare individuals who lack the ability to feel pain could hold the key to better treatments for chronic pain. Identification of two binding sites for endogenous neurosteroids on GABAA receptors is offering the On occasion, pain may persist long after tissues have recovered. Such prospect of new treatments for anxiety and depression. chronic pain is difficult to treat. By taking advantage of advances in GABA is the critical inhibitory neurotransmitter in the CNS. human genetics, Professor John Wood and colleagues are generating It acts on two main classes of receptor, GABAA and GABAB. important insights into the cellular mechanisms of pain, and providing In the brain, binding to the former is modulated by several crucial leads for the development of new pain-relieving therapies. ‘neurosteroids’, which are released in a range of circumstances In 2006, Professor Geoffrey Woods and Dr James Cox in Cambridge including stress, pregnancy and after alcohol consumption. with Professor Wood described six members of a family from Pakistan Abnormalities in their interactions with GABA receptors have who were completely unable to experience pain. The family came to been implicated in numerous conditions, including anxiety, light through the ‘street theatre’ performances of one young boy, who depression and alcoholism. By identifying how and where would stab himself with knives and walk on hot coals for a captive neurosteroids bind to GABAA receptors, Professor Trevor Smart audience; sadly, he died after throwing himself off a house roof. and colleagues have laid the foundations for targeted agents to Although affected family members showed normal responses tackle these debilitating conditions. to heat and cold, pressure, tickle and so on, they were completely To identify the regions of the receptor critical to interactions with unresponsive to painful stimuli. A classical gene-mapping strategy neurosteroids, Professor Smart’s group made use of a form of the pinpointed a region of chromosome 2 as critical to the condition, and fruit fly GABA receptor that shows little response to neurosteroids. within this region the SCN9 gene – encoding a sodium channel, Nav1.7, A comparison of these fruit fly receptors with those in the human already being studied by Professor Wood – stood out as a strong brain suggested that neurosteroids associated with the receptor’s candidate. Sure enough, mutations affecting SCN9 were found in all transmembrane domains. By introducing single amino acids from affected family members. these domains of the fly protein into the human receptor, Professor Curiously, although Nav1.7 is highly specific to pain detection, it has Smart’s team identified one transmembrane domain in a single one other critical role. People with SCN9 mutations have no sense of GABA receptor subunit as critical to neurosteroid action. smell, and mice engineered to lack the Nav1.7 channel are similarly Neurosteroid activity is known to depend on particular chemical unable to detect odours. An unexpected spin off from this work on pain features that promote the formation of hydrogen bonds. By may therefore be a better understanding of the sense of smell. systematically altering residues in the transmembrane region able Recent years have seen dramatic progress in human genetics, to form hydrogen bonds, Professor Smart’s group was able to with sequencing-based methods increasingly being used to identify narrow down the points of interaction to two specific residues. mutations affecting pain detection – either loss of pain sensation The location of these residues suggested that neurosteroids or unusual pain sensitivity. Professor Wood, Dr Cox, who has now were binding at two distinct sites on the receptor. This was moved to UCL and colleagues have identified genes underlying such consistent with the fact that neurosteroids have two effects conditions and use sophisticated mouse engineering techniques to on GABAA receptors – at very low concentrations they are eliminate the corresponding genes just in pain-sensing neurons, to modulators of GABA action but at high concentrations they are characterise their role in the cellular processes underlying pain. direct activators of the receptor. Further analysis confirmed that A collaboration with UCL’s Professor Andres Ruiz-Linares, for binding at one site was responsible for modulation, while binding example, has identified a mutation affecting the TRPA1 ion channel in a at both sites drove full activation. South American family affected by periods of debilitating pain. Agents By structurally mapping GABAA receptor sequence onto the already exist that act on this protein, offering the immediate prospect structure of a related protein, Professor Smart and colleagues of a potential therapy. Similarly, the other key proteins identified are could visualise likely neurosteroid-binding sites. As predicted, important targets for the development of much-needed new agents for amino acid changes affecting such binding sites significantly pain control. affected neurosteroid action. An understanding of the precise molecular interactions Cox JJ et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–8. responsible for neurosteroid modulation has opened the door to rational design of neurosteroid analogues able to bind GABAA Nassar MA et al. Nociceptor-specific gene deletion reveals a major role receptors. Professor Smart is working with colleagues in UCL’s for Nav1.7 (PN1) in acute and inflammatory pain.Proc Natl Acad Sci U S A. Department of Chemistry to construct such modulators. His 2004;101(34):12706–11. group has also developed an animal model that shows signs Weiss J et al. Loss-of-function mutations in sodium channel Nav1.7 cause of heightened anxiety, and will be an important tool for testing anosmia. Nature. 2011;472(7342):186–90. potential new therapeutic agents. Kremeyer B et al. . A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. . 2010;66(5):671–80. Hosie AM, Wilkins ME, da Silva HM, Smart TG. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006;444(7118):486–9.

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damage-sensing neurons in adult animals, revealing much about their function. Pain detection is heavily dependent on sodium channels, including Nav1.7 (see page xx) and Nav1.8. Work on the latter revealed an important difference between mechanical, cold- induced and inflammatory pain – all of which require Nav1.8 – and neuropathic pain and heat sensing, which are independent of Nav1.813. Lorem ipsum dolors sit amet consequat ti tiempolo. Cold pain is particularly interesting as, unlike other A three-way interaction the brain’s energy supply Alzheimer’s disease and in types of neural activity, between , (provided in the form of the aftermath of cerebral pain signalling increases molecular modelling and oxygen and glucose in the ischaemia, when blood as temperatures fall. With synthetic chemistry provides blood) to its fluctuating flow fails to return to normal Professor Peter Reeh from a way to probe connections energy needs. At a tissue levels even after initial vessel Erlangen, Germany, and between ligand binding, level, blood supply is blockages are cleared. colleagues, Professor Wood receptor structure and increased to active brain Hence, understanding the has shown that this effect modulation of receptor areas. Professor Attwell and mechanisms that control depends on the presence function. colleagues discovered that brain energy supply is of Nav1.8, the function of cells known as pericytes, important both to research which is unaffected by low which wrap around and to treatment of major temperatures14. Energy demands capillaries in the brain, may clinical conditions12. play an important role in Professor Wood’s group Neurons are naturally the controlling brain energy continues to pursue other main focus of CNS research, supply10 by dilating during The origins of pain critical components of but an important support role neural activity and thus damage-sensing neurons, is played by a type of glial Pain may be unpleasant, increasing local blood flow. including those responsible cell, oligodendrocytes, which but it helps to keep us alive. Poor recovery of capillary for detection of mechanical form the insulating myelin Specific sensory neurons blood flow after stroke pressure and pain. As well sheath around axons. Loss detect when tissue has been may also reflect abnormal as his group in UCL, he has of this sheath is a significant damaged, sending signals to pericyte function. also established a satellite factor in conditions such the brain that are perceived lab in South Korea. With as multiple sclerosis, Even within neurons, as pain. By combining high-throughput sequencing cerebral palsy and spinal surprisingly sophisticated work on inherited human technologies enabling cord damage. This may be mechanisms exist to meet conditions affecting pain mutations underlying human partly caused by harmful localised energy demands. perception with experimental pain syndromes to be effects of glutamate on and studies in mice, Dr Josef Kittler Professor identified ever more rapidly, oligodendrocytes which, as Professor Attwell have shown ’s group has John Wood the number of leads available and that neurons use intracellular identified critical players in Professor David Attwell for functional studies is colleagues have discovered, transport systems to move pain detection – targets now enough to keep both labs express NMDA receptors mitochondria to sites of high being energetically pursued fully occupied. with unusual properties (see synaptic activity, where by the pharmaceutical page xx). energy needs are highest11 industry. 10 Peppiatt CM, Howarth C, Mobbs P, (see companion volume on Attwell D. Bidirectional control of CNS A second major area of Although rare, inherited pain Basic Life Sciences). capillary diameter by pericytes. Nature. interest for Professor Attwell’s syndromes are invaluable 2006;443(7112):700–4. group is energy use by the Blood supply and energy in revealing important 11 Macaskill AF et al. Miro1 is a calcium sensor for glutamate receptor-dependent brain. Although just 2 per metabolism are of molecular components of localization of mitochondria at synapses. cent of body mass, the brain fundamental importance pain sensing. The genes Neuron. 2009;61(4):541–55. accounts for 20 per cent of to the brain. Widely affected clearly play a 12 Attwell D et al. Glial and neuronal control of brain blood flow.Nature . its energy use. Largely this used functional imaging critical role in pain and, once 2010;468(7321):232–43. Review. reflects the energy demands techniques actually identified, their function can 13 Abrahamsen B et al. The cell and of the pumps that reverse the measure changes in blood be studied in more detail molecular basis of mechanical, cold, ion flows generating synaptic flow, which is assumed to in mice. Professor Wood’s and inflammatory pain.Science . 2008;321(5889):702-5. and action potentials. reflect local brain activity. group has developed highly 14 Zimmermann K et al. Sensory neuron Furthermore, impaired blood efficient methods to knock It turns out that several sodium channel Nav1.8 is essential supply might be a factor in out genes specifically in for pain at low temperatures. Nature. systems exist to match 2007;447(7146):855–8.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 9 SECTION 2

All join together

The complex functions of the nervous system reflect the activities of individual cells but also how the coordinated behaviour of networks of neurons.

Lorem ipsum dolors sit amet consequat ti tiempolo factore nestara. 10 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

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One of the most striking properties of neurons is their Computational processes have generally been conceived in terms of circuits, but research organisation into three- is drawing attention to the unexpectedly dimensional networks of sophisticated roles that single cells – or even often staggering complexity. parts of cells – can play in these processes. This arrangement is generally thought to be critical to the computational capacities of Signals are received by For this work, Dr Tiago neural systems. However, neurons through protrusions Branco, a postdoctoral it is becoming apparent known as dendrites. A fellow in Professor Häusser’s that individual neurons are neuron may have anything lab, was awarded the 2011 capable of surprisingly from one to several Eppendorf and Science complex computations – and thousand dendrites, each Prize for Neurobiology. He even subcompartments of one branching repeatedly has gone on to uncover neurons, dendrites, possess to create a characteristic other interesting features computational abilities. dendritic tree. One of the of input signal processing most striking examples is along the dendrite. Close to the cerebellar Purkinje cell, the cell body, signals sum Cells and circuits where, from one ‘trunk’, some linearly, but only during Professor Michael Häusser’s 200,000 parallel dendrites short time windows. Signals ambitious aim is to work out branch off. further down the dendrite, by contrast, are amplified and how the activities of single The sheer numbers of are combined over longer neurons and cellular circuits dendrites contribute to time windows. As a result, are integrated in specific the great complexity of inputs distant from the axon behaviours. Computational neural networks. However, are surprisingly effective at processes have generally recent work is leading to triggering action potentials. been conceived in terms a reappraisal of their role. Different positions on the of circuits, but Professor In particular, rather than dendrite thus appear to Häusser is drawing attention just passively transmitting perform different functions, to the unexpectedly signals, they also seem sophisticated roles that able to perform neural single cells – or even parts computations (see page xx). 15 Branco T, Häusser M. Synaptic of cells – can play in these integration gradients in single cortical pyramidal cell dendrites. Neuron. processes. 2011;69(5):885–92.

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Gain of function Making connections Neurons do not simply add together the inputs they An innovative combination of in vitro and in vivo techniques receive – they also perform more complex computations. is revealing the brain’s microcircuitry.

A neuron receives multiple synaptic inputs which collectively Study of brain function has typically been either ‘top down’ – such as govern its response – typically by modulating firing rate. functional imaging – or ‘bottom up’, focused on individual neurons. The Simplistically, a neuron’s output could reflect the sum of its inputs middle ground, how collections of neurons operate together, has been but to perform complex computations more nuanced responses more difficult to dissect experimentally. By combining innovative in vivo are required. Professor Angus Silver and colleagues have used imaging and in vitro recording, Dr Tom Mrsic-Flogel and colleagues a combination of experimental manipulation and modelling to have taken important steps towards understanding how neural demonstrate how neurons can achieve ‘gain control’ – where networks are organised in the brain. inputs combine multiplicatively rather than additively.. The staggering complexity of the brain, with its billions of neurons Neurons can be considered as ‘input–output’ devices, and and trillions of synapses, may seem to confound attempts to discern it is of fundamental importance to understand how outputs, fundamental principles of its operation. Yet a great deal is now particularly firing rates, are shaped by different patterns of input. understood about individual neurons and their responses to external Do neurons simply sense the difference between two input signals stimuli. What is much less clear is how the activities of individual (an additive function) or are they capable of multiplying them neurons are integrated and operate collectively. together, thereby achieving an amplifying effect or gain control? Neuroanatomically, the issue is a challenge because of the sheer Early theories suggested that inhibitory inputs into neurons number of neurons and the complexity of their connections. Although could form the basis of gain control. These ideas fell out of favour areas of the brain specialise in particular functions, such as vision or as experimental studies found little evidence for mechanisms to motor control, the role of neighbouring neurons may be quite distinct, support them. However, Professor Silver pointed out, this might while neurons some distant apart may share a common function. reflect the fact the methods being used to generate synaptic input To dissect functional connectivity, Dr Mrsic-Flogel’s group is signals were not sufficiently similar to those occurring in real life. combining two techniques, using an area of the rodent visual system With more realistic inputs, he was able to show that inhibition was as an experimental model. In vivo, two-photon imaging is being indeed able to modulate gain in cerebellar granule cells. used to detect calcium signals and identify neurons that show similar Recently, Professor Silver has extended these findings, by responses to experimental stimuli (simple artificial visual stimuli or examining the role of short-term activity-dependent changes more naturalistic movies). These findings are then superimposed in synaptic strength in neuronal computation. Synapses on the results of electrical recordings from neurons, which reveal between the two cells show ‘frequency-dependent short-term pathways of signalling between individual neurons. depression’ – reduced activation on multiple stimulation, because The total volume of cortex imaged amounted to about xx mm3 supplies of neurotransmitter are depleted or a depression in the (around xx cells), while electrical signals were recorded from more responsiveness of the postsynaptic neuron. than 100 cells. Notably, variation in the degree of short-term depression The findings suggested that there is a correlation between the had a non-linear impact on cell outputs. This too has the effect shared functions of neurons and connections between them. of enabling inhibition to powerfully control the gain of cells. Interestingly, this relationship was strongest when the naturalistic Moreover, simulations suggested that similar effects were movies were being viewed. Hence neurons appear to be organised possible within the dendritic trees of more complex neurons. into networks that link cells showing similar responses to external The results point to the importance of short-term depression stimuli, collating information before transmitting it to other areas of and inhibition in this neuronal computation. Since short-term the brain. Synaptic plasticity may help to strengthen connections depression and inhibition are widespread phenomena, and the between neurons that respond to similar stimuli. effect seems to be robust to potential disruptors such as noise, Dr Mrsic-Flogel’s work provides one of the first glimpses of how it could be a common mechanism for controlling neuronal gain neuronal function is integrated in fine-scale neural circuits. The within the nervous system. method offers promise for further dissection of this critical but currently poorly understood aspect of brain architecture. Mitchell SJ, Silver RA. Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron. 2003;38(3):433–45. Ko H et al. Functional specificity of local synaptic connections in neocortical networks. Nature. 2011;473(7345):87–91. Rothman JS, Cathala L, Steuber V, Silver RA. Synaptic depression enables neuronal gain control. Nature. 2009;457(7232):1015–8.

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16 Mathy A et al. Encoding of oscillations by axonal bursts in inferior olive neurons. Neuron. 2009;62(3):388–99.

17 Kitamura K, Häusser M. Dendritic calcium signaling triggered by spontaneous and sensory-evoked climbing fiber input to cerebellar Purkinje cells in vivo. J Neurosci. 2011;31(30):10847–58.

18 Rancz EA, Häusser M. Dendritic spikes mediate negative synaptic gain control in cerebellar Purkinje cells. Proc Natl Acad Sci U S A. 2010;107(51):22284–9.

19 Saviane C, Silver RA. Fast vesicle reloading and a large pool sustain high bandwidth transmission at a central synapse. Nature. 2006;439(7079):983–7.

20 Hallermann S et al. Bassoon speeds vesicle reloading at a central excitatory synapse. Neuron. 2010;68(4):710–23.

21 Kanichay RT, Silver RA. Synaptic and cellular properties of the feedforward inhibitory circuit within the input layer of the cerebellar cortex. J Neurosci. 2008;28(36):8955–67.

22 Vervaeke K et al. Rapid desynchronization of an electrically coupled interneuron network with sparse excitatory synaptic input. Neuron. 2010;67(3):435–51. Lorem ipsum dolors sit amet consequat ti tiempolo

evaluating either the precise specific activities. Professor Work at the synapse has in a network of inhibitory timing or the intensity of Häusser is using a ‘mouse revealed that nerve terminals interneurons. Depending inputs15. virtual reality’ set up, in which have a larger number of on the patterns of stimulation, animals are held stationary, synaptic vesicles than inputs can either generate Such work is possible so continuous recordings previously thought, around or destroy synchronisation. because of key technological can be made, but navigate 300, and that they can be These network effects innovations, particularly virtual reality environments mobilised and recycled are mediated by the the ability to stimulate and by running on a rollerball. at great speed19. Studies pacemaker currents in these record electrical signals with Dr Stephan Hallemann interneurons and the gap from highly localised As well as dendrites, and colleagues in Leipzig, junction-mediated electrical parts of a neuron. For the Professor Häusser’s group Germany, and colleagues connections between them22. former, neurotransmitters is also looking at how the have implicated the are applied in molecular activities of multiple neurons Work in Professor Silver’s lab cytoskeletal protein Bassoon ‘cages’ which are broken are coordinated in networks. draws heavily on advanced in this rapid reloading20. open by targeted pulses Working primarily with imaging techniques. To of light. Electrical signals cerebellar Purkinje cells The computational capacity examine rapid events, where can be detected by patch and inputs from ‘climbing of individual neurons is of conventional two-photon clamping, while calcium fibres’, which provide the great interest. Neurons do microscopy is too slow, signals are visualised main sensory input to the not simply add together his group has developed using calcium-sensitive cerebellar cortex, such the inputs they receive, high-speed acousto-optic dyes and two-photon studies are shedding light but can amplify (or scale lens technology, which can microscopy. Furthermore, on how multiple signals down) signal rates – gain follow events at millisecond new ‘optogenetic’ tools are processed through control. Professor Silver’s resolution in tens of neurons (see page xx) are providing an archetypal neural group has identified several in three-dimensional additional opportunities to network16,17,18. key features of this critical networks. This exciting manipulate the behaviour property (see page xx). technology may have wider The function of individual of individual neurons. application, in areas such as neurons and networks is In terms of circuitry, Experimental results high-capacity data storage also the focus of Professor Professor Silver has identified feed into computational and 3D lithography. Angus Silver. His group a feedforward inhibitory models, often developed in combines experimental circuit in the cerebellum, Computational tools form a collaboration with the Gatsby studies and computational involving cerebellar mossy further aspect of the group’s Computational Neuroscience modelling to understand how fibre cells, Golgi cells and work. The NeuroMatic suite Unit (see page xx). neurons signal, how they granule cells, which is likely of applications is widely The latest techniques integrate multiple signals to to be important in coding used to gather and analyse visualise neural activity in perform computations, and the timing of responses21. electrophysiological data. living brains, now possible how the behaviour of neural Other studies have explored The neuroConstruct software while animals engage in networks is coordinated. synchronisation of activity application provides a way

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 13 23 Gleeson P, Steuber V, Silver RA. neuroConstruct: a tool for modeling networks of neurons in 3D space. Neuron. 2007;54(2):219–35.

24 Gleeson P et al.NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail.PLoSComput Biol. 2010;6(6):e1000815.

25 Benucci A, Frazor RA, Carandini M. Standing waves and traveling waves distinguish two circuits in visual cortex. Neuron. 2007;55(1):103–17.

26 Benucci A, Ringach DL, Carandini M. Coding of stimulus sequences by population responses in visual cortex. Nature Neurosci. 2009;12(10):1317–24.

27 Nauhaus I, Busse L, Carandini M, Ringach DL. Stimulus contrast modulates functional connectivity in visual cortex. Nature Neurosci. 2009;12(1):70–6.

28 Kanichay RT, Silver RA. Synaptic and cellular properties of the feedforward inhibitory circuit within the input layer of the cerebellar cortex. J Neurosci. 2008;28(36):8955–67. Lorem ipsum dolosr sit amet consequat. Lorem ipsum dolosr sit amet consequat.

to build and visualise 3D past experience, attention, activity after experimental may reflect an impaired neural network models current mood and so on. gene therapy and stem ability to distinguish similar, in exceptional detail23. cell therapies in mice, to rapidly occurring sounds. In addition, Professor The lab is also leading characterise restoration of Dr Linden has been working Carandini, with Professor an international project to vision after treatment. on a strain of mice that Kenneth Harris, also aims develop a standardised XML- show analogous hearing to develop mathematical based computer language abnormalities, detected models that capture the From ear to brain… for exchanging models experimentally in their failure properties of the system and developed using a wide The auditory system has to spot gaps in otherwise enable predictions to be range of tools24. NeuroML is been extensively studied, continuous sounds. made about its responses to in global use, including by to understand both the Interestingly, these deficits specific stimuli. the Whole Brain Catalogue neurobiology of hearing seem to originate in the at the University of California Using the cat model, and deafness. Historically, auditory brain rather than the San Diego. Professor Carandini’s group however, far more attention ear – neurons in parts of the has examined responses has been devoted to the auditory thalamus, a gateway of neural populations to initial transduction of sound for auditory information From eye to brain… a range of more complex signals in the cochlea than entering the cortex, seem Vision has long been used visual stimuli. Such work has to the processing of sound to respond abnormally to as a model system for identified distinctive features signals in the brain. rapidly changing sounds. understanding brain function. of responses to alternating Through experimental Dr Linden also has a growing In particular, much research stimuli25, sequences of studies in mice and interest in mouse models of has flowed from Wiesel and stimuli26 and variations in computational modelling, Dr human genetic conditions, Hubel’s ground-breaking contrast27 (see page xx). Jennifer Linden is shedding including psychiatric discovery that specific More recently, he has also light on complex sound disorders. neurons are sensitive to the begun to use virtual reality processing in the auditory With colleagues in orientation at which simple environments (see above) to cortex (see page xx). In Manchester and King’s stimuli are presented. explore navigation of three- related work, her group is College London, she dimensional space and Professor Matteo Carandini’s also using mouse models helped to identify structural responses to finely controlled research has built on these to improve understanding abnormalities in the visual stimuli. foundations, exploring how of hearing difficulties middle ear as the cause populations of cells rather As well as these connections associated with abnormal of hearing problems in a than individual neurons to UCL’s extensive sound processing. mouse model of Treacher– respond to visual stimuli. His neuroscience community, Collins syndrome28. One area of interest ultimate goal is to understand Professor Carandini’s interest She is now working on is specific language the neural circuitry that in vision also benefits his a model of Di George impairment, where young integrates the complex visual colleagues in the Institute syndrome, an inherited people struggle to acquire stimuli received from the real of Ophthalmology. With condition associated with language skills while world, and also handles the Professor Robin Ali, for a greatly increased risk of developing normally in other multiple inputs from other example, he has developed schizophrenia as well as ways. In some cases, this regions of the brain reflecting systems for assessing neural cardiac, facial and other

14 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

Lorem ipsum dolors sit amet consequat ti tiempolo. Weibel–Palade bodies (blue).

Noisy neighbours I-spy fry eye How does the brain deal with the apparently random Zebrafish use their eyes differently: an understanding of fluctuations of background ‘noise’? the genetic and neural basis of this peculiarity could help explain the widespread phenomenon of brain asymmetry. The brain is constantly carrying out almost impossibly complex computations. Like all complex dynamic systems, it has to contend When a zebrafish first sees a novel object, it will tend to appraise with ‘noise’ – apparently random events that could potentially it with its right eye. As it becomes more familiar, it will be switch interfere with the fidelity of signalling. By combining theoretical to its left. This odd behaviour reflects a common characteristic of modelling and experimental manipulation, Professor Peter Latham vertebrate brains, lateralisation of function. In humans, for example, and Professor Michael Häusser have discovered possible language is predominantly a left-hemisphere function. Over the past strategies that the brain may use to deal with such fluctuations. decade, Professor Steve Wilson and colleagues have gradually Noise is apparent in neural systems as variability in the response been unravelling the complex genetic, cellular and neural pathways to identical stimuli, which could reflect two different effects. It could that underlie the development of asymmetry in the zebrafish brain. represent genuinely random noise, linked to chance molecular The fish brain is well-suited to such studies as it possesses a highly events (such as ion channel opening); in this case, variation carries distinctive set of asymmetric brain structures. Most notably, part of no information. Or it could reflect different inputs from other neural its light-sensitive pineal gland, the parapineal, is always found on systems (such as those signalling internal states); in this case, the left of the midline, while two nearby paired structures, known as variation does carry meaning. habenulae, which relay signals from the front to the back of the brain, Professor Latham and Professor Häusser focused on the former, show striking asymmetries in morphology. purely intrinsic noise. They examined the responses of a neural Of these structures, the parapineal seem to play the key role. system to repeated identical stimuli, then looked to see what During development, parapineal cells are initially found either side of happened when a single additional spike was introduced. Does the midline, but coalesce and migrate only on the left side. A decade this single extra spike change the signals propagated through the ago, Professor Wilson showed that the Nodal signalling was critical network? to this process. Without it, embryos were still asymmetric, but the The extra number of spikes generated depends on the average paripineal formed randomly on the left or right side. number of connections made by a neuron (around 1500) and the Work since has generated a more nuanced picture of a highly average probability that an additional spike will be generated. The complex process. Recent work has identified FGF8 as a factor that latter, determined experimentally, turned out to be 0.004. Modelling can break the initial symmetry: without it, parapineal cells remain using these numbers suggested that one additional spike would central. Once FGF8 has broken symmetry, Nodal is responsible trigger an average of 28 new spikes – implying that a small initial for the leftwards bias in parapineal development. This still pushes perturbation could rapidly escalate into a major change in neural back the question of how Nodal comes to be active asymmetrically. activity. After just five steps, there would be around 17 million extra Indications are that a common signalling pathway, the Wnt pathway, is spikes in the system – a graphic example of the ‘butterfly’s wing’ involved, relieving inhibition on Nodal on the left through the activity of effect in the brain. an additional factor, Southpaw. In fact, chaos is not the result in practice, partly because extra While many gaps remain to be filled, the work connects together spikes are largely cancelled out by ‘missed’ spikes, eventually gene activity, cell behaviour, developmental processes, neural generating a steady state. Even so, modelling suggested that connectivity and even behaviour. Remarkably, one strain of mutant a rogue spike should have a small effect on local signalling, a fish,fsi , shows reversed brain asymmetry, and switch their eye use prediction confirmed by experimental recording. when viewing novel and familiar objects. Oddly, they also appear A key question is the extent to which the eventual steady state to be bolder, being less averse to novel stimuli. Development of differs when a new spike is added. Theoretical analysis suggested additional behavioural assays will enable Professor Wilson to gain a that these fluctuations are proportional to the number of additional better view of how alterations in symmetry affect what fish do. spikes generated – previously calculated at 28. Hence the amount of intrinsic noise in the system is large. Concha ML, Burdine RD, Russell C, Schier AF, Wilson SW. A nodal signaling In terms of information coding, the results argue against pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.Neuron . 2000;28(2):399–409. mechanisms in which the precise timing of signals is important. Rather, to deal with noise, it is likely that information is coded by Regan JC, Concha ML, Roussigne M, Russell C, Wilson SW. An Fgf8- average firing rate in large numbers of neurons. dependent bistable cell migratory event establishes CNS asymmetry. Neuron. 2009;61(1):27–34. London M, Roth A, Beeren L, Häusser M, Latham PE. Sensitivity to Carl M TD et al. Wnt/Axin1/beta-catenin signaling regulates asymmetric perturbations in vivo implies high noise and suggests rate coding in cortex. nodal activation, elaboration, and concordance of CNS asymmetries. Neuron. Nature. 2010;466(7302):123–7. 2007;55(3):393–405

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Grate expectations The neuronal decoder How do populations of neurons deal with multiple stimuli An individual dendrite can discriminate the order in which arriving at the same time? it receives activation signals.

Much is now known about how individual neurons in the brain Brain function depends on the ability to detect and discriminate respond to specific experimental stimuli. In the case of the visual between a series of input signals. Neural systems need to know system, these stimuli are typically gratings of particular orientation. that one stimulus was received before another, as this may carry The real world is more complex, of course, requiring responses to important information. It has been conjectured that networks of multiple stimuli and coordinated activity in populations of neurons. neurons would be able to capture information on the timing of By analysing responses to two gratings in different orientations, stimulation, but Professor Michael Häusser and colleagues have generating a plaid pattern, Professor Matteo Carandini and shown that the timing of signals can, remarkably, be detected by a colleagues have uncovered some intriguing features of how single dendrite. populations of cells in the visual cortex respond to mixed stimuli. Assessing the responses of individual dendrites to individual Using a multi-electrode detection system, Professor Carandini is stimuli in a series is technically challenging, requiring extreme able to record activity across populations of hundreds of neurons sensitivity both spatially (sub-micrometre) and temporally (sub- in response to specific visual stimuli. A simple suggestion might be millisecond). To solve this problem, Professor Häusser used short that the response to two superimposed gratings would be the sum of flashes of light to release tiny amounts of neurotransmitter from individual responses. And, indeed, this was largely true. molecular ‘cages’ at highly localised points on a dendrite, and However, when the contrasts of the gratings differed, something recorded the resulting currents and calcium signals with exquisite interesting happened: the grating with the higher contrast tended to spatial sensitivity. dominate the responses. This tendency was strongest when overall Through this approach, a series of stimuli were delivered contrast was high. In this case the cortex appeared to operate a at various points along a dendrite, either starting at the end ‘winner takes all’ competition. Even though it was perfectly able to and moving inwards, or starting close to the axon and moving drive the cortex when presented alone, the grating of lower contrast outwards. Strikingly, although the dendrite received the same effectively became invisible when presented together with the grating combination of stimuli, the order in which they were given made of higher contrast. a big difference to the response of the axon. The likelihood that Interestingly, these patterns of responses could be modelled by a an action potential would be generated was significantly higher surprisingly simple mathematical description, derived from a model moving inwards than in the outwards direction. originally developed for individual neurons. Furthermore, the model This selectivity was dependent on NMDA receptors. In also correctly predicted responses seen in the visual cortex of human the presence of an NMDA receptor inhibitor, the dendrite’s participants presented with similar images. discriminatory abilities were lost. These findings enabled The results also tally with a well-known perceptual phenomenon, Professor Häusser and colleagues to develop a relatively simple ‘masking’. It has been known since the 1990s that adding a mask model for the dendrite’s behavior, based on an impedance visual stimulus on top of a test visual stimulus can render the latter gradient along the dendrite – a common characteristic of invisible, and that the interaction between the stimuli could be dendrites – and the NMDA receptor’s sensitivity to resulting described by simple arithmetical division. The latest results provide a voltage differences. physiological basis for these observations, in terms of the activity of Furthermore, varying the order in which stimuli were applied populations of neurons. to different dendrites also generated differential responses in an More generally, contrast provides a simple but powerful axon. This effect was also captured in the model. mechanism for studying the responses of neurons to variations in Detection of the order and timing of inputs has tended to be stimuli. Professor Carandini’s group is now increasingly turning to considered a property of networks of cells. This work suggests the mouse to explore both neural and behavioural responses. Such that it can actually be carried out by individual dendrites. Neural work has identified subtle additional factors affecting the animal’s processing is characterised by waves of neural activity through behaviour, including size of likely reward and recent successes and networks, in which both the position and timing of activation failures – emphasising the power of cross-talk from other neural conveys important information. It seems that even a structure systems to affect responses in the visual cortex. as deceptively simple as a dendrite can detect the spatial and temporal characteristics of these signals. Busse L, Wade AR, Carandini M. Representation of concurrent stimuli by population activity in visual cortex. Neuron. 2009;64(6):931–42. Branco T, Clark BA, Häusser M. Dendritic discrimination of temporal input Busse L et al. The detection of visual contrast in the behaving mouse. sequences in cortical neurons. Science. 2010;329(5999):1671–5 J Neurosci. 2011;31(31):11351–61.

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From ear to hear How does the brain convert a stream of impulses from the ear into a coherent auditory experience?

The ear contains remarkable machinery for converting sounds into electrical impulses which are relayed to the brain. Just as remarkable, and far less well understood, is how the brain processes and reconstructs these signals into the richly detailed Lorem ipsum dolors sit amet. soundscapes we experience. By combining experimental work on mice with computational modelling, Dr Jennifer Linden is generating new insights into higher-order processing of complex abnormalities. Di George Professor Wilson is interested sounds in the brain. Higher-order processing of sounds is thought to take place patients show a range of in several key areas of in a particular region of the temporal lobe, the auditory cortex. sensory abnormalities, and neurobiology, particularly eye Yet surprisingly little is understood about the responses of Dr Linden is now assessing formation (see companion neurons in this region and how these responses are integrated auditory function in the volume on Basic Life both with each other and with internal inputs – such as memory, mouse model to investigate Sciences), the development physiological states or emotions, which can significantly affect neural processing of raw sound information. the origins of these of brain asymmetries (see In common with other areas of the cortex, the auditory cortex abnormalities. Ultimately, page xx) and more recently consists of several layers of cells with different morphologies this may provide insight into the cellular environment in and connectivity. It is generally assumed that these layers plays the causes of perceptual which stem cells develop29. different roles in cortical processing, which should be apparent in and psychiatric problems in However, as the house characteristic responses to input stimuli. In practice, this has been surprisingly difficult to confirm experimentally. patients. zebrafish aficionado, he Recently, however, Dr Linden has shown that cells in different also collaborates with layers of the mouse cortex vary in their responses to sound stimuli numerous groups within UCL Building sites that are modulated at the slow rates typical of speech and music. and internationally that are This suggests that cortical circuitry may extract information about interested in using zebrafish slow temporal modulations of auditory stimuli. The findings also Professor Steve Wilson suggest constraints on the possible patterns of connectivity runs one of Europe’s largest to explore the function of between cortical layers. zebrafish facilities. Banks of their favourite genes in a Complementing such experimental studies, Dr Linden also aquaria house thousands vertebrate system. Professor works with Dr Maneesh Sahani of the Gatsby Computational of the animals, popular with Wilson has thus been Neuroscience Unit on computational models of auditory cortical home fish keepers as well involved in studies of multiple responses. The ultimate aim is to develop models that can reliably explain the responses of neurons to distinct aspects of complex as developmental biologists. areas of zebrafish biology, auditory inputs, like the barrage of everyday sounds. Zebrafish are an increasingly from muscle function to brain Much past work has been based on ‘spectrotemporal receptive popular model organism, development. fields’, which attempt to correlate the spectrogram of sounds to combining the advantages the responses they generate. However, Dr Linden and Dr Sahani One notable feature of the of being a vertebrate (like a have documented significant flaws in this model, as higher-order lab’s work is the spectacular mouse) with being easy to patterns in complex sound stimuli can generate misleading imagery it generates. results. They have developed new models that more accurately keep and breed (like a fly). It is a regular winner in predict neuronal responses to sound stimuli. Its embryo is transparent, competitions such as the making cellular studies Christianson GB, Sahani M, Linden JF. Depth-dependent temporal ’s Biomedical response properties in core auditory cortex. J Neurosci. 2011;31(36): easier. 12837–48. Image Awards, including two in 2011. Christianson GB, Sahani M, Linden JF. The consequences of response nonlinearities for interpretation of spectrotemporal receptive fields. J Neurosci. 2008;28(2):446–55.

Ahrens MB, Linden JF, Sahani M. Nonlinearities and contextual influences 29 Cerveny KL et al. The zebrafish flotte in auditory cortical responses modeled with multilinear spectrotemporal lotte mutant reveals that the local retinal methods. J Neurosci. 2008;28(8):1929–42. environment promotes the differentia- tion of proliferating precursors emerging from their stem cell niche. Development. 2010;137(13):2107-15.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 17 There is much to be gained from fruitful dialogue between vision and hearing.

Making sense

Vision and hearing are the In both cases, perhaps Research in the UCL Institute Professor James Bainbridge most critical of our senses. most is understood about of Ophthalmology and the have developed a world- Loss of either can be highly how inputs are detected. UCL Ear Institute covers both leading programme in disabling and a source of A great deal is now known basic understanding and gene therapy, establishing considerable distress. Much about the retina and sight practical intervention, and the world’s first clinical has been learned about the loss caused by abnormalities both signal transduction and trial of gene therapy for basic neuroscience of both or degeneration in retinal higher-order processing. inherited blindness . It has vision and hearing, and this cells. Similarly, much is Ultimately the insights gained also pioneered the use of greater understanding offers now understood about how in one system may have embryonic stem cells to the long-term prospect of sound waves are converted relevance to the other. For treat age-related macular improved treatments and into electrical impulses in example, the therapeutic degeneration, under the ways to slow or prevent loss the intricately constructed advances in gene therapy umbrella of the London of these important sensory cochlea and how loss of hair and stem cell therapy, Project to Cure Blindness abilities. cells leads to hearing loss. particularly advanced for (see companion volume on Vision and hearing show Higher-order processing eye disease, may yet have Translation and Experimental fundamental similarities. Both of visual and auditory application in hearing Medicine). The cornerstone are based on the detection information, by contrast, is disorders. of this work is provided by of external signals – light less well understood. Even In partnership with the National Institute for by the retina in the eye and so, brain areas and networks , Health Research (NIHR) sound waves in the inner ear. associated with these senses the UCL Institute of Biomedical Research Centre Neuronal signals are then have been well described Ophthalmology has uniting hospital and research transmitted to specialised and the neural mechanisms developed a strong focus institute. regions of the brain for involved in sensory in translational research. processing and analysis, perception are gradually Professor Robin Ali and generating visual and being unravelled. auditory perceptions of the outside world.

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A further promising route numbers and densities of One of the most common stimuli to reach the ears to new therapies, being objects . His work draws hearing abnormalities, and thence the auditory explored by Professor Robin on visual illusions, an area tinnitus, is surprisingly cortex . His group is also Ali and Dr Rachael Pearson, in which Dr Beau Lotto poorly understood. It is interested in how the brain with Dr Jane Sowden combines research and often assumed to result deals with different sound in the Institute of Child extensive public outreach from cochlear damage but levels and how the context Making sense Health, is transplantation (alongside research into the patients often show perfectly of a sound affects its neural of photoreceptor precursor vision of bees). responses to hearing stimuli. representation. cells into the retina . Similarly, much of the Dr Roland Schaette has Following encouraging work research in the UCL Ear uncovered evidence that in animal models – most primary auditory signals in 1 Bainbridge JW et al. Effect of gene Institute is of translational therapy on visual function in Leber’s recently showing that, in orientation. In particular, a such patients are relatively congenital amaurosis. N Engl J Med. 2008;358(21):2231–9. mice, transplanted cells major focus is on improving small but then undergo a can integrate and restore compensatory amplification 2 MacLaren RE et al. Retinal the function of assistive repair by transplantation of visual function – efforts devices such as cochlear in the midbrain – with photoreceptor precursors. Nature. 2006;444(7116):203–7. are underway to transplant implants. the unfortunate effect of photoreceptor precursors amplifying ‘noise’ in the 3 Pearson RA et al. Restoration of vision As in the eye, much research after transplantation of photoreceptors. that have been derived from system . Nature. 2012;485(7396):99–103. embryonic stem cells. focuses on the loss of cells critical to sensory In terms of central auditory 4 Dakin SC et al. A common visual Research also covers the processing, Dr Jennifer metric for approximate number and transduction, in this case density. Proc Natl Acad Sci USA. neuroscience of vision. the hair cells of the cochlea. Linden is studying how the 2011;108(49):19552–7. Professor Matteo Carandini, A major cause of hearing organisation of the auditory 5 www.lottolab.org for example, is examining cortex might be linked to loss, researchers such 6 Schaette R, McAlpine D. Tinnitus how the brain deals with its processing of complex with a normal audiogram: physiological as Dr Jonathan Gale are evidence for hidden hearing loss and multiple visual stimuli arriving hoping to develop methods sounds (see page xx). computational model. J Neurosci. 2011;31(38):13452–7. at the same time (see page to protect and maintain Similarly, Professor David xx). Professor Steven Dakin hair cells or to transplant McAlpine has studied 7 Harper NS, McAlpine D. focuses on various aspects how the brain locates the Optimal neural population coding new cells to replace those of an auditory spatial cue. Nature. of visual perception, such as lost to degeneration. three-dimensional source 2004;430(7000):682–6. the special features of faces Underpinning such efforts of sound in the environment 8 Dean I, Harper NS, McAlpine D. that underlie face recognition – an ability linked to the Neural population coding of sound level is wide-ranging work to adapts to stimulus statistics. Nature and the mechanisms used understand the mechanisms differing time taken for sound Neurosci. 2005;8(12):1684–9. by the brain to estimate of degeneration, providing targets for intervention.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 19 SECTION 3

The inner world

The secrets of the most complex structure in the Universe – the human brain – are gradually being revealed.

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The brain fascinates and Enormous advances have been made in beguiles. It generates an understanding brain function. Equally important inner representation of the are the computational models that place outside world and achieves experimental findings in a theoretical framework. astonishing feats of mental time travel. Our thoughts, our feelings, our learning; From description to aim is to understand the language, love and lust: function neurobiological basis of all originate in 1.5 kg of human behaviour – at The tools of brain imaging wobbly jelly. scales ranging from neural continue to advance, yet pathways to the action of Recently, non-invasive Professor Ray Dolan argues individual neurotransmitters. imaging has thrown open that technology is not the a new window on the brain. limiting factor. The key, he Computational modelling Brain structure has been suggests, is to think carefully is an integral part of this revealed by magnetic about what questions to ask. approach, providing a resonance imaging and theoretical framework Professor Dolan’s colleague neural connections by for linking behavioural Professor Karl Friston and ‘tractography’ such as observation to mechanistic others have developed diffusion tensor imaging. understanding. A core focus a widely used tool for Brain function has been has been the neurobiological managing imaging data, visualised by functional basis of decision-making. statistical parametric MRI and magneto- An idealised decision-maker modelling (SPM). A powerful encephalography (MEG). would maximise benefits approach embedded within (‘rewards’) and minimise Thanks to better hardware, SPM is ‘dynamic causal harms (‘punishment’). software and experimental modelling’. While functional Notably, in experimental design, enormous advances imaging provides a snapshot settings (as in real life), have been made in of brain activity, dynamic people show marked understanding brain function. causal modelling infers the deviation from perfect Equally important are the order and dependencies of decision-making. Professor computational models that activations – providing insight Dolan is attempting to place experimental findings into mechanistic chains understand the core in a theoretical framework. of events. Using this, and mechanisms of decision- Together, they are providing other approaches, Professor making and the impact insight into how the brain Dolan and colleagues are of factors ranging from accomplishes its remarkable addressing a wide range of nutritional status30 to the way feats. questions. An overarching

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Deciding for the better I’m sure I’m right… Separate but interdependent brain systems may be Structural imaging has revealed regions of the brain involved in decision making. associated with effective introspection about how well we make decisions. One way decision-making can be conceptualised is in terms of ‘habitual’ mechanisms – repeating actions that have been Most decision making involves some level of uncertainty. We are beneficial in the past – versus more forward-looking processes: often called upon to make rapid decisions in the face of incomplete evaluating future possibilities and selecting the most profitable information, and afterwards may have varying degrees of certainty option. The recent work of Professor Ray Dolan and colleagues about whether we made the right decision. A brain imaging study suggests that such mechanisms do indeed operate in the brain, carried out by Professor Geraint Rees and colleagues has identified but not in isolation. regions of the brain associated with accurate judgment of one’s Decision-making can be viewed as a mechanism to maximise abilities – a neural fingerprint of introspective skills. positives (‘rewards’) and minimise negatives (‘punishments’). For To assess introspective skills, participants undertook a tricky the brain to be able to choose actions optimally, it must be able visual task. As well as monitoring how accurate people were in the to assess rewards – that is, assign a ‘value’ to them. The brain task, Professor Rees and colleagues also asked them how confident is also adept at predicting likely rewards, and actions delivering they were in their answers. These do not necessarily correspond – greater-than-anticipated rewards tend to be repeated. someone may feel they are doing well when they are actually doing Hence ‘habits’ are one important driver of decision-making. badly (or vice versa). For someone with good introspective abilities, But the brain is also capable of ‘goal-directed’ actions, explicitly however, confidence levels should correlate with actual performance. modelling future action–outcome contingencies so as to identify The difficulty of the task was adjusted so every participant got the best option. Distinct areas of the brain associated with these the same proportion of answers correct. But different participants processes have been identified. Yet their relationship to one showed very different abilities to introspect effectively about their another has not been clear. performance. With Professor Nathanial Daw in New York and Professor Furthermore, MRI scans revealed a part of the brain – regions of Peter Dayan from the Gatsby Computational Neuroscience the prefrontal cortex – where the volume of gray matter correlated Unit, Professor Dolan developed a series of tasks to explore with accurate self-appraisal. Importantly, the volume of these regions the contributions of these different systems to decision-making. did not correlate with actual performance or with confidence levels. Contrary to expectations, functional imaging suggested that In follow-up studies using different types of perceptual test, the decision-making typically depended not on either one system or same regions were again linked to more accurate introspection. the other on its own but on a sophisticated combination of both. Hence, they are likely to be involved in generic introspection skills, By refining the computational framework underpinning not those specific to visual tasks. this analysis, Professor Dolan, Professor Dayan and Dr Klaus Interestingly, the area of the prefrontal cortex identified has Wunderlich were able to distinguish precise areas associated undergone extensive development during human evolution, with ‘on the fly’ modelling of future possibilities and with learning suggesting that enhanced introspective or other ‘meta-cognitive’ more associated with extensive training. Notably, while value skills have proven evolutionarily advantageous. The findings also calculations in these systems localised to distinct regions of the raise the intriguing possibility that, given the plasticity of neural brain, signals from these areas converge on a region of prefrontal systems, it may be possible to ‘train’ people and enhance their cortex, which processes the value assessments generated by the introspective abilities. two decision-making systems and enacts a decision based on the more valuable option. Fleming SM, Weil RS, Nagy Z, Dolan RJ, Rees G. Relating introspective The studies suggest there are indeed separate value-based accuracy to individual differences in brain structure. Science. 2010;329(5998): decision-making systems in the brain, but their activities are 1541–3. integrated within the prefrontal cortex (more specifically, the Song C, Kanai R, Fleming SM, Weil RS, Schwarzkopf DS, Rees G. Relating ventromedial prefrontal cortex. It is likely that real-life decision- inter-individual differences in metacognitive performance on different making similarly involves weighing up the input from these perceptual tasks. Conscious Cogn. 2011;20(4):1787–92. different systems to guide choice of action. A better understanding how habitual choices are encoded, and overcome, could be of great significance to the many habit-based behaviours, from diet to addiction, that are not in our long-term interests.

Daw ND et al. Model-based influences on humans’ choices and striatal prediction errors. Neuron. 2011;69(6):1204–15.

Wunderlich K, Dayan P, Dolan RJ. Mapping value based planning and extensively trained choice in the human brain. Nature Neurosci. 2012;15(5):786–91.

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Hence classical diagnostic has been based on pooling criteria systems are often of data from groups of problematic and endlessly subjects. Professor Geraint debated. Rees, however, is interested in a different question – how Professor Dolan has therefore do these neural substrates launched a radical crusade vary between individuals? to provide a neurobiological understanding of mental and One notable example had behavioural traits. With UCL’s an unusual origin – the actor Professor and Colin Firth’s guest editorship colleagues in Cambridge, of BBC Radio 4’s influential he has been awarded £5.4 news programme Today. million funding from the With the BBC’s science and Wellcome Trust to provide technology correspondent a baseline assessment of Tom Fielden, he worked with a cohort of young people Professor Rees to test the who will be followed for five idea that political affiliation Lorem ipsum dolors sit amet years and profiled for a wide might be reflected in the range of behavioural and structure of the brain. neurobiological traits. A sample of young people information is presented (the shape optimal choice and Crucially, the study will completed a standard ‘framing’ effect) 31, as well the ‘vigour’ with which they not be constrained by five-point questionnaire as biases such as over- are pursued35. Alongside existing diagnostic criteria, on their political outlook, optimism32 and a tendency imaging studies, such work generating an entirely from very liberal to very to stick with the status illustrates how decision- unbiased description of traits conservative, and then quo when facing difficult making can be dissected across a population. Equally underwent a structural choices33. in terms of neural pathways importantly, the assessments MRI scan. Remarkably, and neurotransmitter action. The brain has a remarkable are embedded in a coherent significant differences were Similarly, new computational capacity to predict likely computational framework, apparent: liberals had a approaches developed by gains, and can compare providing powerful analytical relatively well-developed Professor Fristion, Professor these predictions with the tools for interpreting data. If anterior cingulate cortex Dolan and Dr Rosalyn Moran rewards actually obtained. successful, this study could (ACC) and conservatives have been used to infer Registering this discrepancy be a first step towards a a proportionately larger molecular events occurring underpins many forms of categorisation of psychiatric amygdala. at the synapse from relatively learning, by promoting disorders based on coarse imaging data – a hint The roles of these areas actions that have proven underlying neurobiological of how imaging data might suggest a possible especially fruitful in the past. mechanisms – a potentially be exploited in the future explanation. The ACC may A collection of deep brain far-reaching shift. (see page xx). provide greater capacity nuclei collectively known as The focus on behaviour, to tolerate novelty and the striatum appears critical One good reason to neurobiological systems uncertainty, typical of more for this capacity34. The brain characterise decision- and computational models liberal ways of thinking. can therefore calculate the making systems is the impact will synergise with the work ‘value’ of possible actions, a that ‘poor’ choices can have of the Sainsbury Wellcome computation that is then used on individuals and those Centre (see page xx). In to guide decision-making. around them. Addiction, computational neuroscience, Recent studies suggest gambling, violence and 30 Symmonds M et al. Metabolic Professor Dolan has also state alters economic decision mak- there may be multiple neural other behaviours can be ing under risk in humans. PLoS One. established close links mechanisms calculating individually and socially 2010;5(6):e11090. with the German Max value, which under certain devastating. Moreover, 31 De Martino B, Kumaran D, Seymour B, Planck Society, including Dolan RJ. Frames, biases, and rational circumstance may come into skewed decision-making decision-making in the human brain. a joint Summer School in conflict (see page xx). characterises numerous Science. 2006;313(5787):684–7. Computational Psychiatry psychiatric conditions of 32 Sharot T, Korn CW, Dolan RJ. How As well as choosing an and Aging and the possibility unrealistic optimism is maintained enormous individual and option, the brain has to of a more extensive joint in the face of reality. Nat Neurosci. economic significance, from 2011;14(11):1475 –9. consider how energetically initiative. depression to schizophrenia. 33 Fleming SM, Thomas CL, Dolan to pursue this option. A RJ. Overcoming status quo bias in the Currently, the neurobiology combination of modelling human brain. Proc Natl Acad Sci USA. of these conditions is not Perception 2010;107(13):6005–9. and experimental work, in well understood. In practice, 34 O’Doherty J et al. Dissociable collaboration with Dr Marc Great progress has been psychiatric conditions are roles of ventral and dorsal striatum in Guitart-Masip and Professor made in understanding the instrumental conditioning. Science. diagnosed purely on the 2004;304(5669):452–4. Peter Dayan, suggests that neuroanatomical basis of basis of symptoms, with little 35 Guitart-Masip M et al. Vigor in the interplay between dopamine perceptual and cognitive consideration of underlying face of fluctuating rates of reward: and serotonin systems could phenomena. Generally this an experimental examination. J Cogn mechanistic causes. Neurosci. 2011;23(12):3933–8.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 23 The amygdala has been environmental location – the implicated in fear and first description of ‘place emotional responses, cells’37. This led Professor and perceptions of threat, O’Keefe to make the initially psychological traits controversial but ultimately associated with more influential suggestion that conservative attitudes. the hippocampus held some The correlations are kind of ‘cognitive map’ of the consistent with known outside world. differences in physiological Subsequently, patterned and neural responses activation of neurons was between liberals and identified in the entorhinal conservatives. But as they cortex, which provides the are only associations, it is major cortical input into impossible to assign cause the hippocampus. These and effect. ‘grid cells’ form a distinctive Notably, an algorithm trained triangular lattice representing Lorem ipsum dolors sit amet to analyse scans ended the external environment. up with a good ability to First seen in rodents, Patients with memory loss due to hippocampal discriminate the very liberal Professor Burgess recently damage also show a marked impairment in from the conservative (71 showed they were also their ability to imagine fictitious or future per cent success rate). present in the human brain experiences. The key problem seems to be an (see page xx). And the resulting academic inability to create spatially coherent scenes paper may be the first to Professor Burgess in the mind’s eye. include both a journalist and has made much use an Oscar-winning actor as of immersive virtual coauthors36. reality set-ups, creating Imaging during various Professor Maguire has also artificial environments that maze-navigation tests examined another aspect The space within us participants navigate while suggest that the left and right of hippocampal function undergoing functional hippocampus specialise in – its role in imagining the Movement is integral imaging. Using this these functions – the right future. Patients with memory to human existence. approach, his group has primarily handling spatial loss due to hippocampal Furthermore, as well as examined the role of the information and the left damage also show a marked being able to physically hippocampus and other temporal information39. impairment in their ability move from location to brain areas during tasks to imagine fictitious or another, we also have the Cognitive maps and the such as route-finding in the future experiences. The key mental capacity to imagine hippocampus are also the dark, planning journeys and problem seems to be an ourselves somewhere else. focus of Professor Eleanor mentally imagining oneself inability to create spatially The work of Professor John Maguire and colleagues. in different locations. These coherent scenes in the O’Keefe and Professor Neil Her group has developed experimental studies are mind’s eye. Burgess has illuminated a special interest in the also used to devise and test key aspects of these changes the hippocampus computational models. remarkable navigational and undergoes as trainee taxi conceptualising abilities. Such studies have revealed drivers learn ‘the Knowledge’ the critical role played by – memorising 25,000 Navigation is a complex boundaries in the formation streets and thousands of activity. It requires integration of cognitive spatial maps. landmarks in central London. of visual information, internal 36 Kanai R, Feilden T, Firth C, Rees G. For example, when Such work provides a rare proprioceptor and other data Political orientations are correlated participants were imagining opportunity to study the with brain structure in young adults. during locomotion, as well Curr Biol. 2011;21(8):677–80. themselves in different parts plasticity of the adult brain as memory and planning. 37 O’Keefe J, Dostrovsky J. The of an artificial environment, longitudinally, comparing A critical structure in these hippocampus as a spatial map. increasing the numbers of drivers before and after Preliminary evidence from unit activity abilities is the hippocampus, in the freely-moving rat. Brain Res. boundaries was more helpful they have completed four acting in partnership with 1971;34(1):171–5 than adding extra landmarks years’ training. Taxi drivers various regions of the cortex. 38 Bird CM et al. Establishing the or more detail38. who successfully completed boundaries: the hippocampal contribution to imagining scenes. In the 1970s, in some the course showed marked Remarkably, imaging has J Neurosci. 2010;30(35):11688–95. of the first recordings expansion of the posterior also revealed a striking 39 Iglói K et al. Lateralized human from freely moving region of the hippocampus hippocampal activity predicts asymmetry in hippocampal rats, Professor O’Keefe (unlike those who failed navigation based on sequence or place function. The hippocampus memory. Proc Natl Acad Sci USA. discovered that certain or dropped out). The 2010;107(32):14466–71. is responsible for both cells in the hippocampus downside, however, was a 40 Woollett K, Maguire EA. Acquiring spatial navigation and preferentially fired when an corresponding loss in some “the Knowledge” of London’s layout episodic memory (recall of drives structural brain changes. animal was in a particular other aspects of memory40. Curr Biol. 2011;21(24):2109–14. events in one’s own life).

24 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

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A new view of pain A map in the head Simply seeing the body can reduce sensations of pain. The human brain contains ‘grid cells’ that provide an internal representation of external space. The brain has remarkable abilities to integrate information from multiple sensory systems. These sensory systems are not How do animals know where they are? A critical role is played independent, and inputs from one can have surprising effects by ‘grid cells’, which appear to create an internal map of on another – as Professor Patrick Haggard and colleagues have external space composed of equilateral triangular tiles. A grid discovered in their studies on vision and pain. cell fires whenever an animal passes over one of a series of In 2001, Professor Haggard found that participants could better locations arranged at the vertices of a triangular grid across the discriminate tactile stimuli when they could see their arm, even if they environment. Although well-characterised in rodents, only recently could not see the stimuli themselves. Notably, this ability increased have indications of their presence been seen in humans, thanks to still further when the arm was magnified. the work of Dr Caswell Barry and Dr Christian Doeller in Professor Follow up studies of this intriguing discovery examined whether Neil Burgess’s group. a similar effect applied to pain perception. With a mirror box set-up, Identifying grid cells in humans is challenging. It is difficult to painful stimuli could be applied to participants’ arms outside their record from individual neurons in the human brain, while functional field of vision, while maintaining an intact body image. Strikingly, imaging techniques typically lack the spatial or temporal resolution when participants could see their arms, their subjective ratings of to identify the localised neural activity that would reveal their pain were reduced, as were the brain signals caused by painful existence. However, Professor Burgess’s group reasoned that stimulation. certain predicted features of grid cell activity, such as the fact that Furthermore, as with touch, magnification further enhanced all of the grid patterns are aligned, and become sharpened during this analgesic effect (while making the hand look smaller actually rapid locomotion, might provide a way to detect signs of their reduced it). Vision alone increased heat-pain thresholds by, on activity by fMRI in humans. average, 3.2°C. Sight of a stranger’s hand or neutral object, by To test this idea, participants were scanned while they explored contrast, had no impact. a virtual reality scene – a grassy plain bounded by cliffs which Recently, Professor Haggard has gone a step further, investigating distant landmarks to help with orientation. Participants collected what is happening within the brain that could explain these striking and replaced objects within this area. findings. Using an infrared laser, he subjected participants to a Focusing on brain regions known to contain grid cells in rodents, painful stimulus while scanning their brain activity. When participants the researchers saw tell-tale patterns of brain activity with sixfold could see their hand during painful stimulation, perceptions of pain symmetry as a function of running direction – precisely what would were again reduced. This was found to correspond to enhanced be expected from activation of grid cells in a triangular lattice. connectivity between the brain’s well-described ‘pain matrix’ and As predicted, the strength of the signal recorded varied with the a network of regions in the posterior of the brain associated with speed at which participants moved within the virtual environment. visual perception of the body. Hence ‘visually induced analgesia’ The results confirmed that the entorhinal cortex in humans does does not simply reflect lower activity in pain networks but stems from indeed contain a triangular representation of external space. modulation by networks associated with body perceptions. A particularly interesting feature of grid cells, and associated These intriguing studies suggest novel ways in which pain might systems that create an internal map of the world, is that they seem be treated. Although pain control has traditionally addressed pain to be (at least in part) an innate feature of the brain. In rodents, signalling, it may be possible to influence higher-level responses to a cognitive map is generated by integrating information from, in control perceptions of pain. addition to grid cells, place cells (which provide a representation of specific locations within an environment) and head direction cells Kennett S, Taylor-Clarke M, Haggard P. Noninformative vision improves the (which provide a kind of neural compass). Working with Professor spatial resolution of touch in humans. Curr Biol. 2001;11(15):1188 –91. Burgess, Dr Tom Wills and Dr Francesca Cacucci in Professor John Longo MR, Betti V, Aglioti SM, Haggard P. Visually induced analgesia: seeing O’Keefe’s lab recently showed that head direction cells and place the body reduces pain. J Neurosci. 2009;29(39):12125–30. cells appear very early in rat development, before the animals Mancini F, Longo MR, Kammers MP, Haggard P. Visual distortion of body size leave their nest and explore the world around them. Thus they modulates pain perception. Psychol Sci. 2011;22(3):325–30. seem to be born with an innate sense of direction.

Longo MR et al. Linking pain and the body: neural correlates of visually Doeller CF, Barry C, Burgess N. Evidence for grid cells in a human memory induced analgesia. J Neurosci. 2012;32(8):2601–7. network. Nature. 2010;463(7281):657–61.

Wills TJ, Cacucci F, Burgess N, O’Keefe J. Development of the hippocampal cognitive map in preweanling rats. Science. 2010;328(5985): 1573–6.

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Reading the signs From synapse to behaviour A study of reformed Colombian guerillas has revealed key Statistical modelling may be a ‘mathematical microscope’ brain areas and connections involved in learning to read. revealing synaptic events associated with specific behaviours. The vast majority of children pick up spoken language skills automatically early in life. Learning to read and write, however, One of the greatest challenges in neuroscience is to link observable takes considerable effort and practice. Identifying brain functions human behaviours with specific changes at synapses. Only under important in developing literacy is challenging as children are exceptional circumstances can neuronal recordings be taken within typically developing in many different ways at the same time the brain. However, using statistical modelling, Dr Rosalyn Moran, as they are learning to read, so it is difficult to disentangle the Professor Karl Friston, Professor Ray Dolan and colleagues have precise impact of language. Reintegration of illiterate Colombian been able to extract information about molecular events at the guerillas into mainstream society provided Professor Cathy Price synapse from MEG recordings. and colleagues with a unique opportunity to study brain changes MEG detects the magnetic fields generated by neuronal activity. associated with the acquisition of written language skills. One of its major advantages is its very high temporal resolution – Working with colleagues in Spain and Colombia, Professor Price in the millisecond time range. It is therefore well-suited to studies was able to compare brain structure of individuals who had learned examining dynamic changes in neuronal activity. to read Spanish as adults (‘late-literates’) with those of matched MEG data are also amenable to analysis by ‘dynamic causal adults who were still illiterate. Late literates had enhanced grey modelling’, whereby changes in brain activity are modelled as a matter volumes in five areas at the back of the brain previously sequence of activations through networks of brain areas (see main implicated in reading abilities. They also showed connectivity text). Hence, a particular dynamic pattern of MEG activations can differences, with additional white matter in a region of the corpus in theory be modelled in terms of underlying causes, which can callosum, the cables linking the two hemispheres of the brain. include information about the molecular properties of neurons and This information provided an opportunity to explore these regions their interactions. and connections in adults who had learnt to read when young. To test this, Dr Moran attempted to deconstruct the impact of Tractography revealed a pathway through the area of the corpus dopamine on working memory. As expected, administration of a callosum identified in the late-literates, linking the left and right dopamine precursor, L-DOPA, generated a small but significant dorsal and angular gyri (regions previously implicated in language increase in working memory performance. Working memory is processing). Although tracts through the corpus callosum are laid thought to involve areas of the pre-frontal cortex. Three classes of down before birth, it is possible that the precise linkages can be MEG recordings showed changes in this area during memory tasks, reshaped later as adults learn to read. and one class was sensitive to the dopamine boost. Functional connections in the previously identified areas were A dynamic causal model was developed to simulate these explored in fMRI studies and computational modelling, with reading findings. It integrated various aspects of both excitatory (AMPA and being compared to object naming. The results again pointed to NMDA receptors) and inhibitory (GABA receptor) signalling, as well the importance of connections between hemispheres, rather than as what is known about their sensitivity to dopamine. The model was between gyri on the same hemisphere. Furthermore, the left angular then adjusted until it provided the best fit with the experimentally gyrus appears to play a ‘top-down’ modulatory role, possibly to aid obtained MEG data. discrimination of visually similar words, where context can provide This analysis suggested that the dopamine-associated clues to word identity. improvements in working memory stemmed from effects on both Brain areas involved in reading have been well-characterised, AMPA and NMDA receptors. Notably, the strength of these effects but this study has provided a rare opportunity to study how they are predicted the degree of improvement in memory performance. formed. As well as revealing more about the structure and function Reassuringly, the results are also consistent with what is known from of these brain networks, they may also shed light on conditions in experimental studies of dopamine’s effects on NMDA and AMPA which they go wrong. In dyslexia, for example, reduced grey and signalling. white matter volumes may be consequences of limited reading The study has provided proof of principle that the molecular experiences rather than a cause of reading difficulties. basis of complex human behaviours can be inferred by modelling. It offers the exciting prospect of dissecting the molecular and cellular Carreiras M et al. An anatomical signature for literacy. Nature. basis of behavioural phenomena non-invasively, and how they 2009;461(7266):983–6. may be altered in conditions characterised by abnormal cognitive processing.

Moran RJ et al. An in vivo assay of synaptic function mediating human cognition. Curr Biol. 2011;21(15):1320–5.

26 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

Although IQ is reasonably stable over the life course, the brain’s dramatic rewiring during adolescence could potentially lead to changes over shorter time frames. Cross-sectional studies have shed little light on this issue, as so many uncontrollable variables could account for differences in IQ within a population. Professor Price therefore undertook a longitudinal approach, measuring IQ and performing structural brain scans on 33 young people at average age 14 and then again around four years later. Two aspects of IQ were assessed, verbal and non-verbal. Interestingly, Lorem ipsum dolors sit amet coinsequat ti tiempolo. individuals’ IQ scores varied markedly between assessments, some going up and some going down. Professor Maguire’s and it is well known that the our own body, and raises Furthermore, IQ changes group has also made key brain includes a detailed the possibility of novel were associated with contributions to one of the ‘somatosensory map’. But psychological methods of changes to specific areas most intriguing areas of information from vision pain control. of the brain – including cognitive neuroscience – the and proprioception is also speech areas of the brain ability to predict or decode used to generate a sense Language and learning for verbal IQ (and, oddly, mental states from patterns of our physical form, and areas associated with finger Development and in brain activity. Their early the brain may contain a movements for non-verbal rehabilitation of the brain work analysed hippocampal ‘physical body map’ of the IQ). Hence, at this important systems responsible for activity to predict the internal world. Interestingly, stage in their education, language are the main location of participants in a this stored body model, like young people’s IQ scores interests of Professor Cathy virtual reality environment41. the somatosensory map, show more plasticity than Price. Unusually, work with Recently, it has even proven is hugely distorted – we previously thought45. South American colleagues possible to predict which perceive our fingers as much provided a rare opportunity specific episodic memories shorter and our hands much to look at the development participants were recalling wider than they actually are43. of reading skills in an adult solely by examining the Curiously, this body map population – Colombian patterns of activity in their is highly sensitive to guerrillas being reintegrated hippocampus42. temperature. Cooling hands into society (see page xx).

increased the strength of the A more general aim is to Automatic for the people ‘rubber hand’ illusion – an understand how speech and experimental ploy where the reading skills recover after Professor Patrick Haggard 41 Hassabis D et al. Decoding neuronal brain is tricked into thinking damage to the brain, which ensembles in the human hippocampus. is interested in two intriguing Curr Biol. 2009;19(7):546–54. an artificial limb is actually may suggest new ways to and related aspects of 42 Chadwick MJ, Hassabis D, part of the body – while restore impaired language consciousness: how we Weiskopf N, Maguire EA. Decoding warmth reduced the strength abilities. individual episodic memory traces in form an internal mental the human hippocampus. Curr Biol. of the illusion44. representation of our bodily Language skills develop 2010;20(6):544–7. form and how we attribute Professor Haggard has during childhood, and 43 Longo MR, Haggard P. An implicit body representation underlying human agency to our own actions – uncovered other curious difficulty with language position sense. Proc Natl Acad Sci USA. how do we decide when we influences on pain can create profound 2010;107(26):11727–32. ‘willed’ something to happen perception, such as vision problems for young people. 44 Kammers MP, Rose K, Haggard P. Feeling numb: temperature, but not rather than it happening (see page xx). This and Interestingly, Professor thermal pain, modulates feeling of automatically? other work, for example on Price has discovered that body ownership. Neuropsychologia. 2011;49(5):1316–21. phantom limb pain, hints language areas of the brain The sensory system in the Ramsden S . Verbal and at the importance of a are linked to fluctuations 45 et al skin provides information non-verbal intelligence changes coherent representation of in IQ during childhood. in the teenage brain. Nature. about the limits of our body, 2011;479 (7371):113 – 6.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 27 The Sainsbury Wellcome Centre will take advantage of new technological opportunities to draw links between neural circuits and behaviour.

Making connections: The Sainsbury Wellcome Centre

Individual neurons – indeed, The problem to a large Yet exciting ways forward It is therefore a propitious even subcompartments of degree is technological. are beginning to emerge. time to be launching a neurons, dendrites – can Many tried and tested A raft of technological new initiative in neural perform computational methods exist to explore advances (see Box) is circuitry and behaviour. The tasks. Yet the nervous the electrophysiology of beginning to provide the Sainsbury Wellcome Centre, system’s most sophisticated neurons. Much is now tools for dissecting the neural jointly funded by the Gatsby computational activities known at a molecular level pathways underpinning Charitable Foundation and are likely to arise from about how neurons work behaviour. Alongside this the Wellcome Trust, is being the coordinated actions and communicate with experimental progress, established to apply existing of networks of neurons. one another. Alongside a further important and novel experimental A critical readout of this this ‘bottom up’ approach, role is being played by tools and computational computational activity is the various forms of structural computational modelling. approaches to generate observable behaviour of an and functional imaging have Huxley and Hodgkin’s new insight into the neural animal, be it an experimental provided ‘top down’ insight landmark studies of action circuitry underpinning mouse or a person. However, into high-level brain function. potential generation included behaviour. In time, as the links between collective Many regions and networks computational models, well as shedding light on neural activity and behaviour of the brain have been and they remain central to fundamental neurobiological are extremely poorly implicated in a whole host of neuroscience, providing processes, it should understood. human behaviours. But there a theoretical framework also provide insight into remains a significant gap – for interpreting the results neurobehavioural conditions imaging techniques cannot of experiments and a way such as schizophrenia, yet provide the resolution of generating predictions depression and autism. to monitor the responses of that can be explored individual neurons in neural experimentally. networks.

28 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences Connecting brain to behaviour

Research on neural circuitry is being and other new methods, electrophysiology is still transformed by a raft of new technologies. likely to play a critical role – not least because of its great sensitivity and high time resolution. Studies of neural activity in the living brain present a considerable technological challenge. Equally important advances have been made Ideally, an investigator needs to stimulate and in the detection of neural activity. As well as record from specific neurons – or parts of conventional electrical recording through patch neurons – on a timescale consistent with the clamping, it is now also possible to visualise natural processes being studied, generally in the dynamic intracellular processes through millisecond range. fluorescent reporters. These include voltage- sensitive dyes or calcium sensors, which are Such studies have been greatly aided by recent sensitive to intracellular calcium levels and reveal technological innovations. The use of ‘caged calcium fluxes within the cell. Exquisite specificity compounds’ – neurotransmitters encased in can again be achieved by using genetic chemical shells until released by a flash of light techniques to engineer specific cells to express – has enabled neuron activation to be controlled particular calcium indicators. with a high degree of spatial and temporal resolution. In combination, imaging systems can provide remarkable spatial detail over multiple scales – A further advance has been to combine uncaging spanning a 1 µm dendritic spine, an individual with ‘two-photon excitation microscopy’, which dendrite, a neuron or a neural network. permits high-resolution three-dimensional imaging of living tissue. By tracking the responses Additional techniques are beginning to reveal of surrounding cells to this highly localised neuromicrocircuitry, including ‘Brainbow’ or activation, functionally connected neural networks viral-based approaches for differential labelling of can be identified. individual neurons and their connections. It is also possible to identify functional connections in such Even with such methods, in densely packed collectives (see page xx). regions of the brain it can still be difficult to activate specific neurons efficiently. A great Equally importantly, this dissection of neural step forward has been the development of activity can increasingly be related to fine-scale ‘optogenetic’ tools, which combine genetic analysis of complex behaviours. Sophisticated targeting with precise light delivery to activate image recording and image analysis can generate individual neurons with great precision. data on freely moving animals. Furthermore, virtual reality set ups can be used to record from The key principle is to engineer neurons so an immobilised experimental animal – typically that they express light-sensitive ion channels a mouse – as it interacts with a highly controlled (originally identified in phototoxic algae). These virtual environment. Through such methods, it may are generally delivered into cells by viral vectors. therefore be possible to close the gap between So, instead of electrical impulse, a brief flash of neuron and behaviour. light is used to stimulate a cell by opening up newly introduced ion channels. Even with these

A new building is being constructed to house the Centre, close to UCL’s main central London campus to encourage collaboration and interactions with UCL’s world-leading community of neuroscientists. The building, designed by Ian Ritchie Architects Ltd, will house 12 groups. At its heart will be the Gatsby Computational Neuroscience Unit, led by Professor Peter Dayan, emphasising its centrality to the Centre’s vision. A team led by Interim Director Professor John O’Keefe is currently identifying a suitable Director who will shape the long-term strategy for the Centre and decide its final composition. Building work is due to be completed in 2014.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 29 SECTION 4

Decline and fall

Loss of neurons underlies a range of devastating conditions affecting mental and physical capacities.

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Lorem ipsum dolors sit amet consequat ti tiempolo factoira

Neurodegenerative and Rare forms of Alzheimer’s disease and neuromuscular diseases Parkinson’s disease have provided considerable wreak havoc on mental insight into the molecular mechanisms of and physical function, and disease. are very difficult to treat. In part, this is because the mechanisms of disease A more common cause of collaborations dissecting are poorly understood. inherited Parkinson’s disease conditions such as multiple Interestingly, although is LRRK248. Although still sclerosis and epilepsy. responsible for a relatively rare, mutations in LRRK2 Similarly, Professor John small number of cases, rare are common enough to be Hardy, who identified the inherited forms of Alzheimer’s considered a possible cause first gene associated with disease and Parkinson’s of disease in Parkinson’s Alzheimer’s disease, the disease have provided disease patients, particularly b-amyloid gene50, while considerable insight into the in certain populations where at Imperial College, has molecular mechanisms of up to one in ten patients been involved in several disease. have LRRK2 mutations49. international multicentre LRRK2 genetic tests are now In Parkinson’s disease, for studies. These have commercially available, and example, Professor Nick pinpointed cholesterol are used to guide treatment Wood has led genetic studies and identify family members revealing significant insight 46 Valente EM et al. Hereditary early- at risk. onset Parkinson’s disease caused into disease processes. By by mutations in PINK1. Science. analysing three families, Nevertheless, most patients 2004;304(5674):1158–60. 47 Gandhi S et al. PINK1-associated two from Italy and one from do not have mutations in Parkinson’s disease is caused by Spain, Professor Wood was genes identified by traditional neuronal vulnerability to calcium- induced cell death. Mol Cell. able to pinpoint mutations in genetic approaches. 2009;33(5):627–38. the PINK1 gene as a cause Recently, insight into these 48 Gilks WP et al. A common LRRK2 46 of disease . The sequence cases has come from mutation in idiopathic Parkinson’s of the PINK1 gene suggested genome-wide association disease. Lancet. 2005;365(9457):415–6. that PINK1 protein was studies, which sweep the 49 Healy DG et al. Phenotype, genotype, and worldwide genetic penetrance of located in mitochondria, entire genome for factors LRRK2-associated Parkinson’s disease: reigniting interest in this influencing the risk of a case-control study. Lancet Neurol. 2008;7(7):583–90. organelle’s role in Parkinson’s disease. Professor Wood 50 Chartier-Harlin MC et al. Early- disease. PINK1’s normal has led a major international onset Alzheimer’s disease caused by role may be to protect consortium in Parkinson’s mutations at codon 717 of the beta- amyloid precursor protein gene. Nature. mitochondria from cellular disease (see page xx), 1991;353(6347):844–6. stress47. and has contributed to

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 31 Lorem ipsum dolors sit amet. Lorem ipsum dolors sit amet.

Imaging the future of multiple Beware the black spot sclerosis Visible on MRI brain scans as black spots, ‘microbleeds’ Can advances in imaging provide multiple sclerosis may be more harmful than once thought. patients with a clearer view of their future? Brain function depends intimately on blood flow through a network When they receive a diagnosis, multiple sclerosis patients typically of small arteries ramifying through the brain. Damage to these tiny ask how their disease is likely to progress. Unfortunately, while blood vessels can cause blood to leak into surrounding brain tissue some probabilities can be given, it is very hard to predict what will (haemorrhagic stroke or intracerebral haemorrhage) while vessel happen to any one individual. Thanks to advances in MRI, however, blockage can disrupt oxygen supply (ischaemic stroke). Stroke patients – and indeed significant numbers of healthy older people Dr Olga Ciccarelli is hoping to provide more specific answers. However, confirmation of diagnosis and information about the – often also have one or more small areas of bleeding, cerebral speed of clinical progression require follow-up of cohorts of patients ‘microbleeds’. Advances in MRI have made microbleeds easier to over several years. Early longitudinal studies revealed that MRI detect, and Dr David Werring has found that they may be clinically detection of white matter lesions in the earliest phases of disease more important than previously thought. was a useful indicator of multiple sclerosis in suspected cases, Although not seen on CT or conventional MRI scans, microbleeds while recent multicentre studies have begun to provide a more are clearly visible as black spots in more advanced (T2*- nuanced picture of the types of damage seen and later symptoms. weighted gradient echo) MRI. They are linked to the presence of a Central to these advances have been enhanced tools for haemoglobin breakdown product, haemosiderin, and indicate areas characterising structural and other abnormalities. Dr Ciccarelli and of local blood seepage out of damaged small vessels. colleagues have applied new ‘tractography’ methods to assess Despite being relatively common and often present in key areas deficits in white matter connectivity, to complement measures of of the brain, they have generally been considered to be of little white matter degeneration, as well as more sophisticated methods clinical significance. Dr Werring’s studies have challenged this of characterising changes in grey matter volume. idea, suggesting not only that microbleeds are potentially harmful Furthermore, MRI can also provide potentially important in themselves but also that they may be markers of the severity of metabolic information. Recent evidence from Dr Ciccarelli and her underlying small-vessel abnormalities. colleagues have suggested that alteration of specific metabolites For example, using a battery of neuropsychological tests on in some brain regions, and abnormal mitochondrial function in cells stroke clinic patients, Dr Werring found an association between of the spinal cord, may be the major determinants of cognitive and microbleeds and various kinds of cognitive impairment, even after physical impairment, respectively, beyond the structural damage to controlling for other forms of cerebrovascular disease. grey and white matter. Hence, Dr Ciccarelli and colleagues’ work is Longitudinal studies of ischaemic stroke patients suggest that also shedding light on the mechanisms underlying this still poorly the presence of microbleeds is a key indicator of the risk of further understood disease. microbleeds. Clinically, microbleeds could be an important factor to consider in assessing future cerebral bleeding risk in such patients. Brex PA et al. A longitudinal study of abnormalities on MRI and disability Blood-thinning agents are often used to reduce the risk of further from multiple sclerosis. N Engl J Med. 2002;346(3):158–64. ischaemic events, but could also increase the risk of intracerebral haemorrhage, a risk that may be predicted by the presence of Bodini B et al. T2 lesion location really matters: a 10 year follow-up study in primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. microbleeds. 2011; 82(1):72–7. As well as developing new methods to automate detection of microbleeds, Dr Werring is now leading a large multicentre study to Bodini B et al. Corpus callosum damage predicts disability progression and explore their impact. The CROMIS programme, funded by the British cognitive dysfunction in primary-progressive MS after five years.Hum Brain Mapp. 2012 Feb 13. Heart Foundation and the Stroke Association is following a cohort of stroke patients to see if blood-thinning treatments are associated Ciccarelli O et al. Assessing neuronal metabolism in vivo by modeling with more severe bleeding. The programme will also look in more imaging measures. J Neurosci. 2010;30(45):15030–3. detail at the links between microbleeds and cognitive impairment, Ciccarelli O et al. Spinal cord repair in MS: does mitochondrial metabolism while genetic studies will aim to identify new genetic risk factors for play a role? Neurology. 2010;74(9):721–7. microbleeds and haemorrhagic stroke.

Werring DJ et al. Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI. Brain. 2004;127:2265–75.

Gregoire SM et al. MRI detection of new microbleeds in patients with ischemic stroke: five-year cohort follow-up study.Stroke . 2010;41(1):184–6

Seghier ML et al. Microbleed detection using automated segmentation (MIDAS): a new method applicable to standard clinical MR images. PLoS One. 2011;6(3):e17547.

32 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

M1080332-Alzheimer_s_brain-SPL M2400243-Enhanced_LMofbraincells_in_Parkinsons_disease-SPL

metabolism and the immune Dr Jason Warren and Potentially of more immediate significance is a system as potentially colleagues, for example, major study examining changes in people with important factors in have explored links between the Huntington’s mutation before symptoms susceptibility to disease51. brain tissue loss and traits become apparent. as diverse as personality The main value of whole- changes55 and the ability to genome studies is to identify distinguish flavours56 and biochemical pathways aspects of cell function are The work is particularly recognise people’s voices57. potentially involved in disease affected. Professor Tabrizi important as it provides While focal lesions, from processes. These can then has a special interest in ‘biomarkers’ that could be injury or stroke, typically be followed up in functional its effects on immune cell used to track the impact of affect discrete areas of the studies, for example in animal function – although death a new wave of therapeutics brain, FTLD and similar knockouts. An increasing of neurons is of most in clinical trials. Indeed, conditions tend to affect focus is on induced clinical importance, mutant Huntington’s disease could wider areas and therefore pluripotent stem cells, which huntingtin also affects the be a trailblazer for a radical 52,53 reveal more about the impact can be differentiated in immune system . Such new approach to treatment of of loss of connectivity across specific types of adult cell. studies could identify new neurodegenerative disease, therapeutic leads or help to with at-risk individuals being multiple brain regions. explain some of the variability treated in advance of clinical Tracking Huntington’s in age of onset or speed of disease. This bold new Huntington’s disease is a decline. philosophy lies at the heart of UCL’s new £20 million scientific puzzle, a medical Potentially of more immediate Leonard Wolfson Centre for 51 Jones L et al. Genetic evidence challenge, and a personal significance is a major implicates the immune system and Experimental Neurology (see cholesterol metabolism in the aetiology catastrophe. Caused by study examining changes in page xx). of Alzheimer’s disease. PLoS One. mutations affecting a protein people with the Huntington’s 2010;5(11):e13950. known as huntingtin, its main mutation before symptoms 52 Wild E et al. Abnormal peripheral impact is on the brain, where chemokine profile in Huntington’s become apparent. Professor Dementia – not just disease. PLoS Curr. 2011;3:RRN1231. the death of neurons leads Tabrizi is leading an Alzheimer’s 53 Björkqvist M et al. A novel pathogenic to the gradual loss of international multicentre pathway of immune activation detectable Although dementia is cognitive and motor skills. study, TRACK-HD (see page before clinical onset in Huntington’s generally associated with disease. J Exp Med. 2008;205(8): Symptoms typically appear xx), which has identified 1869 –77. Alzheimer’s disease, there in mid-adult life. substantial changes in brain are many other forms. A 54 Klöppel S et al. Functional structure well before overt compensation of motor function in In a varied programme of second important cause pre-symptomatic Huntington’s disease. symptoms appear. During research, Professor Sarah is frontotemporal lobar Brain. 2009;132(6):1624–32. early stages, the brain’s Tabrizi is making important degeneration (FTLD), where 55 Mahoney CJ et al. Neuroanatomical plasticity may enable other profiles of personality change in contributions to both the neurodegeneration primarily frontotemporal lobar degeneration. Br J systems to compensate for scientific and medical affects the forebrain. FTLD Psychiatry. 2011;198(5):365–72. neuronal death, leading to challenges presented covers a range of conditions, 56 Piwnica-Worms KE, Omar R, only minor loss of function54. Hailstone JC, Warren JD. Flavour by Huntington’s disease. providing opportunities to processing in semantic dementia. Eventually, though, these Part of her work is on the identify associations between Cortex. 2010;46(6):761–8. compensatory mechanisms mechanisms by which mutant areas of damage and the 57 Hailstone JC et al. Voice processing huntingtin exerts its effects are overwhelmed. in dementia: a neuropsychological appearance of particular and neuroanatomical analysis. Brain. – a complex area, as many symptoms. 2011;134(9):2535–47.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 33 Composed only of protein, infectious prion particles are responsible for lethal neurodegenerative conditions.

Changes in auditory thought to cause disease by processing are a particular catalysing the conversion focus of Dr Warren’s work. of an endogenous (cellular) As well as loss of musical prion protein – of currently skills (see page xx), Dr unknown function – into the Warren has also examined infectious form. The abnormal how recognition of non- form aggregates into large speech sounds deteriorates complexes. in a variety of dementia One puzzling feature of Lorem ipsum dolors consequat. syndromes58 – a potentially prions is how a protein underestimated deficit, showing little genetic as an impaired inability Music in the brain variation can nonetheless to recognise everyday The impact of neurodegeneration may shed light on exist as different ‘strains’, environmental sounds can how the brain processes music. with differing transmissibility affect quality of life59. All human populations possess some form of musical culture, and toxicity. The answers, a sign of its great significance to human existence. Music More unusually, Dr Warren suggests Professor Collinge, making and musical appreciation are important aspects of and Dr Jonathan Rohrer have lie in the conformation of many people’s lives, and their loss in neurodegeneration proposed that the composer prion protein. can have a major impact. However, as Dr Jason Warren and Ravel may have had a form colleagues have shown, such cases can also provide insight Important clues have of FTLD caused by mutation into the brain processes involved in this fascinating aspect of come from the distinctive of a progranulin gene60. human behaviour. dynamics of prion infections. Like language, music is a complex concept encapsulating Ravel developed progressive After experimental several distinct aspects of brain function. As well as basic apraxia and aphasia in later transfer of infectious sound processing, music also incorporates emotion recognition, life, losing musical skills (but memory, symbolic representation (musical notes) and abstract prion protein, abnormal not his musical knowledge), concepts (such as songs). Understanding how the brain protein accumulates over and became withdrawn and integrates such multidimensional elements could shed light a prolonged period but not just on music but also on how other complex concepts listless during his final years has little clinical impact. are handled. – symptoms consistent with Then, once clinical signs do Neurodegenerative conditions degrade regions of the brain, a diagnosis of FTLD. More impairing cognitive and other abilities. Although the areas of the appear, neurodegeneration generally, Dr Warren and Dr brain affected are typically the same for any particular condition, proceeds extremely rapidly. the extent to which they are affected differs from person to Rohrer are aiming to provide person. Hence the loss of particular skills can often be linked to a more detailed view of the The reason, suggests damage to specific brain regions. structural changes seen in Professor Collinge, is that Insight into expert music abilities has come from studies of two FTLD, and to characterise prion propagation and musicians, one with semantic dementia and one with Alzheimer’s disease, who were compared to a control group of unaffected changes associated with toxicity are entirely distinct. 61 expert musicians. Interestingly, the patients showed marked specific mutations . Toxicity is caused not by differences in a set of tests examining their abilities across the infectious form of prion several areas of musical cognition. The patient with semantic protein but by another The puzzle of prions dementia struggled to extract the emotional value of music or structural variant – potentially, to identify sounds made by different musical instruments, while the Alzheimer’s patient struggled to identify compositions and Prions are a fascinating an intermediate on the recognise musical notations. but deadly biological In other studies, Dr Warren and colleagues have looked curiosity. Composed only 58 Goll JC et al. Auditory specifically at deficits in emotion recognition in patients with of protein, infectious prion object cognition in dementia. frontotemporal lobar degeneration, which often disrupts particles are responsible for Neuropsychologia. 2011;49(9):2755–65. social and emotional functioning. As well as being less able to lethal neurodegenerative 59 Goll JC et al. Non-verbal sound recognise emotions in faces and voices, patients also struggled processing in the primary progressive to spot them in music. Deficits were specifically associated conditions such as aphasias. Brain. 2010;133(1):272–85. with loss of grey matter in an extensive cortical network which Creutzfeld–Jakob disease 60 Warren JD, Rohrer JD. Ravel’s last overlapped with areas previously found to be important in (CJD) and bovine spongiform illness: a unifying hypothesis. Brain. emotion processing and other skills such as conceptualisation encephalopathy, the origin of 2009;132(Pt 6):e114. and theory of mind. variant CJD. A world-leading 61 Rohrer JD et al. Clinical and Collectively the work begins to paint a complex picture of neuroanatomical signatures of tissue music processing that integrates many aspects of brain function: expert on prions, Professor pathology in frontotemporal lobar there is no discrete ‘music area’. Somehow, though, the brain degeneration. Brain. 2011;134(9):2565 – John Collinge of the MRC 81. unites these disparate aspects into the experience of music. Prion Unit at UCL has done much to unravel the complex Omar R et al. The cognitive organization of music knowledge: a clinical analysis. Brain. 2010;133(Pt 4):1200–13. biology of prions, alongside

Omar R et al. The structural neuroanatomy of music emotion recognition: work on diagnostic tests and evidence from frontotemporal lobar degeneration. Neuroimage. potential therapeutics. 2011;56 (3):1814 –21. Infectious prion proteins are

34 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences conversion pathway from Neuromuscular transition to experimental of mouse muscle function cellular to infectious prion conditions medicine studies in people. and biomarkers for tracking protein62. Only when this This work falls under the muscle deterioration – with While neurodegenerative form begins to accumulate umbrella of the MRC Centre MRI showing promise as conditions have a devastating do cells begin to suffer. for Neuromuscular Diseases, a sensitive and reliable impact on mental function, Experimental infections in which also incorporates indicator of loss of muscle neuromuscular diseases mice have provided strong groups at the University function. have a similarly catastrophic support for this model63. of Newcastle, noted for its effect on physical abilities. strengths in mitochondrial In mice, depleting cellular As well as relatively Multiple sclerosis disease. prion protein prevents common conditions such Multiple sclerosis is caused disease64. Less drastically, as muscular dystrophies The Centre is coordinating by loss of the insulating stabilisation of the and motor neuron disease, a number of clinical myelin sheath surrounding endogenous conformation, many rare conditions arise trials and experimental nerves in the CNS, but the preventing its conversion from abnormalities in the medicine studies, including exact mechanisms of disease to a toxic intermediate, neuromuscular system. a promising approach to remain poorly understood. might also protect against ‘repurposing’ an existing Here again, rare conditions Dr Olga Ciccarelli, with disease. Using a battery drug for a class of have shed light on Professor Alan Thompson of biophysical techniques, channelopathy patients (see disease mechanisms. and colleagues, is hoping Professor Collinge and page xx). Other exciting Many conditions stem that advances in imaging colleagues have identified a work, being led by Professor from abnormalities in may reveal more about specific site where binding of Francesco Muntoni, is ion channel function – disease processes and also a complex organic molecule exploring novel antisense hence the collective term provide patients with a better stabilises cellular prion RNA therapy for Duchenne ‘channelopathies’. Defective idea of how their disease is protein – a starting point muscular dystrophy (see mitochondria are a second likely to progress (see page for the rational design of companion volume on major cause of serious xx). prion-stabilising agents65. Translation and Experimental disease. Professor Collinge has also Medicine). MRI is now commonly used identified how antibodies Professor Mike Hanna leads in diagnosis, revealing Other important strands to cellular prion protein can a large interdisciplinary characteristic lesions in of include intensive block interaction with the initiative integrating clinical the brain and spinal cord. neuromuscular phenotyping infectious form, preventing its care at the National Hospital Advances in MRI are of mutant mice, as well as conversion to toxic form66. and Great Ormond Street providing a more detailed an extensive muscle cell Hospital and translational view of these changes, and A further strand of work is biobanking programme, research across multiple UCL enabling links to be drawn focusing on blood-based which is collecting material departments. The aim is to between specific features assays to detect variant from routine biopsies of both gain a better understanding of damage and symptoms, CJD67– an important tool, as adults and children. The of disease processes and such as cognitive decline or the numbers of people with Centre is also playing a lead pursue new therapeutic loss of motor function. asymptomatic infections is role in efforts to develop leads, but also to make the still unknown. better assessment tools

62 Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science. 2007;318(5852):930–6.

63 Sandberg MK et al. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature. 2011;470(7335):540–2.

64 Mallucci G et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science. 2003;302(5646):871–4.

65 Nicoll AJ et al. Pharmacological chaperone for the structured domain of human prion protein. Proc Natl Acad Sci USA. 2010;107(41):17610–5.

66 Antonyuk SV et al. Crystal structure of human prion protein bound to a therapeutic antibody. Proc Natl Acad Sci USA. 2009;106(8):2554–8.

67 Edgeworth JA et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011;377(9764):487–93.

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NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 35 Lorem ipsum dolors sit amet. Lorem ipsum dolors sit amet.

A brief history of kuru Genes and degeneration The epidemic of the prion disease kuru in Papua Genome-wide scans have identified a host of genes New Guinea is a powerful example of genetic selection in influencing people’s risk of Parkinson’s disease. humans. The past decade has seen a surge in studies into the genetics of In the 1950s, Australian doctors became aware of a deadly common diseases. The ability to track huge numbers of genetic neurodegenerative condition affecting large numbers of people, markers across the entire genome, in large groups of patients, particularly women and children, in the Northern Highlands of Papua has enabled international consortia to identify genetic variants New Guinea. The disease, kuru, turned out to be a transmissible associated with increased risk of disease. Professor Nick Wood has spongiform encephalopathy caused by an infectious protein (a led one such consortium, which has identified numerous variants prion). It was being spread by a local tradition in which the recently linked to Parkinson’s disease. deceased were consumed by their relatives. Having studied the Although several genes have been implicated in Parkinson’s condition for 20 years, Professor John Collinge and colleagues are disease, these generally represent rare cases in which a mutation is still making important discoveries about this extraordinary epidemic. severe enough to trigger disease on its own. In most cases, genes Although ritual feasting was halted, decades later people were still are likely to play a more subtle role, influencing the risk of disease. dying from kuru. Studies of these recent and historical cases have Because of their small effects, identifying such genes has been painted a surprising picture of human evolution. difficult. In recent years, a major breakthrough has occurred with Infectious prions trigger a change in endogenous (cellular) the use of high-throughput screens comparing the presence of prion proteins, causing them to form large toxic assemblies. They hundreds of thousands of genetic markers in large samples of are responsible for the late-onset neurodegenerative condition patients and controls without the disease. Such large-scale studies Creutzfeld–Jakob disease (CJD), as well as variant CJD, following usually depend on extensive collaboration, such as Professor transfer of cattle prion to humans. Wood’s International Parkinson’s Disease Genome Consortium. Susceptibility to CJD is strongly influenced by genetics, Since the impact of genetic variants is small, data from multiple particularly at codon 129 of the cellular prion protein gene. In all studies are generally pooled in a meta-analysis to improve the variant CJD patients identified to date, both copies of this gene have statistical power to detect effects. Other statistical techniques can a methionine (Met) residue at codon 129. Heterozygosity at this site be used to discriminate ‘real’ association signals from ‘noise’. confers resistance to CJD, probably because non-identical proteins Using these approaches on more than 12,000 cases and 21,000 form assemblies less efficiently. controls, and comparing findings with an independent study of Among 3000 people from the Eastern Highlands, including 3000 cases, the Consortium identified 16 loci affecting disease 709 who had consumed human remains, 152 had died from kuru. risk. Some correspond to previously suggested risk loci, whereas Those exposed to human prion but who survived were typically others are entirely new. heterozygotes, but an entirely new group of survivors was also The genetic markers used in genome-wide studies tag particular seen. Some genetically vulnerable Met–Met homozygotes who regions of the genome, so may not themselves be the actual had escaped kuru had a novel change at codon 127 – a variant not genetic variants affecting disease risk. Using post-mortem brain present in kuru-free areas of Papua New Guinea or anywhere else in samples from patients with neurological disease, Consortium the world. researchers also analysed gene activity in regions around the Thus the codon 127 change seems to have undergone selection, loci implicated in the genome-wide study, which revealed several thanks to the protection it provides against kuru. Since consumption genes potentially contributing to increased disease susceptibility. of family members only began early in the 20th century, its spread The challenge now is to examine the biological roles of the genes has been remarkably quick. identified and how they influence disease risk, which may suggest Positive selection at codon 127 is superimposed upon balancing new therapeutic approaches. In addition, the search continues for selection for heterozygosity at position 129. Further, the global other genetic risk factors, as those identified to date explain only a distribution of the different prion protein variants led Professor proportion of the total genetic contribution to disease. Collinge and colleagues to propose that this balancing selection had occurred during past human evolution – suggesting that kuru-like International Parkinson’s Disease Genomics Consortium (IPDGC) et al. epidemics may have happened at other times in our evolutionary A two-stage meta-analysis identifies several new loci for Parkinson’s disease. PLoS Genet. 2011;7(6):e1002142. history. International Parkinson’s Disease Genomics Consortium (IPDGC) et al. Mead S et al. Balancing selection at the prion protein gene consistent with Imputation of sequence variants for identification of genetic risks for prehistoric kurulike epidemics. Science. 2003;300(5619):640–3. Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377(9766):641–9. Mead S et al. A novel protective prion protein variant that colocalizes with kuru exposure. N Engl J Med. 2009;361(21):2056–65.

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Following successful pilot The information will also be of studies, Dr Ciccarelli is now help to patients considering leading long-term projects whether to undergo the to assess whether initial procedure. damage provides pointers The risk with surgical to longer-term damage and intervention is that some symptoms in patients with other important neural the progressive form of systems will be damaged. the disease. She and her These risks can be minimised colleagues are also using by sophisticated brain imaging to try to understand imaging before surgery. why some people with As well as structural MRI, multiple sclerosis and acute functional imaging and lesions in the spinal cord get tractography can reveal key better after an attack while Lorem ipsum dolors sit amet. brain areas to be avoided others become increasingly in individual patients. With disabled68. On TRACK for early diagnosis funding from the Wellcome The TRACK-HD study has found significant changes in Trust and the UK Department people with Huntington’s disease mutations many years Surgery for seizures of Health, Professor Duncan’s before clinical symptoms appear. team has begun a study to Epilepsy can generally be superimpose images from Huntington’s disease is rare, affecting 5–10 of every 100,000 controlled by drugs. But people, but is impossible to treat, ultimately lethal, and associated these systems, and of the when the drugs do not work, with highly distressing mental and physical deterioration. Unusually blood supply to the brain, surgery may be the best for a neurodegenerative condition, it is wholly genetic, and anyone into a common 3D image to who inherits a faulty Huntington’s gene will succumb to the disease. alternative if the source of the identify the best routes to Against this discouraging backdrop, Professor Sarah Tabrizi has seizures can be identified. A target areas of brain tissue. been leading a major international study mapping early changes in unique long-term follow-up pre-symptomatic individuals and patients with early signs of disease of more than 600 patients, This world-leading research – work that could ultimately support interventions that slow or even prevent the onset of disease. carried out by Professor John has depended on an intimate It is becoming clear that the clinical signs of Huntington’s disease, Duncan and colleagues, has association between clinical which typically appear when patients are in their forties, follow a provided the clearest view practice and research. long period in which tissue damage is occurring the brain. Work in yet of its therapeutic impact. A further important role mice even suggests that, when mutant huntingtin is removed during has been played by the this phase, nerve cells can actually recover. This raises hope that The National Hospital for Epilepsy Society, a charity intervening at presymptomatic stages could delay or even prevent Neurology and Neurosurgery the development of clinical symptoms. that provides substantial has played a pioneering Although an appealing idea, testing it presents major challenges. support for research and, in role in developing surgical Clinical trials in Huntington’s disease are already difficult, as decline particular, has established is gradual over many years. In presymptomatic or early disease, interventions for epilepsy. outstanding imaging facilities what are needed are ‘biomarkers’ that can be used to assess the Unlike other assessments, at its national centre in impact of treatments. Professor Duncan’s follow up The TRACK-HD study was set up to identify such biomarkers. Chalfont in Buckinghamshire, spanned not just the initial By applying a battery of tests to carriers of the Huntington’s with UCL researchers period after surgery but also disease mutation, including those with early disease and those in housed in accompanying a presymptomatic phase, the study was able to document highly annual appraisals for up to 20 laboratory space. significant changes over just two years – even in individuals who years69. would not be expected to show clinical symptoms for another The overall findings were decade. The most dramatic changes were seen in brain scans, with 68 Ciccarelli O, et al. Spinal cord repair extensive loss of the striatum, white matter and, to a lesser extent, very positive: around half of in MS: does mitochondrial metabolism grey matter in the cortex. patients were seizure-free play a role? Neurology. 2010;74(9):721– The landmark TRACK-HD study has provided important evidence 7. after ten years (apart from that sensitive and specific biomarkers exist for tissue damage in 69 de Tisi J et al. The long-term outcome advance of symptom onset in Huntington’s disease. As well as minor events with no loss of of adult epilepsy surgery, patterns of awareness) and 28 per cent seizure remission, and relapse: a cohort paving the way for clinical trials of new therapies in Huntington’s study. Lancet. 2011;378(9800):1388–95. disease, the work is also a pathfinder for ‘early intervention’ of seizure-free patients had strategies in more common neurodegenerative conditions such stopped taking anti-epileptic as Alzheimer’s disease – a principle now being applied in the new drugs. More than 80 per Leonard Wolfson Centre for Experimental Neurology (see page xx). cent had at least one year Tabrizi SJ et al. Biological and clinical manifestations of Huntington’s disease with no seizures. The work in the longitudinal TRACK-HD study: cross-sectional analysis of baseline also provided other useful data. Lancet Neurol. 2009;8(9):791–801. information, such as the Tabrizi SJ et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month likelihood of further seizures longitudinal analysis. Lancet Neurol. 2011;10(1):31–42. and the varying outcomes of Tabrizi SJ et al. Potential endpoints for clinical trials in premanifest and different surgical procedures, early Huntington’s disease in the TRACK-HD study: analysis of 24 month which should aid both observational data. Lancet Neurol. 2012;11(1):42–53. surgical decision-making and later clinical management.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 37 The best approach in neurodegenerative diseases may be to identify those at risk and to begin treatment before the full ravages of the disease are irreversible, or even apparent. Neurodegeneration: A path towards earlier intervention

Neurodegenerative For patients, slowing Experimental Neurology on symptoms is difficult, conditions – such as the decline associated Centre at UCL. Spanning all particularly when it comes Alzheimer’s disease, with neurodegenerative the major neurodegenerative to distinguishing between Parkinson’s disease and conditions and preserving conditions, it draws on the Alzheimer’s disease (or Dementia with Lewy bodies, quality of life are the highest world-leading research other dementias) and normal Huntington’s disease and priorities. Scientifically, of eight internationally ageing – especially at critical Creutzfeld–Jakob disease – this may also make the recognised principal early stages. are devastating to individuals most sense. By the time investigators (see Box) There has long been hope and their families, and symptoms are obvious, and the clinical expertise that brain imaging might impose a huge burden on considerable damage and patient resources of provide a way to diagnose health and social services. has already accrued in the National Hospital for neurodegenerative In the UK, the annual costs the brain. Treatments Neurology and Neurosurgery conditions, to track their of caring for people with that target symptomatic (and UCLH more generally). progression over time, dementia, some £23 billion, disease have yet to show Its ambitious long-term aim and to link symptoms exceed those of cancer and widespread, long-term is to boost the translation to specific neurological heart disease combined. benefits to patients. of new therapies, with a changes. Professor Nick With an ageing population, Furthermore, the later particular focus on early- Fox has led extensive the numbers of people stages of neurodegenerative stage clinical studies. research suggesting with neurodegenerative conditions may represent a that this may indeed be disorders are set to self-perpetuating ‘runaway Early signs possible. In Alzheimer’s increase dramatically unless phase’, which interventions disease, structural imaging treatments are found that can are powerless to prevent. The challenges are by MRI can reveal early delay or prevent onset. It may therefore make undoubtedly considerable. neurodegeneration, while Despite this enormous more sense to target this One of the biggest is PET can now also be used impact, treatments for runaway train before it whether it is possible to to identify specifically the neurodegenerative gains momentum, delaying identify individuals at early beta-amyloid deposits conditions are lacking. The the onset of serious stages of disease, or even characteristic of the disease. treatments that do exist damage and symptoms. As presymptomatically. Exciting recent research suggests In fact, imaging is just only provide only modest neurodegenerative diseases one strand of work on symptomatic benefit (e.g. are generally late-life this may be an achievable goal. potential ‘biomarkers’ of for Alzheimer’s disease) conditions, this approach neurodegenerative disease. while the main therapy could yield substantial Alzheimer’s disease Objective, accurate and for Parkinson’s disease, benefits: delaying the onset has historically been quantifiable measures of L-DOPA, eventually loses its of Alzheimer’s disease by diagnosed at post-mortem disease progression are beneficial effects. For many five years would halve its examination, which reveal needed to assess patients’ neurodegenerative diseases, prevalence. the characteristic protein status and to monitor their no specific treatments have This is the principle accumulations and damaged progress. Importantly, been shown to have any underpinning the £20 brain tissue typical of the they are valuable tools benefit. million Leonard Wolfson disease. Diagnosis based in intervention studies,

38 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

Centre principal investigators

Professor John Collinge Professor Nick Fox Professor Professor Martin Rossor Professor Anthony Schipara Professor Sarah Tabrizi Professor Alan Thompson Professor Nick Wood

identifying early signs of families with known inherited The Centre will aim to test A further important role will beneficial change. And, forms of neurodegenerative promising new leads, rapidly be in training. The Centre given the emphasis on early conditions, who are much identify drugs suitable for will offer novel fellowships intervention, they have the more likely to develop testing in bigger trials, and in neurodegeneration, for potential to reveal harmful disease than the general explore novel preventive neuroscientists, for clinical neurological events before population. treatments in presymptomatic academics and for engineers symptoms become apparent. Important information will at-risk individuals. In the who will all focus on different Indeed, it may even be also come from a sample longer-term, the Centre aspects of the problem. possible to identify ‘proximity of the 1946 Birth Cohort. will act as a focal point for The four-year fellowships biomarkers’ – signs that Considerable health and collaborations with UCL’s will include an initial year in clinical deterioration is lifestyle information has been internationally leading basic which fellows are exposed imminent and treatment a accumulated over many scientists, promoting two-way to a range of diseases and matter of urgency. years – since birth – and flows of knowledge to drive scientific specialities, before As well as brain imaging, this will allow changes on forward the development of they specialise in their final several other approaches imaging or cognitive testing new remedies. three years. will be taken to identify to be related to lifelong data Although drug development With its unmatched range of informative biomarkers. A sets. in neurodegenerative scientific expertise and close particularly promising area The Centre will also conditions has been clinical connections, UCL is is analysis of key metabolites integrate genetic and disappointing, there are uniquely placed to undertake and breakdown products genomic studies. Genetic reasons to be optimistic. this groundbreaking initiative. in cerebrospinal fluid. characterisation has the Immunotherapy-based It has the potential to make a Neuropsychological tests, potential to add further targeting of beta-amyloid and profound impact in an area to assess abilities such as levels of discriminatory other features of Alzheimer’s where the potential benefits concentration and memory, information to identify at-risk disease hold promise, while for people, and for society will also be used, though patients or for understanding the work of Professor Mark more generally, are almost their sensitivity needs to be differences in responses to Pepys (see companion immeasurable. improved before they can be therapies. volume on Translation and used as reliable guides to Experimental Medicine) Bateman RJ et al. Autosomal-dominant different stages of illness. hints at future possibilities. Alzheimer’s disease: a review and proposal for the prevention of Crucially, biomarkers are Treatments Encouraging progress Alzheimer’s disease. Alzheimer’s Res is being made in rare Ther. 2011;3 (1):1 needed that span the critical Early characterisation conditions, such as prion Schott JM, Bartlett JW, Fox NC, Barnes phase before symptoms are will only truly pay off if disease and Huntington’s J. Increased brain atrophy rates in apparent and early disease. interventions can be found to cognitively normal older adults with disease. Potentially, the low cerebrospinal fluid Abeta1-42. To identify such biomarkers, limit the loss of brain tissue. Ann Neurol 2010; 68:825–34. Centre can play a nationally cohorts are required not just The Centre will therefore also and internationally significant Freir DB et al. Interaction between prion of patients but also those carry out early human trials protein and toxic amyloid β assemblies role in accelerating the can be therapeutically targeted at likely to develop conditions. of new interventions – a key validation of new treatments, multiple sites. Nat Commun. 2011;2:336. UCL researchers have bottleneck in the translational increasing the likelihood of Ridha BH et al. Tracking atrophy extensive collections of pathway. progression in familial Alzheimer’s success in phase III trials. disease: a serial MRI study. Lancet Neurol. 2006;5:828–34.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 39 SECTION 5

Brains and behaviour As well as the physical environment, humans have to navigate the complex social space of human interactions. The brain both shapes and is shaped by these social interactions.

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Complex human behaviours While childhood development has been depend on the brain’s extensively studied for decades, the critical sophisticated neural period around adolescence and the transition to engineering. The brain must adulthood has been relatively neglected. also be flexible enough to develop, learn and adapt. Furthermore, humans are Consortium, led by Dr Andre the neurobiological basis strikingly social animals: Strydom and supported of behavioural changes, interactions with other people by a £2.5 million Strategic particularly in social are therefore a significant Award from the Wellcome cognition (see page xx). Trust. The interdisciplinary influence on the brain and its In autistic spectrum team, which also includes development. disorders, social skills UCL’s Professor John Hardy, development is highly Professor Dean Nizetic abnormal. The exact nature The developing brain (Queen Mary, University of autism remains unclear of London) and Professor Abnormalities in brain and, as Professor David Annette Karmiloff-Smith development can lead to Skuse has pointed out, (Birkbeck College), will cognitive impairment. A shifts in diagnostic criteria explore the origins of the common form of learning could influence the support cognitive deficits seen disability, Down syndrome, provided to vulnerable in individuals with Down has been associated with young people (see page xx). syndrome, as well as their trisomy 21 for more than 50 Furthermore, he suggests, increased risk of dementia. years, yet the links between autism is best seen as the chromosomal abnormality The brain undergoes extreme of a continuum. and symptoms have been profound changes after birth, Less severe deficits in social difficult to establish. reflected in the emergence and language skills may Much insight has been of increasingly sophisticated predispose to disruptive provided by a mouse model behaviours. While childhood behaviour in young children, of the condition, developed development has been with inevitable impact on by Professor Elizabeth extensively studied for education and well-being. decades, the critical period Fisher and Professor Victor Dr Eamonn McCrory and around adolescence and the Tybulewicz of the MRC Professor Essi Viding have transition to adulthood has National Institute of Medical explored how behavioural been relatively neglected. Research. Professor Fisher traits in young people are Professor Sarah-Jayne and Professor Tybulewicz linked to emotional brain Blakemore and colleagues are contributing to a new structures such as the London Down Syndrome have done much to identify

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amygdala. One strand of Furthermore, the degree of explored the neurobiological Professor Frith has found research has examined activation correlated with the basis of empathy and that the amygdala is central amygdala activity in children extent of exposure to family fairness. Seeing someone to pro-social attitudes73. with conduct disorder and violence70. else in pain, for example, Among a group of pro-social ‘callous-unemotional’ traits – which can trigger feelings participants, the greater In healthy adults, the a seeming disregard for the of empathy, is characterised the perceived unfairness of amydala and anterior insula feelings of others (see page by activity in the brain’s pain distribution, the greater the are known to be part of xx). A second focus is on pathways, though not those activity in the amygdala. a network that detects children who have suffered associated with the sensory threat and anticipates Furthermore, similar or been exposed to violence experience of pain71. Hence pain. Activity in these responses were seen when in the family home. observers genuinely ‘feel’ the regions is particularly high participants carried out pain of others. Family violence is generally in individuals with anxiety a challenging cognitive hidden from view, but up to disorder and in troops Notably, though, these test, suggesting that they 16 per cent of children may exposed to combat (but responses can be were automatic rather than experience direct physical without any psychiatric modulated by our feelings calculated. This challenges abuse and up to 25 per conditions). Hence exposure towards others. When brain the idea that automatic cent witness violent acts to family violence appears responses were assessed responses are typically between their care-givers. to leave children in a state after an economic game, the selfish and need to be As well as the initial distress, of heightened ‘threat strength of responses was overridden by the ‘thinking the experience significantly readiness’. This may be lower when pain was inflicted brain’, the prefrontal cortex. raises the risk of later mental advantageous in the short on those who had been health problems such as term, enabling them to avoid felt to be playing unfairly72. anxiety and post-traumatic potentially violent situations, Indeed, an associated stress disorder. but over the longer term it increase in activity in leaves them at significantly reward areas correlated Physically abused children increased risk of anxiety and with expressed wishes for appear to be particularly other psychiatric conditions. revenge – a signature of sensitive to signs of anger, Schadenfreude in the brain. which in turn is associated 70 McCrory EJ et al. Heightened neural with heightened levels of Social interactions Such findings suggest reactivity to threat in child victims of anxiety. In functional imaging that humans have an family violence. Curr Biol. 2011; in press. Social behaviours depend studies of 20 children innate sense of fairness, a 71 Singer T et al. Empathy for pain critically on empathy and exposed to family violence, characteristic repeatedly involves the affective but not sensory ‘theory of mind’, appreciating components of pain. Science. but with normal levels seen in economic games 2004;303(5661):1157–62. that other people have of anxiety, activity in the where people distribute 72 Singer T et al. Empathic neural needs, desires and amydala and anterior insula sums in ways that, contrary responses are modulated by the motivations. perceived fairness of others. Nature. was abnormally high on to economic models, do 2006;439(7075):466–9. exposure to angry faces (but With Dr Tania Singer, now not simply maximise their 73 Haruno M, Frith CD. Activity in the not to faces showing other at the University of Zurich, own gains. In work with amygdala elicited by unfair divisions predicts social value orientation. emotions such as sadness). Professor Chris Frith has Masahiko Haruno in Kyoto, Nat Neurosci. 2010;13(2):160–1.

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Two heads are (usually) better The brain and bad behaviour than one Neuroscientific techniques are being used to identify Joint decision-making is a good idea – but only when different subgroups of children with conduct problems. certain important conditions are met. Conduct problems can seriously disturb children’s education (and It may seem self-evident that sharing of information and collective that of their peers), and raise the risk of longer-term behavioural decision-making is a good idea. It will certainly be important problems with significant personal and public health impact. as humans face difficult and profound questions requiring The neurobiological basis of conduct disorder is beginning to be unravelled, and and collaborative action. A study carried out by Dr Bahador Bahrami, Professor Essi Viding Dr Eamon McCrory believe that a subgroup showing distinct ‘callous/unemotional’ traits Professor Chris Frith and colleagues does indeed suggest that two heads are, in general, better than one – but sometimes may exist – with important implications for treatment. performance is actually made worse by joint decision-making. Children scoring highly on measures of callous/unemotional traits The research was based on a simple paradigm in which pairs lack empathy. They may behave cruelly and typically show little of participants were presented with a difficult perceptual test. The remorse, and their behaviour is not swayed by usual threats and participants could share varying amounts of information, in order punishments. There is already some evidence that they represent to test a range of possible models of joint decision-making. The a distinct subgroup – twin studies, for example, suggest that models differed in how much information was shared between such traits are markedly more heritable than conduct problems in participants, such as their confidence in their choice, and how general. much feedback they received about their decisions. Signatures of behavioural abnormalities can also be seen Overall performance was best when participants communicated in the brain. In particular, children with conduct problems and their degree of confidence about their answers. However, when the callous/unemotional traits typically show reduced activation of sensitivity of one participant was artificially reduced by introduction the amygdala, part of the brain’s emotional system, when shown of ‘noise’ into the visual image, performance actually dropped images of fearful (but not sad) faces. This effect, also seen in adults below that achieved by the superior partner. So, under these with psychopathy, implies a reduced ability to respond to fear in circumstances, two heads were definitely not better than one. people’s faces. The collective model involves both communication and Recently, Professor Viding and Dr McCrory examined the feedback learning. In further experiments, the researchers found response of boys with conduct problems in tests based on more that communication, as might be expected, was essential for complex social scenarios that required processing of other people’s high performance but, surprisingly, explicit feedback was not. thoughts or emotions. Brain responses to other people’s thoughts Even though they were not aware of it, pairs communicating their were the same in boys with conduct problems as in their typical uncertainty performed better. peers. However, they showed lower activation in the amygdala The results suggest that a cooperating pair can outcompete an when responding to other people’s emotions. individual, if they share information and, importantly, one of them is This suggests that boys with conduct problems know what other not particularly poor at the task being undertaken. people think, but are less responsive to how other people feel. This is notable, as past studies of groups have found that they Within the group of boys with conduct problems, the degree of are rarely as good at decision-making as the highest-performing amygdala activation fell with increasing callous/unemotional scores. individual members of the team. Many ideas have been put forward The results therefore suggest that poor conduct is linked to to explain why groups underperform, from ‘social loafing’ to atypical amygdala activity. In some children, the amygdala appears ‘groupthink’. This study suggests that, by contrast, when the validity to be less responsive to other people’s emotions. It is possible of shared information cannot be checked, ordinary decision-making that children with callous/unemotional traits represent a distinct strategies may automatically become suboptimal. subgroup within the broader population of children with conduct problems. The findings also suggest that it may be more difficult to Bahrami B et al. Optimally interacting minds. Science. 2010;329(5995): promote empathy in this group because they are intrinsically less 1081–5. able to generate emotional responses.

Viding E, Blair RJ, Moffitt TE, Plomin R. Evidence for substantial genetic risk for psychopathy in 7-year-olds. J Child Psychol Psychiatry. 2005;46(6): 592–7.

Jones AP, Laurens KR, Herba CM, Barker GJ, Viding E. Amygdala hypoactivity to fearful faces in boys with conduct problems and callous- unemotional traits. Am J Psychiatry. 2009;166(1):95–102.

Sebastian CL et al. Neural responses to affective and cognitive Theory of Mind in children with conduct problems and varying levels of callous- unemotional traits. Arch Gen Psychiatr. (in press)

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Diagnosis uncertain Brain changer Is autism a discrete condition or at the extreme end of Extensive rewiring of the brain occurs during adolescence, a continuum? The hotly debated answer could have with profound implications for social interactions. important implications for both treatment and policy. As well as adult behaviour, psychologists have long been fascinated Autism research is a highly charged field. As well as the much- by childhood, when many interesting aspects of behaviour first publicised controversies about its possible causes, a more subtle appear. Between the two, however, is the sometimes troubling debate has centred on the precise categorisation of autism and period of adolescence, a time of profound change that has come related conditions. As the work of David Skuse and colleagues under far less scrutiny. Professor Sarah-Jayne Blakemore’s indicates, the outcomes are of more than academic interest. group is redressing the balance, aiming to relate changes in the The definitions of autism and autistic spectrum disorders such as behavioural and emotional development of adolescents to the Asperger’s have evolved over time but rest on assessment across dramatic remodelling going on in their brains. a ‘triad’ of traits: abnormal social interactions, impaired language Adolescence is marked by significant changes in both grey use in social situations, and a mixed bag of abnormalities including matter and white matter, and by considerable new synapse sensory sensitivities and stereotyped and repetitive behaviours. formation and synaptic pruning. Externally, young people change Few would argue that this current diagnostic situation is profoundly as they make the transition to adulthood – redefining satisfactory, but in the absence of well-established biological relationships with parents, forming stronger bonds with peers, and markers, categorisation inevitably means attaching labels to generally asserting their own independence. At the heart of these particular constellations of symptoms. In psychiatry, standardised changes are shifts in social relationships. labelling is achieved primarily through so-called DSM guidelines. Alongside structural remodelling, Professor Blakemore’s Currently being revised, the latest DSM guidelines sweep away functional imaging studies have revealed significant changes during existing categories, leaving a far more narrowly defined ‘autistic adolescence. For example, although both adults and adolescents spectrum’. used broadly similar neural circuits when thinking about people’s The debate touches upon both theory – what exactly is ‘autism’ – intentions, the regions of these circuits activated shifted noticeably and practice: what happens if new diagnostic criteria are applied? between adolescence and adulthood. Professor Skuse’s work touches upon both issues. Other studies examined the ability to switch between externally His argument is that autism represents one end of a spectrum, prompted and internally generated thoughts, as well as resistance rather than being a discrete, separable entity. Furthermore, insisting to distraction. While the latter increased gradually with age, the that a diagnosis of autism must include repetitive behaviours, as ability to switch between internal and external viewpoints jumped the latest DSM guidelines do, would exclude many children with markedly at adolescence. Furthermore, the brain areas pressed significant social communication and language difficulties. into action did not correspond exactly to those showing structural In support of this view, his work with the Bristol-based Avon changes, suggesting that the differences reflected more than just Longitudinal Study of Parents and Children (ALSPAC) cohort and in structural maturation of brain tissue. London has revealed that poor conduct in primary school is often Interesting differences were also seen when processing of ‘basic’ linked to undiagnosed social communication and language deficits. emotions (disgust, fear) was compared with that of ‘social emotions’ Moreover, the biological evidence also points to a link between (guilt, embarrassment) in adolescents and adults. Both the areas autism and more general abilities. Research on the ALSPAC cohort activated and functional connections differed in the two groups. has shown a clear association between an autism risk allele and And while theory of mind is generally assumed to have emerged by social and language skill deficits in a general population. around age 4, tests examining the ability to adopt the viewpoint of While the academic debate rages, the social consequences could others showed clear improvements with age during adolescence. be considerable. Unrecognised social and language skill deficits are Collectively, the results hint at complex changes in brain function likely to be holding back the education of numerous young children. during adolescence, significantly affecting social interactions. As Restricting diagnoses still further could mean even fewer children well as feeding into important areas such as education, such work receive the specialist help they need to overcome their problems. may also shed light on psychological and psychiatric disorders, most of which first appear during adolescence. Gilmour J et al. Social communication deficits in conduct disorder: a clinical and community survey. J Child Psychol Psychiatr. 2004;45:9–78. Burnett S, Bird G, Moll J, Frith C, Blakemore SJ. Development during Donno R et al. Social communication deficits in disruptive primary-school adolescence of the neural processing of social emotion. J Cogn Neurosci. children. Br J Psychiatr. 2010;196:282–9 2009;21(9):1736–50.

St Pourcain B et al. Association between a high-risk autism locus on 5p14 Burnett S, Blakemore SJ. Functional connectivity during a social emotion and social communication spectrum phenotypes in the general population. task in adolescents and in adults. Eur J Neurosci. 2009;29(6):1294–301. Am J Psychiatr. 2010;167:1364–72, Dumontheil I, Hassan B, Gilbert SJ, Blakemore SJ. Development of the selection and manipulation of self-generated thoughts in adolescence. J Neurosci. 2010;30(22):7664–71. Dumontheil I, Apperly IA, Blakemore SJ. Online usage of theory of mind continues to develop in late adolescence. Dev Sci. 2010;13(2):331–8.

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identity, but struggled to Dr MacSweeney’s research Emotional expressions are very ancient, and identify the emotion being is part of a large programme hard-wired into the brain conveyed75. Hence the of research falling under the same brain areas appear umbrella of the Deafness, Sound patterns not travel – the Namibians to be involved in extracting Cognition and Language found western sighs emotional information across (DCAL) Centre, the largest Vision is one way in which ambiguous for example. a range of sensory systems. of its kind in Europe. Led by we gain insight into the Non-verbal Professor Bencie Woll, its emotional state of others, Interestingly, the culturally communication main aims are to understand but speech can also convey common expressions were how communication is Communication is not meaning. And other sounds mostly associated with basic shaped by deafness and just based on language we make, from shrieks of negative emotions, such use of sign language, and – multiple other systems laughter to sighs of despair, as disgust or fear. More how deafness and early come into play when also reveal our state of mind. positive expressions (with language experience impact the exception of laughter) we communicate in In the 1950s, Professor Paul on cognition. Strikingly, as tended to be more culturally person. In sign language, Ekman famously confirmed Professor Gary Morgan and specific. Possibly, positive physical gestures are that facial expressions colleagues have discovered, expressions may develop integral to communication. of emotions were shared lack of sign language as a way of binding groups Neuroscientific studies of across cultures. Working with exposure can significantly together and excluding sign language are relevant to Professor Ekman, Dr Sophie affect the development of outsiders. The results imply signing, but also shed more Scott has identified a similar theory of mind skills in young that emotional expressions general light on how the 77 phenomenon with auditory deaf children . are very ancient, and hard- brain handles language. emotional traits74. wired into the brain. Using functional imaging 74 Sauter DA, Eisner F, Ekman P, Scott Dr Scott looked at how SK. Cross-cultural recognition of basic Dr Scott has also explored and other techniques, Dr emotions through nonverbal emotional two very different groups – the brain processing Mairead MacSweeney and vocalizations. Proc Natl Acad Sci USA. westerners and an isolated 2010;107(6):2408–12. underlying emotional colleagues have shown that Namibian tribe – responded 75 Banissy MJ et al. Suppressing encoding in speech. When sign language and spoken to emotional utterances such sensorimotor activity modulates the transcranial magnetic languages are processed discrimination of auditory emotions as laughter, sighs and so similarly in the brain, though but not speaker identity. J Neurosci. stimulation was used to 2010 ;30 (41):13552–7. on. The meaning of many there are some notable temporarily disable brain 76 MacSweeney M, Capek CM, expressions was common 76 areas involved in emotional differences . Ultimately Campbell R, Woll B. The signing brain: to both cultures, and each the neurobiology of sign language. responses to visual stimuli, the research should help could correctly interpret Trends Cogn Sci. 2008;12(11):432–40. participants could still children born profoundly the others’ expressions. For 77 Morgan G, Kegl J. Nicaraguan Sign recognise a speaker’s deaf, who generally find it Language and Theory of Mind: the issue some, though, meanings did difficult to learn to read. of critical periods and abilities. J Child Psychol Psychiatry. 2006;47(8):811–9.

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NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 45 NEUROSCIENCE AND MENTAL HEALTH research at UCL

Component institutes The encompasses researchers Most of the neuroscience and mental health research Neuroscience Domain across the whole of the UCL School of Life at UCL is carried out by groups in the Faculty of Brain and Medical Sciences and their work with colleagues Sciences, which comprises: outside the school. • UCL Division of Psychology and Language Sciences Domain Chair: Professor Trevor Smart • UCL Institute of Ophthalmology • UCL Ear Institute http://www.ucl.ac.uk/neuroscience • UCL Institute of Neurology • UCL Mental Health Sciences Unit • UCL Institute of Cognitive Neuroscience

Dean: Alan Thompson

http://www.ucl.ac.uk/brain-sciences

UCL in London Partners Researchers in the UCL School of Life and Medical UCL School of Life and Medical Sciences works closely Sciences occupy a range of buildings on UCL’s central with a range of local, national and international partners. Bloomsbury Campus, at the nearby Of particular significance are its close links to local NHS and /Archway Campus sites, bodies, collectively forming UCL Partners, one of just and other central London locations. five UK Academic Health Science Centres. These links underpin UCL’s NIHR Biomedical Research Centres at UCLH, the UCL Institute of Child Health (with Great 1 UCL Main Campus Ormond Street Hospital) and the UCL Institute 2 UCL Hospital of Ophthalmology (with Moorfields Eye Hospital). 3 Great Ormond Street Hospital and The School has also developed ties with nearby academic UCL Institute of Child Health centres, including the London School of Hygiene and Tropical Medicine and Birkbeck College. As well as many 4 Moorfields Eye Hospital and joint research initiatives, the institutions also liaise at a UCL Institute of Ophthalmology strategic level. 5 Royal Free Hospital and UCL School of Medicine With the MRC, Wellcome Trust and Cancer Research 6 Whittington Hospital and Archway Campus UK, UCL is also a founding partner of the Francis Crick Institute, led by Professor Sir Paul Nurse, which is due to open in 2015. UCL also establishes wider partnerships in the UK, for example with Imperial College to set up the London Centre for Nanotechnology, and with Imperial, King’s College London, the MRC and GlaxoSmithKline on the ‘Imanova’ clinical imaging initiative. The agreement 6 was forged under the umbrella of the Global Medical Excellence Cluster (GMEC), a public–private partnership 5 bringing together world-leading academic, health and industrial partners in South-East England. As well as numerous international research collaborations, London UCL has developed a strategic alliance with Yale 2 1 4 3 University, the Yale–UCL Collaborative, to promote cross-fertilisation and joint ventures across education, research and application.

46 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences

Support: Resource centres and platforms Research income The scale of UCL’s research enables it to provide a range ‘Live’ grants as at 1 September 2011 of technical infrastructure platforms to support research. These include outstanding facilities and technical expertise in molecular and cellular imaging, as well as pre-clinical and clinical imaging, and several sites specialising in high-throughput sequencing and genome analysis. Other core platform technologies cover small-chemical libraries, proteomics, biological services and transgenics, and informatics. UCL researchers are also involved in numerous biobanking initiatives and cohort studies, providing access to extensive collections of materials and data. UCL also provides capital infrastructure funding to enable labs to develop their equipment base. For clinical research, a Research Support Centre provides access to essential support for work on people and patients, including liaison with the UCLH/UCL NIHR Biomedical Research Centre, UCL Clinical Trials Unit and UCLH/UCL Clinical Research Facility. The Translational Research Office works to promote the NIHR and other UK Government £177.1m translation of research into therapies, techniques and MRC £194.6m products with therapeutic value. Other UK Research Councils £83.3m www.ucl.ac.uk/platforms/ UK charities £500.4m www.ucl.ac.uk/slms/research_support_centre Commercial (UK and international) £53.6m EU £78.4m Other international, inc. NIH £62.6m Other £14.7m

UCL Research Strategy Total £1164.7m

The UCL Research Strategy calls for a transformation Figures refer to research within the UCL School of Life and Medical Sciences. NIHR: National Institute for Health Research; MRC: Medical Research Council; of the understanding of the role of our comprehensive NIH: National Institutes of Health. research-intensive university in the 21st century. In addition to highlighting the need to nurture and celebrate individual curiosity-driven research, the strategy sets out for UCL an innovative cross-disciplinary research agenda – designed to deliver immediate, medium- and long-term benefits to humanity. UCL will marshal the breadth of its expert perspectives, in order to address issues in their full complexity and contribute to the resolution of the world’s major problems. Its key aims are to: • continue to foster leadership grounded in excellence in discipline-based research • expand the distinctive cross-disciplinarity of our research, collaboration and partnerships • increase the impact of our global university’s research, locally, regionally, nationally and internationally.

NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 47 Sponsors of research

We are grateful to all the individuals and organisations who support Epilepsy Research UK, Eular – European League Against Rheumatism, research in the UCL School of Life and Medical Sciences. Eurocoating S.P.A, European and Developing Countries Clinical Trials, European Association for the Study of Liver, European Commission, European Huntington’s Abbott France, Abbott Laboratories, Ablynx NV, Academy of Medical Sciences, Disease Network, European Organisation For Research and Treatment of Cancer, Action Medical Research, Action on Hearing Loss, Adam Dealy Foundation, European Orthodontic Society, European Parliament, European Respiratory Against Breast Cancer, Age UK (Formerly Research Into Ageing), Agennix AG, Society, European Society for Immunodeficiencies, Eve Appeal, Experimental Aims 2 Cure, Alcohol Education and Research Council, Alder Hey Children’s NHS Psychology Society, F Hoffmann La Roche Ltd, Fidelity Foundation, Fight For Sight, Foundation Trust, Alexion Pharmaceuticals, Allergan Inc., Alpha-1 Foundation, Fondation de France, Food Standards Agency, Foundation for Fighting Blindness, Alzheimer’s Society, Alzheimer’s Research UK, Amyotrophic Lateral Sclerosis Foundation for Liver Research, Foundation for the Study of Infant Deaths, Association, Anatomical Society of Great Britain & Ireland, Centre, Foundation Leducq, Frances and Augustus Newman Foundation, Frost Charitable Anthony Nolan Bone Marrow Trust, Apatech Ltd, Apitope Technology (Bristol) Ltd, Trust, Fundacao Bial, Gatsby Charitable Foundation, Gen-Probe Life Sciences Ltd, Aqix Ltd, Argonne National Laboratory, Ark Therapeutics Ltd, Arthritis Research Genentech Inc., General Charitable Trust of ICH, General Medical Council, UK, Arts and Humanities Research Council, Assisted Conception Unit, Association Genethon, Genex Biosystems Ltd, Genzyme Corp., Gilead Sciences Inc., for International Cancer Research, Association Francaise Contre les Myopathies, GlaxoSmithKline, Glaxosmithkline (China) R&D Co. Ltd, Global Alliance for TB Association Monegasque Contre Les Myopathies, Association of Coloproctology Drug Development, Government Communications Planning Directorate, Great of Great Britain and Ireland, Asthma UK, Astra Zeneca (UK) Ltd, Ataxia UK, Britain Sasakawa Foundation, Great Ormond Street Hospital Charity, Great Autonomic Disorders Association – Sara Matheson Trust, AVI BioPharma Inc., Ormond Street Hospital Special Trustees, Grifols UK Ltd, Grovelands Priory AXA Research Fund, Bachmann-Strauss Dystonia and Parkinson Foundation, Hospital, Grunenthal GMBH, Guarantors of Brain, Guide Dogs for the Blind Baily Thomas Charitable Trust, Baily Thomas Charitable Trust, Barts and The Association, Gynaecological Cancer Research Fund, H J Heinz Co. Ltd, Harbour London Charity, Batten Disease Family Association, Baxter Healthcare Corp., Foundation, Health and Safety Executive, Health Foundation, Health Protection Bayer – AG, Bayer SAS, Big Lottery Fund, Bill & Melinda Gates Foundation, Agency, Healthcare Commission, Healthcare Quality Improvement Partnership, Biochemical Society, Biocompatibles Ltd, Biogen, Biogen Idec Inc., Biomarin Heart Research UK, Helpage International – Africa Regional Development, Henry Pharmaceutical Inc., Biorex R&D, Biotechnology and Biological Sciences Smith Charity, Hestia Foundation, High Q Foundation, Histiocytosis Research Research Council, Birkbeck College, Biss Davies Charitable Trust, Boehringer Trust, Hospital For Sick Children, Human Early Learning Partnership, Human Ingleheim, Bone Cancer Research Trust, Brain Research Trust, Breast Cancer Frontier Science Program, Human Genome Sciences Inc., Huntington’s Disease Campaign, Bristol Myers Squibb, British Academy, British Council for Prevention Association, Ichthyosis Support Group, Illumina Cambridge Ltd, Imperial College of Blindness, British Heart Foundation, British HIV Association, British Lung Consultants Ltd, Imperial College of Science, Technology and Medicine, Inhibox Foundation, British Medical Association, British Neurological Research Trust, Ltd, Institut de Recherche Servier, Institut Straumann AG, Instrumentarium Science British Orthodontic Society, British Pharmacological Society, British Psychological Foundation, Intensive Care Society, International Association for the Study of Pain, Society, British Retinitis Pigmentosa Society, British Skin Foundation, British International Balzan Foundation, International Child Development Programme, Society for Haematology, British Tinnitus Association, British Urological International Glaucoma Association, International Primary Care Respiratory Group, Foundation, BUPA Foundation Medical Research Charity, Burdett Trust for International Serious Adverse Events Consortium, International Spinal Research Nursing, Burroughs Wellcome Fund, Cambridge University Hospital NHS Trust, Ipsen Fund, Ipsen Ltd, Iqur Ltd, ISTA Pharmaceuticals, ITI Foundation, Foundation Trust, Camden and Islington Health Authority, Canadian Institutes of Jabbs Foundation, James S McDonnell Foundation, James Tudor Foundation, Health Research, Cancer Fund, Cancer Research Institute USA, Cancer Research Janssen Pharmaceutica NV, Janssen-Cilag Ltd, Japan Society for the Promotion UK, Carbon Trust Ltd, Carl Zeiss Surgical GMBH, Celera Corp., Cell Medica Ltd, of Science, Jean Corsan Foundation, Jerini Ophthalmic Inc., John Templeton Centocor Inc., Central and East London CLRN, Central Research Fund, Cephalon Foundation, John Wyeth & Brother Ltd, Johns Hopkins University, Johnson & Inc., Charles Wolfson Charitable Trust, Chemel AB, Child Growth Foundation, Child Johnson Consumer Services EAME Ltd, Juvenile Diabetes Foundation, Katherine Health Research Appeal Trust, Children Living with Inherited Metabolic Diseases Dormandy Trust, Kay Kendall Leukaemia Fund, Kidney Research UK, Kids (CLIMB), Children With Cancer UK, Children’s Brain Diseases, Children’s Cancer Company, Kids Kidney Research, King’s Fund, King’s College London, Legal and and Leukaemia Group, Children’s Liver Disease Foundation, Children’s Research General Assurance Society Ltd, Leonard Cheshire Disability, Leukaemia and Fund, Children’s Trust, Chordoma Foundation, Chronic Fatigue Syndrome Lymphoma Research, Leverhulme Trust, Lincy Foundation, Linkoping University, Research Foundation, Chronic Granulomatous Disease Trust, Chugai Pharma Linnean Society of London, Lister Institute of Preventive Medicine, Liver Group, Europe Ltd, Cincinnati Children’s Hospital Medical Center, Circulation Foundation, London Borough of Camden, London Deanery, London School of Hygiene and CLEFT – Bridging The Gap, Clement Wheeler Bennett Trust, CMT UK, Cobra Tropical Medicine, Lowe Syndrome Trust, Lowy Medical Research Institute, Bio-Manufacturing PLC, Cochlear Research and Development Ltd, Coda Ludwig Institute for Cancer Research, Lund University, Lupus UK, Lymphoma Therapeutics Inc., Cogent (Holdings) Ltd, Colgate-Palmolive Europe, College of Research Trust, Macmillan Cancer Relief (UK Office), Macular Disease Society, Optometrists, Colt Foundation, Creating Resources for Empowerment and Action Marc Fisher Trust, Marie Curie Cancer Care, Mars Symbioscience, Mary Kinross Inc., Cure Parkinson’s Trust, Cure PSP – Society for Progressive Supranuclear Charitable Trust, Mason Medical Research Foundation, Matt’s Trust Fund for Palsy, Cyberonics Inc., Cystic Fibrosis Research Trust, Cystinosis Foundation Cancer, Maurice Hatter Foundation, Max Planck Institute for Molecular Genetics, Ireland, Cystinosis Research Network Inc., David and Elaine Potter Charitable Max Planck Institute of Biology and Ageing, Medac GmBH, Medical Research Foundation, Davis Schottlander & Davis Ltd, Deafness Research (Formerly Council, Medical Research Council of Canada, Medical Research Foundation, Defeating Deafness), Defense Advanced Research Projects Agency, Department Melford Charitable Trust, Mend Central Ltd, Meningitis Research Foundation, for Children, Schools and Families, Department for Education and Skills, Meningitis Trust, Merck Ltd, Merck Serono, Mermaid, Michael and Morven Heller Department for International Development, Department of Health, Department of Charitable Foundation, Michael J Fox Foundation for Parkinson’s Research, Health and Human Services, Department of Trade and Industry, Dermatitis and Middlesex Hospital Special Trustees, MIND, Mologic Ltd, Monument Trust, Allied Diseases Research Trust, Deutsche Forschungsgemeinschaft, Diabetes Moorehead Trust, Moorfields Eye Hospital (LORS), Moorfields Eye Hospital Research and Wellness Foundation, Diabetes UK, Diagenode SA, Doctors Development Fund, Moorfields Eye Hospital Special Trustees, Moorfields Hospital Laboratory, Dowager Countess Eleanor Peel Trust, Duchenne Parent Project, NHS Foundation Trust, Motor Neurone Disease Association, Moulton Charitable Dystonia Medical Research Foundation, Dystrophic Epidermolysis Bullosa Trust, Mr and Mrs Fitzpatrick, MRCP(UK), MSS Research Foundation, Multiple Research Association, East Midlands Specialised Commissioning Group, Sclerosis International Federation, Multiple Sclerosis Society of Great Britain and Economic and Social Research Council, Edinburgh University, Edmond J Safra Ireland, Mundipharma Research Ltd, Muscular Dystrophy Association, Muscular Philanthropic Foundation, Effort – Eastman Foundation, Efic, Eisai (London) Dystrophy Campaign, Myasthenia Gravis Association, Myeloma UK, National Research Laboratories Ltd, El.En. S.p.A, Elan Pharmaceuticals Ltd, Eli Lilly and Association for Colitis and Crohn’s Disease, National Brain Appeal, National Co. Ltd, Emergency Nutrition Network, Engineering and Physical Sciences Cancer Institute, National Centre for Social Research, National Centre for the Research Council, Epic Database Research Company Ltd, Epilepsy Action,

48 NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences Replacement, Refinement and Reduction of Animals in Research, National Contest London Hospitals, University College London Hospitals Charities, University for Life, National Eye Institute, National Geographic, National Health and Medical Medical Center Hamburg–Eppendorf, University of Alabama at Birmingham, Research Council, National Institute for Health and Clinical Excellence, National University of California, University of Coimbra, University of Iowa, University of Institute for Health Research, National Institute of Academic Anaesthesia, National Kansas Medical Center, University of Kwazulu-Natal, , Institute of Mental Health, National Institutes of Health, National Kidney Research University of Oulu, , University of Rochester, University of Fund, National Multiple Sclerosis Society, National Osteoporosis Society, National Southampton, University of Sussex, University of Washington, University of Screening Committee, Natural Environment Research Council, NCL Stiftung, Western Australia, Varian Ltd, Ventana Medical Systems Inc., Veterinary Netherlands Organisation for Scientific Research, Neuroblastoma Society, Laboratories Agency, Vitaflo International Ltd, Vital Therapies Inc., Vitol Charity New England Research Institutes Inc., Newlife Foundation For Disabled Children, Fund, Wayne State University, Weight Concern, Weizmann UK, Wellbeing of NHS Blood and Transplant, NHS Executive, NHS Patient Safety Research Women, Wellchild, Wellcome Trust, Welton Foundation, Wockhardt UK Ltd, Wolfson Programme, Nicholls Foundation, Nicox SA, NIHR School of Primary Care Foundation, World Cancer Research Fund, World Health Organization, World Research, Nippon Telegraph and Telephone Corporation, No Surrender Charitable Vision International, Wyeth Laboratories and Wyeth Pharmaceuticals Inc. Trust, Nobel Biocare AB, North Essex Mental Health Partnership NHS Trust, Northern California Institute for Research and Education, Novartis Pharma AG, Novartis Pharmaceuticals Corp., Novartis Pharmaceuticals UK Ltd, Novo Nordisk Pharmaceuticals Ltd, Nuffield Foundation, Ocean Park Conservation Foundation, Ocera Therapeutics Inc., Octapharma, Office for National Statistics, Options Consultancy Services Ltd, Organisation for the Understanding of Cluster Headache, Organon Laboratories Ltd, Orphan Europe (UK) Ltd, Ovarian Cancer Action, Overweight and Heart Diseases Research Trust, Oxalosis and Hyperoxaluria Foundation, Oxford Optronix Ltd, Oxigene Inc., Ozics OY, Paediatric Rheumatology Discretionary Fund, Palaeontological Association, Pancreatic Cancer UK, Parkinson’s Disease Society, Path Vaccine Solutions, Pathogen Solutions UK Ltd, Pathological Society of Great Britain and Ireland, Paul Hamlyn Foundation, PCI Biotech, Pelican Cancer Foundation, Peptide Protein Research Ltd, Pervasis Therapeutics Inc., Peter Samuel Fund, Petplan Charitable Trust, Pfizer Ltd, Philips Medical Systems NL BV, Philips Oral Healthcare Inc., Physiological Society, Planer Plc, Polycystic Kidney Disease Charity, Primary Immunodeficiency Association, Procter and Gamble Technical Centre Ltd, Progressive Supranuclear Palsy (PSP Europe) Association, Prostate Action, CREDITS Prostate Cancer Research Centre, PTC Therapeutics Inc., Qatar National Research Fund, Race Equality Foundation, Rank Bequest, Raymond and Beverly Commissioned photography:. Sackler Foundation, Raynaud’s and Scleroderma Association, Repregen Ltd, Other images from. Research in Motion Ltd (Canada), Research into Childhood Cancer, Rheumatology Discretionary Fund, Rho Inc., RMS Innovations UK Ltd, Roche Bioscience, Roche Text: Ian Jones, Jinja Publishing Ltd Products Ltd, Rockefeller Foundation, Roddick Foundation, Ronald McDonald Design: Jag Matharu, Thin Air Productions Ltd House Charities UK, Rosetrees Trust, Roslin Cells Ltd, Royal Academy of Engineering, Royal Centre for Defence Medicine, Royal College of Anaesthetists, © UCL. Text may not be reproduced without permission. The UCL ‘dome’ logo Royal College of General Practitioners, Royal College of Ophthalmologists, Royal and the letters ‘UCL’ are the registered trademarks of UCL and may not be College of Paediatrics, Royal College of Physicians, Royal College of Radiologists, used without permission. Royal College of Surgeons of England, Royal Free Cancer Research Trust, Royal TAP1559/22-01-13/V3 Free Hampstead NHS Trust, Royal Free Hospital Special Trustees, Royal National Institute for the Blind, Royal Society, Samantha Dickson, Sanofi Pasteur, Sanofi-Aventis, Santhera Pharmaceuticals Ltd, Sarah Cannon Research UK Ltd, Sarcoma Alliance for Research Through Collaboration, Save The Children, Science and Technology Facilities Council, Scope International AG, Selcia Ltd, Sheffield Teaching Hospitals NHS Foundation Trust, Shire Human Genetic Therapies AB, Siemens plc, Sir Halley Stewart Trust, Sir Jules Thorn Charitable Trust, Skeletal Cancer Action Trust Plc, SMA Trust, Smith & Nephew Plc, Society for Endocrinology, Society for Pediatric Radiology, Sport Aiding Medical Research For Kids (SPARKS), St George’s Hospital Medical School, St Peter’s Research Trust, Stanford University, Stanley Medical Research Institute, Stanley Thomas Johnson Foundation, Stanmore Implants Worldwide Ltd, Stroke Association, Sue Harris Bone Marrow Trust, Summit plc, Supreme Biotechnologies Ltd, Susan G Komen Breast Cancer Foundation, Swiss National Science Foundation, Syngenta, Sysmex Ltd, Takeda Cambridge Ltd, Takeda Europe Research and Development Centre Ltd, Takeda Pharmaceutical Co. 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NEUROSCIENCE AND MENTAL HEALTH UCL School of Life and Medical Sciences 49 About UCL UCL is one of the world’s top universities. Based in the heart of London it is a modern, outward-looking institution. At its establishment in 1826 UCL was radical and responsive to the needs of society, and this ethos – that excellence should go hand-in-hand with enriching society – continues today. UCL’s excellence extends across all academic disciplines; from one of Europe’s largest and most productive hubs for biomedical science interacting with several leading London hospitals, to world-renowned centres for architecture (UCL Bartlett) and fine art (UCL Slade School). UCL is in practice a university in its own right, although constitutionally a college within the federal University of London. With an annual turnover exceeding £800 million, it is financially and managerially independent of the University of London. UCL’s staff and former students have included 21 Nobel prizewinners. It is a truly international community: more than one-third of our student body – around 25,000 strong – come from nearly 140 countries and nearly one-third of staff are from outside the UK. www.ucl.ac.uk

UCL Gower Street London WC1E 6BT Tel: +44 (0)20 7679 2000