The Royal Society For further information Science Policy Centre Report 01/11 January 2011 The Royal Society Brain Waves Module 1: Neuroscience, society and policy

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Brain Waves Module 1: Neuroscience, society ISBN 978-0-85403-879-4 and policy

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Contents

1 Introduction and summary 1 The Brain Waves Project 1 Summary 1 Acknowledgements 2

2 Contemporary neuroscience and technology 5

2.1 The scope and limits of neuroimaging 7 Background 7 Neuroimaging techniques 7 Uses of neuroimaging 11 Limits of neuroimaging 13 Policy questions and issues 16 Conclusion 17 References and further reading 18

Box 1: Neuroimaging and lie detection 18

2.2 Neuropsychopharmacology 19 Background 19 New developments in neuropsychopharmacology 19 Varied drug effects in the brain 20 Conclusion 26

The Royal Society Brain Waves Module 1 I January 2011 I iii References and further reading 27

Box 2: Cognitive enhancing drugs 28

2.3 Neural interfaces and brain interference 31 Background 31 Early studies that provided the impetus for NIS developments 32 The current state of the science 32 Potential clinical applications 33 NISs as tools for neuroscience research 34 Recurrent NIS and ‘cognitive prostheses’ 35 Technical challenges and opportunities 35 Less / non-invasive NISs and extrapolation to the games and toy industry 36 Conclusion 37 References and further reading 37

Box 3: Neural interface systems 38

Box 4: Transcranial magnetic stimulation 39

2.4 A determinist view of brain, mind and consciousness 41 Background 41 Implicit assumptions 41 The evidence 42 Conscious versus unconscious processing 42 Wrong intuitions 43 Differences between unconscious and conscious decisions 44 Why is intuition in confl ict with neurobiological evidence? 45 Potential consequences for our legal systems 45 Punishment and confi nement 46

iv I January 2011 I Brain Waves Module 1 The Royal Society Attenuating conditions 46 References and further reading 47

Box 5: The biological becomes personal: philosophical problems in neuroscience 49

2.5 Reward, decision-making and neuroeconomics 51 Background 51 Aims of neuroeconomics: perspective of neuroscience 51 Aims of neuroeconomics: perspective of economics 52 Current state of neuroeconomic research: how the factors that infl uence decisions are represented in the brain 53 Current state of neuroeconomic research: how one possible action is selected from multiple options 54 Current state of neuroeconomic research: social decisions 54 Policy questions 56 Neuromarketing 57 References and further reading 57

3 Neuroscience and society 59

3.1 Benefi ts and opportunities 61 Background 61 Application to policy 61 Opportunities 64 Challenges and solutions 65 Conclusion 66 References and further reading 66

3.2 Risks 69 Background 69 Is increased knowledge of the brain itself hazardous? 69

The Royal Society Brain Waves Module 1 I January 2011 I v Policy issues 70 Drugs for social control? 71 The military and neurotechnoscience 75 Conclusion 76 References and further reading 76

3.3 Neuroethics 77 Background 77 Neuroimaging 78 Genetic neuroscience 79 New medical applications 79 Harmful uses 80 Neuro-enhancement 81 Machine minds? 83 Policy concerns in neuroethics 84 References and further reading 85

3.4 Governance of neuroscience: challenges and responses 87 Three lessons 87 Seven syndromes 90 Three principles 93 References and further reading 96

vi I January 2011 I Brain Waves Module 1 The Royal Society 1 Introduction and summary The Brain Waves project • Module 2: Neuroscience: implications Developments in neuroscience, the study for education and lifelong learning; of the brain and nervous system, are • Module 3: Neuroscience, confl ict and likely to provide signifi cant benefi ts for security; society. Increasing understanding of the brain and advances in technologies to • Module 4: Neuroscience, responsibility study it will enable improved treatment of and the law. neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and mental illnesses, including depression and Summary schizophrenia. They will increase our This Module 1 report is a collection of insights into normal human behaviour essays that together provide a primer of and mental wellbeing, as well as enabling current developments in neuroscience and other enhancement, manipulation, and highlight interesting issues and questions even degradation of brain function and for society and policy. It is not intended as cognition. an exhaustive review of the science, nor to make specifi c policy recommendations. Neuroscience and neurotechnology Rather, it raises key issues and questions, reach far and wide into disparate fi elds. many of which will be explored in more The array of ‘neuro’ disciplines lend depth in subsequent modules. themselves to applications in diverse areas of public policy such as health, education, In Section 2 of the report we review the law, and security. More broadly, progress state of development of neuroscience in neuroscience is going to raise questions and neurotechnology, discuss the about personality, identity, responsibility, translation of this knowledge into useful and liberty, as well as associated social applications or inferences, and raise some and ethical issues. The aim of the Royal of the implications. Section 2.1 explores Society’s Brain Waves project is to explore neuroimaging. Here, we describe some what neuroscience can offer, what are its of the existing tools used to study the limitations, and what are the potential brain, their limitations, and associated benefi ts and the risks posed by particular issues for healthcare, business, applications. criminal justice, and privacy. In Section 2.2 we address developments in neuropsy- This report is the fi rst in a series of four chopharmacology, their application for ‘modules’. Three subsequent modules mental health medicines, wider issues of will consider specifi c policy issues in recreational use, as well as emerging more detail: applications for cognitive enhancement.

• Module 1: Neuroscience, society and Neural interfaces and brain interference policy; are the subject of Section 2.3, which

The Royal Society Brain Waves Module 1 I January 2011 I 1 reviews those providing direct input to issues such as personal identity, physical the brain to modulate activity and those and moral enhancement, responsibility, that use outputs of brain activity to and artifi cial intelligence. Finally, in Section control external devices or prostheses. 3.4 we draw lessons from the wider Applications in diverse areas of health- governance of science and technology, care and the games industry are dis- suggesting approaches to marshalling cussed. Sections 2.4 and 2.5 address neuroscience in order to maximise the what new developments in neuroscience benefi ts and minimise any risks. may mean for our understanding of Professor Colin Blakemore FRS, Chair, behaviour and decision-making. Section Steering Group, Brain Waves project 2.4 argues that understanding of con- scious and unconscious decision-making processes presents a challenge to our concepts of responsibility and free will. Acknowledgements Section 2.5 explores how recent work in The Brain Waves project is overseen by a behavioural neuroscience is leading to Steering Group, chaired by Professor Colin insights about the neurobiological basis Blakemore FRS. These experts also serve of economic decision-making. as members of three broader Working Groups for Modules 2, 3, and 4. The Royal In Section 3 we examine some of the Society would like to thank all members of opportunities and risks these scientifi c the Steering Group, most of whom have developments present, as well as the authored essays for this volume and all of ethical questions they raise, and whom have overseen its development governance issues that need to be and editing: considered. Section 3.1 describes some of the benefi ts and opportunities in • Professor Colin Blakemore FRS (Chair), neuroscience, with a particular focus on Professor of Neuroscience, University new drugs to combat mental illness and of Oxford; cognitive decline, and the associated role of the private sector. Section 3.2 explores • Professor Uta Frith FRS, Emeritus some of the potential risks of certain Professor, Institute of Cognitive applications, such as the risks of Neuroscience, University College ‘medicalising’ behaviour with pharm- London; aceutical interventions, the potential • Professor John Harris, Director, dangers to human rights and privacy Institute for Science, Ethics and posed by invasive applications of Innovation (iSEI), School of Law, neuroimaging, and the potential hazards University of Manchester; to international security presented by the militarisation of neuroscience. • Professor Nicholas Mackintosh FRS, Emeritus Professor, Department of The burgeoning fi eld of neuroethics is the Experimental Psychology, University of subject of Section 3.3, which probes Cambridge;

2 I January 2011 I Brain Waves Module 1 The Royal Society • Professor Geraint Rees, Director, The essays in this volume were written Institute of Cognitive Neuroscience, by individual experts in their fi elds. There University College London; are some issues on which, necessarily, their views and conclusions differ, as • Professor Trevor Robbins FRS, well as their perceptions of benefi ts Professor of Cognitive Neuroscience, and risks. This range of views is not Department of Experimental unusual, or even particular to the fi eld Psychology, University of Cambridge; of neuroscience, but demonstrates the • Professor Steven Rose, Emeritus diversity of opinion in what is still a Professor, Department of Life relatively young area of science. The Sciences, The Open University; views expressed are those of the authors and do not necessarily represent the • Professor Barbara Sahakian, Professor views of the Royal Society. of Clinical Neuropsychology, Department of Psychiatry, University of The Royal Society would also like to thank Cambridge; the Review Panel for reviewing and approving this report: • Professor Wolf Singer, Director, Department of Neurophysiology, Max • Dame Jean Thomas DBE FRS (Chair), Planck Institute for Brain Research, Biological Secretary and Vice- Germany; President, the Royal Society; • Professor Andy Stirling, Science • Professor Tim Bliss FRS, Division of Director, Science and Technology Neurophysiology, National Institute for Policy Research (SPRU), University of Medical Research; Sussex; • Professor Barry Everitt FRS, • Professor Irene Tracey, Director, Oxford Department of Experimental Centre for Functional MRI of the Brain Psychology, University of Cambridge; (FMRIB), University of Oxford • Professor Karl Friston FRS, Scientifi c We are very grateful for the contributions Director, Wellcome Trust Centre for from: Neuroimaging, University College London. • Author of Section 2.5: Professor Wolfram Schultz FRS, Wellcome Science Policy Centre staff working on this Principal Research Fellow and project, and who have contributed to this Professor of Neuroscience, report, are as follows: Department of Physiology, Development and Neuroscience, • Dr Neil Davison, Senior Policy Adviser University of Cambridge; and (Security and Diplomacy) • Co-author of Section 3.3: Dr Sarah • Tessa Gardner, intern (September – Chan, Research Fellow, School of Law, December 2010) University of Manchester. • Sarah Mee, Policy Adviser

The Royal Society Brain Waves Module 1 I January 2011 I 3 • Ian Thornton, Policy Adviser Science Policy Centre The Royal Society • Dr Rochana Wickramasinghe, Policy 6-9 Carlton House Terrace Adviser (to September 2010) London SW1Y 5AG • Rapela Zaman, Senior Policy Adviser tel: +44 (0)20 7451 2548 email: [email protected] If you have any questions about this report please contact Dr Neil Davison in the fi rst instance.

4 I January 2011 I Brain Waves Module 1 The Royal Society 2 Contemporary neuroscience and technology

The Royal Society Brain Waves Module 1 I January 2011 I 5 6 I January 2011 I Brain Waves Module 1 The Royal Society 2.1 The scope and limits of neuroimaging

Professor Geraint Rees, University College London

Background ridges visible to the naked eye. These are The term ‘neuroimaging’ refers to a group made up of a thin layer of gray matter of technologies that allow some aspect of (where neuronal cell bodies are found) human brain structure or function to be underpinned by extensive white matter (or measured without having to perform ‘wiring’). Within the brain, subcortical surgery. These technologies all measure nuclei of gray matter contain further the activity or structure of large neuronal cell bodies. populations of brain cells (neurons), in Computed tomography (CT) is a technique contrast with invasive techniques used in that uses x-rays to visualise brain anatomy animals that measure the activity of in sections. It is deployed in hospitals individual neurons. Human neuroimaging throughout the developed world for instead measures aggregate signals from immediate assessment of stroke and after hundreds of thousands of neurons. head injury, due to its ability to detect However, unlike more invasive techniques, rapidly bleeding within the skull or bone human neuroimaging acquires these injury respectively. For research (and signals from many tens of thousands of increasingly many clinical) purposes, it has locations throughout the entire brain largely been supplanted by magnetic simultaneously. The techniques described resonance imaging (MRI). below differ in their spatial resolution— how well they can distinguish between The advantage of MRI is that the different two points close together, affecting how components of brain structure, such as ‘sharp’ the image is. They also vary in subcortical structures, white matter and temporal resolution—the precision of the gray matter, can be given different image with respect to time. There is often contrasts so that the detailed anatomical a trade-off between the two; however a structure of the brain can be visualised. combination of techniques can be used. The typical spatial resolution of such structural images is between 0.5 and 1 mm3, which represents anatomical Neuroimaging techniques groups of several hundred thousand Structural MRI neurons. Structural neuroimaging acquires In the white matter of the brain, the measurements of brain anatomy non- diffusion of water is limited by the cell invasively. The surface of the brain (cortex) membranes of long, conducting neurons. is a convoluted structure of folds and Diffusion–weighted MRI measures the rate

The Royal Society Brain Waves Module 1 I January 2011 I 7 and direction in which water molecules Functional MRI diffuse within the brain, and so can allow Functional MRI (fMRI) refers to the use of visualisation of the white matter. By MRI scanning to detect some aspect of applying mathematical ‘tracking’ brain function (rather than simply algorithms to these images, the structure structure) (see Figure 1 and Figure 2). and direction of neuronal tracts that The most widely used type of functional connect different brain regions can be MRI is known as Blood Oxygenation Level visualised. Dependent (BOLD) imaging. This measures

Figure 1 This is a MRI image of the visual cortex in one hemisphere of the brain. (The visual cortex is the part of the brain that is active when you look at something.) The dark grey stripes represent gray matter at the bottom of sulci and the light grey stripes represent gray matter associated with brain gyri. Overlaid on the infl ated anatomical image are colored patches representing functional MRI signals associated with stimulating different regions of the visual fi eld. (Reproduced courtesy of Geraint Rees, University College London.)

V1v V3A V2v V3v V3B V3d V2d V4 V1d

*

V2d

V1d

V1v

8 I January 2011 I Brain Waves Module 1 The Royal Society Figure 2 The visual cortex is highlighted in this brain image created using functional magnetic resonance imaging (fMRI). The surface of the brain has been expanded so the parts that are normally hidden away down the folds are ‘blown out’ and are shown as darker areas. (Reproduced courtesy of Mark Lythgoe and Chloe Hutton, University College London.)

changes in the level of oxygenation in Nevertheless, BOLD contrast fMRI has a the blood, which changes locally in the number of advantages over previous ways brain as neurons become active and of imaging brain function such as Positron consume oxygen. This leads to Emission Tomography (PET) (described compensatory changes in blood fl ow to later), because it is entirely non-invasive the active area that can be detected. BOLD and has much higher spatial resolution. contrast fMRI is therefore an indirect Typically BOLD contrast fMRI is combined measure of neural activity, through the with rapid acquisition of brain imaging effects of changes in local blood fl ow in data. This enables the researcher to the brain. Because blood fl ow is regulated acquire a continuous series of images of on a spatial scale of a few millimetres, this the brain, one every few seconds over a limits the spatial resolution of this period of 30 or 40 minutes, while the technique; and because blood fl ow participant performs a particular task. This changes relatively slowly over a few allows for inferences about the nature of seconds, this limits the ability of the the brain processes and their localisation technique to discriminate very rapid during the task on the basis of the changes in neural activity associated with patterns of brain activity that are perception, thought and action. measured.

The Royal Society Brain Waves Module 1 I January 2011 I 9 Functional MRI can also measure other mathematical uncertainty associated with aspects of brain function, such as blood the process of reconstructing how activity fl ow, and it might also be possible in future in specifi c brain areas gives rise to to use MRI to detect the electrical currents electrical signals in the scalp. For these associated with neurons directly. reasons EEG/MEG are often used together with functional MRI as complementary approaches; one with temporal but less EEG and MEG spatial resolution, the other with greater Although not always considered ‘imaging’ spatial but less temporal resolution. techniques, electroencephalography (EEG) and magnetoencephalography (MEG) share the ability of other technologies to produce Other functional neuroimaging a moment-by-moment topographic ‘map’ techniques of human brain activity. In contrast to the Other neuroimaging technologies are less other technologies, EEG and MEG measure widespread but fi ll important niches by the tiny electrical currents or associated providing unique capabilities. magnetic fi elds, respectively, that are associated with the summed activity of Positron emission tomography (PET) many hundreds of thousands of neurons in requires the injection of a radioactive the human brain. These techniques tracer molecule. Detectors placed around measure such activity through hundreds of the head or other body part being imaged electrodes/sensors on the scalp and can can sense the radioactive decay of the produce an image of brain activity tracer molecule in the body. This allows associated with thought processes. They the reconstruction of images of the brain provide a measure of brain activity that or other organs where the image is directly refl ects the electrical activity of sensitive to the particular molecule used. neurons in the brain (albeit large groups of Oxygen-15 labelled water can provide such neurons) in contrast to the indirect images of cerebral blood fl ow, similar to measure of signals related to blood fl ow functional MRI, which has now largely measured by fMRI and PET. supplanted PET for providing dynamic images of brain activation. When the The principal advantage of such a measure radiotracers are molecules that bind to is that it can track the activity of neurons receptors or other sites of drug action much more rapidly over a timescale of a then PET can be used to image the few milliseconds. EEG and MEG therefore concentration, or changes in have superior temporal resolution to other concentration, of neurotransmitters (the techniques. However their ability to resolve chemical messengers in the brain) at activity in specifi c brain areas is more receptors. This is a particular feature of limited, both because it is diffi cult to PET not shared with other neuroimaging measure electrical or magnetic signals techniques, and may be particularly from areas deep within the brain (such as important in understanding psychiatric the thalamus) and because of the intrinsic diseases.

10 I January 2011 I Brain Waves Module 1 The Royal Society Near infrared spectroscopy (NIRS) is a with perception, thought and action. Often method that measures the absorption of this is achieved through intermediate light at near infra-red wavelengths. In brain psychological or computational theories imaging, the resultant spectrum can be that make predictions about how particular related to the concentration of oxygenated brain structures give rise to observed and deoxygenated haemoglobin in blood. behaviour. These can then be tested by This approach can be used non-invasively seeking evidence for signals from those by applying a near infra-red source and brain structures consistent with theoretical array of detectors to the intact skull, which predictions. is not entirely opaque to infra-red light, The ultimate goal of this work is to arrive at particularly in babies and infants who have an account of how mental processes are relatively thin skulls. NIRS can thus be manifested in the human brain, and how used as a non-invasive neuroimaging this gives rise to observable behaviour in technique measuring brain activation in terms of speech and motor actions or other babies and infants. In comparison to the behaviours. This approach has also been other techniques, NIRS is portable and can applied widely to studying disorders of the be used at the bedside for medical brain, whether caused during development applications. However it has relatively low or in adult life, and associated with spatial resolution due to the diffi culty in neurological or psychiatric disease. localising scattered light through the intact skull, and the limited penetration of infrared light into the cortex. Studying brain disorders In addition to these approaches, there are The major use (by volume and cost) of a number of other techniques such as neuroimaging technologies is in single photon emission computed healthcare. This is principally to provide tomography (SPECT) that is lower in spatial diagnostic imaging for use in clinical resolution than PET and largely used as a decision-making. In the last twenty years, clinical technique and not in neuroscientifi c neuroimaging technologies have become research. (This essay has not discussed widely available in the developed world invasive optical imaging approaches used and this has been driven by healthcare. to image exposed brain tissue in animals For example, in Europe from 1999 to such as 2-photon imaging.) 2009, the number of MRI scanners increased from an average of 0.54 to 1.38 per 100,000 people (European Uses of neuroimaging Community Health Indicators). Most of Neuroimaging provides measurements of these scanners are in health care facilities brain structure and activity associated with and not all are capable of the advanced relatively large populations of neurons neuroimaging data acquisition and throughout the brain. It has been used to analysis discussed here. However, MRI determine how and where in the human scanning is now readily available at brain such measurements are correlated reasonable cost (typically around £500

The Royal Society Brain Waves Module 1 I January 2011 I 11 per hour) both inside and outside research action. This leads to signifi cant problems institutions. when such abilities are impaired through neurological damage, so an ability to non- The widespread dissemination and use invasively ‘read out’ such intentions or of neuroimaging technologies coupled perceptions would have potential with the invention of functional MRI in importance (see also Section 2.3). the early 1990s, which permitted easy and non-invasive measurement of brain Recent advances in neuroimaging data function, has led to an explosion in analysis have enabled a limited type of scientifi c studies of cognitive processes ‘brain reading’ or non-invasive detection of in the normal and abnormal brain. In particular perceptions, thoughts, or this domain, perhaps the widest use of intentions to make an action. To date, all brain imaging technologies are to these applications of neuroimaging are identify the processes through which restricted to decoding thought or action in information in the brain is manipulated to quite limited experimental settings, where drive human cognition. Signifi cant only a small number of possible thoughts or progress has been made in actions are entertained. Moreover, they understanding the neural basis of generally rely on analyses performed some cognitive processes such as attention and minutes or hours after the data have been memory. Work in healthy volunteers collected. In the future, developments might (explored below in more detail) is mean that collection and analysis of fMRI complemented by large numbers of data can take place in real time. This would studies describing how such processes raise the possibility of being able to decode break down in abnormal development an individual’s thought and intended action, (eg autism) or following brain damage without requiring the participant to speak or (eg stroke or Alzheimer’s disease). These move, in near real-time (see also Section areas of research have generated 2.3). Nevertheless, there are important thousands of research papers. limitations to these potential applications that may be insurmountable, as discussed below. Studying the normal human brain Humans are particularly skilled at judging By understanding the relationship between the mental states of others, and this forms brain signals and either sensory processing the basis of much social interaction. While (the interpretation of stimuli), thought, or there are approaches to detecting an intention to make an action, functional individual’s current perception or brain imaging techniques hold out the behaviour, humans are also skilled at prospect that they might be able to provide concealing their mental states through their a non-invasive ‘read out’ of perception, behaviour. For millennia there has been thought and intention respectively. At interest in detecting such concealed present, determining the thoughts and information. One type of concealment intended actions of others requires them occurs during deception, and a large to voluntarily speak to us or make an

12 I January 2011 I Brain Waves Module 1 The Royal Society number of bodily markers of deception These uses of neuroimaging share two have been proposed including the common conceptual themes. Either they physiological signs that form the basis of are attempting to identify the presence of a polygraph tests. particular cognitive operation (eg lying) or they are attempting to detect particular More recently, there has been substantial mental contents (eg having previously interest in using neuroimaging to detect seen a particular object). Thus while these deception (see also Sections 3.2, 3.3, and approaches have been examined in the Box 1). Much work has focused on the context of detecting deception, they have neural mechanisms that underpin lying many other potential applications. For versus truth telling. These show that a example, there has been widespread particular area of the brain (the prefrontal interest in detecting mental contents as a cortices) is particularly involved in tool to potentially communicate with inhibiting truthful responses and seriously brain-injured individuals. Thus the generating the false responses ethical and policy implications of working characteristic of lying. Local brain activity in one area have to be understood in the or patterns of brain activity can also context of other potential uses of the distinguish truth-telling from lying on a technology. trial-by-trial basis for individual cases. But there are signifi cant limitations to these approaches, including the use of Limits of neuroimaging countermeasures (covert or overt Generic limits measures taken by the subject in order to It is worth noting that all neuroimaging distort or undermine any conclusions) and techniques require participants who can the inability to generalise from studies of (and want to) comply with the procedures groups of individuals to single individuals. and instructions entailed. The most Lying typically requires a deliberate important technical limitation of human conscious effort. A different approach to neuroimaging is that all currently available detecting deception focuses on techniques are constrained to unconscious processing and/or recognition measurements of aggregate signals from of specifi c knowledge about an event. The hundreds of thousands of neurons at a so-called Guilty Knowledge Test utilises a time. Thus any signals critical for series of multiple-choice questions, each perception, thought or actions that are having one relevant alternative (eg some encoded at a fi ner spatial scale may be aspects of a crime under investigation) and hard to detect using neuroimaging. several neutral alternatives, all chosen to The techniques outlined above differ in be indistinguishable by an innocent their relative strengths and weaknesses. participant. If the subject’s physiological Functional MRI relies on measurement of (or brain imaging) responses to the signals associated with the oxygenation relevant alternative are consistently greater level of haemoglobin in the blood. This than for the neutral alternatives, then changes at a relatively fi ne spatial scale knowledge of the event is inferred.

The Royal Society Brain Waves Module 1 I January 2011 I 13 and so the spatial resolution of functional with subjective reports or observable MRI is of the order of a few millimetres. behaviour of the individual being scanned. But its temporal resolution is relatively Such correlations do not imply a causal poor, because blood fl ow changes that relationship between the brain activity and alter oxygenated haemoglobin behaviour. For example, if two or more concentration lag several seconds behind brain regions show activity patterns that the electrical activity of neurons. In are correlated with a particular behaviour, contrast, the electrical techniques of MEG it may be that one or more of those areas and EEG have millisecond temporal are not necessary to generate the resolution because they measure the behaviour and could be damaged by electrical signals associated with neuronal illness without affecting performance. To activity directly at the scalp. However, identify a causal relationship therefore because these signals summate over requires that neuroimaging data is space and are altered by the scalp and combined with other evidence, such as tissues, the spatial resolution of these that obtained through studying individuals techniques is relatively poor compared to with brain damage or transiently disrupting fMRI. Thus neuroimaging techniques are brain function through transcranial complementary in their limitations, which magnetic stimulation (TMS) (see Section often leads to their use together to 2.3 and Box 4). investigate a particular scientifi c problem. There are also barriers to the use of The principal disadvantage of PET is the currently available neuroimaging in real- need for extensive radiochemistry world environments. All the technologies infrastructure (both people and equipment) discussed here are widely available in to develop new radiotracers. Existing hospital and research environments in the radiotracers can often be made on site developed world, but there are signifi cant with relatively small needs for additional obstacles to more widespread deployment equipment. Nevertheless the technique in the community. MRI technologies remains comparatively expensive and require a large, heavy fi xed installation that infl exible compared to all other can only be transported in a large neuroimaging techniques. The temporal articulated truck. Scanning participants resolution of PET is extremely low; typically with MRI requires that they lie supine in one image is acquired every thirty seconds an enclosed space, limiting access and or so. Moreover, the need to use ionising interaction with the external environment, radiation places exposure limits on the although a number of ingenious numbers of scans that can be acquired experimental approaches have been (typically a maximum of 12, compared to devised to circumvent this. Similarly MEG no limits on fMRI where typically hundreds requires a cumbersome installation that or thousands of scans are acquired for requires careful electrical shielding. EEG is each participant). the most portable technology and can in principle be used in the home setting. All neuroimaging techniques measure However, local interference from other brain activity that can only be correlated

14 I January 2011 I Brain Waves Module 1 The Royal Society electrical devices is not trivial and can studies, attempting to understand specifi c signifi cantly limit performance. Moreover, conscious content in an individual and the electrodes that are applied to the scalp operate as a ‘brain reading’ device, suffer for EEG cannot be worn for extended from a potential limitation of periods or in most real-life situations. generalisation. Because the number of Emerging technological developments potential thoughts or perceptions an may circumvent this possibility with the individual can have at any one time is creation of easily wearable and virtually limitless, a general-purpose brain unobtrusive electrodes, but this at present reading device would need to be able to remains a future development. generalise not just over all the thoughts an individual had previously experienced, but In addition to these generic limitations of also any possible or indeed conceivable the technologies, particular methods have future experiences. Moreover, specifi c limitations that have already been experimentally the process of ‘brain discussed above. Specifi c issues relating reading’ is typically studied in isolation, to the application of neuroimaging whereas in everyday life people typically technologies are described below. have two or more streams of thought concurrently. It is not clear whether ‘brain reading’ techniques would be able to cope Specifi c issues with such concurrency of thought. While neuroimaging techniques have proven impressive in their ability to provide Thus, irrespective of the possible policy new insights into how mental processes issues that arise through recent are realised in the human brain, these developments in our ability to ‘brain read’, insights are typically provided by studying potentially serious and possibly relatively large groups of individuals. While insurmountable empirical limitations are they can provide insights into the group already apparent. average (or typically, representative) The potential ability of neuroimaging to patterns of brain activity, they can provide uncover covert mental states has received less insight into the variability of these much recent attention. In fact, this has patterns of brain activity associated with always been an area of intense interest to an individual. The ability of these fi ndings policymakers. The polygraph is a well- to guide therapeutic decisions or inform known approach to detecting deception (a policy about individuals is thus typically covert mental state). Although not a limited. This is not an intrinsic limitation, neuroimaging technique, it has been but refl ects a relative dearth of studies repeatedly evaluated and its validity and concerning inter-individual variability. reliability have been challenged for The use of functional neuroimaging decades in systematic reviews and technologies to decode specifi c instances evaluations. In addition to questions about of what a subject is thinking at a precise its reliability and validity, the polygraph is moment has been impressive. But these particularly vulnerable to

The Royal Society Brain Waves Module 1 I January 2011 I 15 countermeasures. Such vulnerability to for diagnostic purposes and clinical care, countermeasures is shared by all but represent a potential resource neuroimaging efforts to date that attempt unparalleled in scope and scale for the to detect deception through measuring large-scale study and characterisation of brain activity directly. illness. At the same time, large scientifi c projects such as UK Biobank that tracks Moreover, it remains unclear whether biomedical indicators and their relation to any neuroimaging technique is in fact the health of a very large sector of the UK superior to the poor performance of the population are beginning to consider polygraph, as there have been no direct adding neuroimaging measures. An comparisons. One of the important important emerging policy area is the limitations of any such evaluation is structure and organisation of such that techniques for detecting collections of tens or hundreds of deception are typically developed and thousands of images, including who validated in populations of young controls access to such resources, the role individuals simulating deception. It is of patient consent, and the ethical issues not clear whether such simulated surrounding their potential use to identify deception corresponds in any way to predisposition to disease, or to reveal deception carried out in the real world. information about groups of individuals Moreover it is not clear whether any perhaps only loosely connected to the indices of deception (whether brain initial reason for their undergoing clinical based or otherwise) detected in young neuroimaging. healthy adults generalise in any way to older individuals or groups with mental Many of the important applications of illness – to name but two groups over- neuroimaging assess some form of brain represented in prison populations. These plasticity (changes in connections among issues limit both the validity and the different parts of the brain) either in potential use of neuroimaging response to injury (such as stoke) or technologies in detecting deception (see imbalance in the chemical messenger also Box 1). systems of the brain (neurotransmitters). This raises the possibility of developing assays of functional reorganisation and plasticity to diagnose neuropsychiatric Policy questions and issues syndromes, fi nd associations with genetic Healthcare predispositions, and help predict likely The widespread availability and use of outcomes for patients and their carers. clinical neuroimaging, coupled with the computerisation of health service imaging platforms, means that there are now very Business large numbers of (principally structural) The role of neural processes in determining brain images collected within the National economic decisions has been a subject of Health Service. These are mainly used

16 I January 2011 I Brain Waves Module 1 The Royal Society intense research interest worldwide in Mental Privacy recent years. This has led to commercial Underpinning many of the policy areas interest in ‘neuromarketing’ and the described above is the concept of mental possibility that neuroimaging measures privacy, discussed further in other of brain activity might help in the design essays (see Sections 3.2 and 3.3). Our or marketing of commercial products, or mental contents are typically not perhaps be used as a more effective directly observable and individuals can way to evaluate marketing efforts choose whether and to what extent than simply asking people (see to reveal their mental states through Section 2.5). communication. But the advent of non- invasive imaging technologies that might, in principle, permit the decoding of Security and criminal justice mental states raises the possibility There has been a great deal of interest in of detecting mental states without understanding whether an ability to requiring direct communication from detect covert mental states or deception the individual (provided the participant is might be useful in security and criminal able and willing to co-operate). Moreover, justice arenas. Despite considerable the possibility that functional or structural limitations to currently available images encode additional information techniques described above, there is about an individual or their behavioural often an unspoken assumption that these dispositions raises the possibility that can be overcome by technical such images acquired for other incidental development. From a neuroscientifi c point reasons might be reanalysed after of view, this is an empirical question and acquisition to reveal this ‘hidden’ one whose answer is by no means information. certain. This uncertainty and current limitations have not stopped consideration of the use of neuroimaging techniques to Conclusion assess the credibility of a witness or There has been a rapid development in suspect, assess an offender’s criminal both the deployment and the capability of liability and responsibility, and more neuroimaging techniques in the last recently to attempt to prognosticate on twenty years, particularly with the advent the dangerousness of an offender or their of non-invasive functional imaging likelihood to reoffend (Zeki and approaches. Nevertheless, despite some Goodenough (eds) 2004). These issues spectacular advances in our understanding are also discussed in other essays (see of the neural basis of mental processes, Sections 3.2 and 3.3) and will be the practical limitations of both the addressed in Module 4 of the Brain Waves techniques and their use in ‘real world’ project on neuroscience, responsibility situations limits their potential use outside and the law. clinical and research arenas.

The Royal Society Brain Waves Module 1 I January 2011 I 17 References and further reading Zeki S and Goodenough O (eds) (2004) Law European Community Health Indicators, and the brain. Philosophical Transactions of available at: http://ec.europa.eu/health/ the Royal Society B, Vol 359. ph_information/dissemination/echi/query/

Box 1: Neuroimaging and lie detection Professor Geraint Rees, University College London

Neuroimaging technologies (see Section 2.1) for lie detection show some promise in being able to explore the neural correlates of deception (a covert mental state), but none currently has anywhere near suffi cient sensitivity, specifi city and reliability to be deployable in the criminal justice system of England and Wales. Indeed, it remains uncertain whether such technologies will ever be suffi ciently robust to be used in such ‘real world’ settings. Nevertheless, despite the technological barriers there remains considerable interest and pressure to consider the use of such technologies, and great public interest in situations worldwide where neuroimaging evidence has been used as evidence in criminal cases.

The polygraph is a well-known approach to detecting deception. Although not a neuroimaging technique—it relies on the measurement of skin conductance, which can be infl uenced by arousal during deception—it has been repeatedly evaluated and its validity and reliability have been challenged for decades in systematic reviews and evaluations. In addition to questions about its reliability and validity, the polygraph is particularly vulnerable to countermeasures—covert or overt measures taken by the subject of the polygraph in order to distort or undermine any conclusions.

Such vulnerability to countermeasures is shared by all neuroimaging efforts to date that attempt to detect deception through measuring brain activity directly. Moreover, it remains unclear whether any neuroimaging technique is in fact superior to the poor performance of the polygraph, as there have been no direct comparisons. One of the important limitations of any such evaluation is that techniques for detecting deception are typically developed and validated in populations of young individuals simulating deception. It is not clear whether such simulated deception corresponds in any way to deception carried out in the real world. Moreover it is not clear whether any indices of deception (whether brain-based or otherwise) detected in young healthy adults generalise in any way to groups over-represented in prison populations, such as older individuals and those with mental illness. These issues limit both the validity and the potential use of neuroimaging technologies in detecting deception.

These issues will be addressed in more detail as part of Module 4 of the Brain Waves project on neuroscience, responsibility and the law.

18 I January 2011 I Brain Waves Module 1 The Royal Society 2.2 Neuropsychopharmacology

Professor Trevor Robbins FRS, University of Cambridge

Background classifi cation of the main neurotransmitters The fi eld of neuropsychopharmacology subdivides them according to the speed encompasses drugs that affect cognition, and nature of their effects on neuronal behaviour, and the brain. The brain itself circuits. comprises multiple networks, each of Fast signaling neurotransmitters which link billions of nerve cells (‘neurons’), which large interconnected neural networks interact via the release of chemical signals, constitute mainly the amino acids termed ‘neurotransmitters’, that diffuse glutamate and GABA (gamma- from one nerve cell to the other across the aminobutryic acid), and slow modulatory gaps between them (synapses). neurotransmitters, whose action is neither By binding to specialised proteins in the exclusively excitatory nor inhibitory include cell membrane called receptors, the monoamines; dopamine, noradrenaline neurotransmitters change the sensitivity of and serotonin (or 5-hydroxytryptamine, the nerve cell membranes to potential 5-HT). Finally, very slow modes of action inputs from other cells. Receptors function are generally characteristic of neuropeptide in two main ways: i) through short term neurotransmitters such as cholecystokinin effects induced by neurotransmitter and vasopressin, which may be co- binding that allows the passage of ions released with the ‘classical‘ into and out of the cell, which rapidly neurotransmitters, thus modifying their change its function or ii) through longer effects (see Stahl 2008). term changes induced by a biochemical cascade inside the nerve cell which eventually interacts with genetic material New developments in in the cell nucleus. neuropsychopharmacology Neuropsychopharmacology has focused Although originally it was considered that mainly on understanding the molecular each nerve cell released only one basis of action of drugs that alter the neurotransmitter and that there were two activity of the chemical neurotransmitter main chemical transmitters (one excitatory systems by one or more mechanisms. and the other inhibitory) these concepts Drugs may be classifi ed as ‘agonists’ that have been overturned in the last three simulate the action or evoke the release of decades by the realization that there are natural neurotransmitters at specifi c literally dozens of neurotransmitters, and receptors, or ‘antagonists’ that block the that most neurons can release more than actions or the re-uptake of natural one type, thus enabling a very precise and neurotransmitters at specifi c receptors. We sophisticated modulation of the activity of now understand a good deal about entire the receiving nerve cells. A simple

The Royal Society Brain Waves Module 1 I January 2011 I 19 pharmacological classes of drugs that be related to them, but also drug effects. share common mechanisms of action to Indeed, given the molecular specifi city of exert effects in the brain. drug action, such mapping may be done more effectively than for individual Recent important developments are brain variability in behaviour itself. imaging techniques (see Section 2.1) that have enabled researchers to link the Prominent examples include molecular actions of drugs to specifi c demonstrations that the cognitive behavioural or physiological effects in enhancing effects of amphetamine may humans. Positron emission tomography depend on a polymorphism in the brain (PET) can be used to map the location of that regulates the activity of dopamine in neurotransmitter receptors in the brain and the prefrontal cortex of the brain; thus can be utilised in conjunction with either benefi t or impairment may occur in pharmacological treatments to infer the response to the same dose of the drug in activity of central neurotransmitter systems different individuals (eg Mattay et al. in the human brain. This technique has 2003). A second example is the fi nding been used, for example, to show that drug that depression produced by the drug addicts have reduced dopamine receptors ecstasy is also highly variable in users and in the striatum area of the brain (Volkow can be related to variability in et al. 1997), thus confi rming leads from mechanisms controlling the activity of animal work that the dopamine system is serotonin in the brain. Genetic differences implicated in addiction. may also modulate the capacity of cannabis to trigger psychosis. Such The use of functional magnetic resonance observations have enormous implications imaging (fMRI) has been important for for calculating the risk associated with establishing ‘event related’ correlations drug-taking and for predicting benefi ts of between brain activity and behaviour over drugs in the treatment of mental illness time. Pharmacological fMRI is a recent (‘personalised medicine’), as well as for development which enables the analysis of ‘cognitive enhancement’ in healthy drug effects on cognition and behaviour— individuals. however, it has two main diffi culties: fi rst its lack of neurochemical specifi city in relation to PET and secondly the possibility Varied drug effects in the brain of misleading responses arising from drug In functional terms, it makes sense to actions on cardiovascular factors. subdivide the main drug actions into those Another major area of development is which bring about detrimental or pharmacogenomics (Royal Society 2005). incapacitating effects by impeding or The human genome project has enabled damaging neural activity, and those which the identifi cation of gene variants that defi ne bring functional effects by modulating individual variation in genetic make-up. Such neural activity. The latter effects may be genetic polymorphisms not only allow produced by drugs: i) used as mental differences in cognition and behaviour to health medicines, such as anti-psychotic or

20 I January 2011 I Brain Waves Module 1 The Royal Society anti-depressant medications; ii) used for receptor may be implicated (eg euphoric their cognitive or performance enhancing and analgesic effects of opiates). effects (eg including sexual performance In terms of basic neuroscience research it or for effects on personality); and iii) used is relevant to note that each of these drug recreationally or abused, leading to sub-divisions can also be used to discover addiction. more about brain function. Some of these categorisations are signifi cant; for example, several so-called cognitive enhancing drugs do not produce Mental health medicines subjective effects that usually accompany Mental health medicines are continuously recreational use, and also do not lead to being monitored, with controversies often obvious physical dependence. arising about effi cacy and safety of drugs, Nevertheless, there is a good deal of for example certain anti-depressants. overlap among these categories; for Patents for many compounds are due to example, some abused drugs such as expire soon and there has been a worrying methamphetamine undoubtedly have failure to produce many more effective neurotoxic effects, while a drug producing drugs that utilise new mechanisms of cognitive enhancing effects could also be action, although there are some possible ‘abused’ (eg both in terms of criminal use exceptions (eg ketamine for depression such as cheating in competitive and drugs affecting glutamate examinations, and in terms of a transmission for schizophrenia). This has psychological dependence, leading to led several of the major pharmaceutical excessive drug intake). Moreover, virtually companies to close down programmes in all drugs of abuse, from opiates to psychiatry and neuroscience, which could stimulants, have been used at one time or result in considerable harm to both health another in a medical context. Stimulants and the economy in the UK and other were formerly used as slimming agents; countries (see also Section 3.1). On the they are still used in the treatment of other hand, the relative success of drugs attention defi cit hyperactivity disorder used to treat positive symptoms in (ADHD). Heroin was originally employed in schizophrenia and severe clinical cough mixtures, and opiate drugs are still depression means that companies will employed as powerful pain-killing continue to make large profi ts from the (analgesic) agents. Nicotine may have sale of mental health medicines. cognitive enhancing effects and variants of nicotine are being pursued as possible One major diffi culty may be increasing cognitive enhancing agents. Cannabis has regulatory controls on drug development been suggested to be benefi cial in the accompanied by a shift to risk aversion on treatment of multiple sclerosis. Some of the part of the drug companies in the face this plurality of action arises from the fact of adverse side effects. Another may be that many drugs have multiple sites of that the expensive clinical Phase 3 trials action in the brain, even though the same can be scientifi cally suspect due to poorly

The Royal Society Brain Waves Module 1 I January 2011 I 21 controlled factors. Relatively minor dysphoric (opposite of euphoric) advances have come in the form of more withdrawal states, which are also sophisticated means of drug delivery, postulated to occur following stimulant which minimise the number of withdrawal. However, the tendency administrations involved in medicating towards compulsive drug seeking and certain patient groups, for example ‘out-of-control’ drug taking, which are the formulations for ADHD that require only hallmarks of addiction, is not an inevitable once daily dosing. consequence of drug use; there is considerable individual variation in the degree to which individuals are vulnerable Recreational drugs to addictive properties of drugs, probably Use and abuse: Many different classes of arising from both genetic and drug are used to produce subjective environmental infl uences. It has for effects (such as changes in mood, example, been estimated that only about including euphoria or sedation) in the 20% of persistent cocaine users actually recreational context. Some of these drugs become addicted or ‘dependent’ on are legal (eg alcohol, nicotine) but most are cocaine. not (eg stimulants such as cocaine and Addiction and dependence: Addiction has methamphetamine, opiates such as heroin, been the subject of several recent major and hallucinogens such as cannabis and reviews, notably the wide-ranging, ecstasy (MDMA)). Distinct molecular interdisciplinary Foresight project Brain actions of these different drugs have been science, addiction and drugs (published as to a large extent identifi ed. However, Drugs and the Future, Nutt et al. 2006) and similar neurobehavioural principles may the subsequent Academy of Medical govern how they might become drugs of Sciences (2008) report of the same name. abuse. For example, many of these drugs Several key issues were raised by these have some common effects on brain reports including: i) the relative absence of dopamine systems, which may be effective medications for addiction; ii) the responsible for some of their reinforcing absence of reliable and informative (‘rewarding’) actions. epidemiological data concerning addiction We now have a considerable in the UK; iii) the lack of accurate understanding of the basis in the brain of information about adverse effects and risks the effects of recreational drugs, both entailed by using certain drugs, such as through studies with experimental animals ecstasy and cannabis, which has led to (who may self-administer them) and controversies about how such drugs neuroimaging studies of drug-using should be classifi ed under the Misuse of humans (Robbins et al. 2010). Some of the Drugs Act by the Home Offi ce, and drugs (eg alcohol, heroin) have obvious considerable confusion arising from a physical withdrawal syndromes which are failure to appreciate the importance of associated with drug dependence. These individual differences in susceptibility to drugs may also produce psychological drug effects; and iv) the likelihood of novel

22 I January 2011 I Brain Waves Module 1 The Royal Society drugs of abuse emerging periodically. A major impetus for the emergence of These may be previously known cognitive performance enhancers has been compounds for which new properties are the focus by pharmaceutical companies on discovered, or new compounds claimed to the treatment of cognitive disorders such as offer ‘legal highs’ (eg mephedrone) which dementia (including Alzheimer’s and are not controlled and are available to buy Parkinson’s disease), and more recently on the web. Many ‘new’ drugs are often stroke, schizophrenia and ADHD. variations on a theme in terms of chemical Economic arguments underpinning this structure, for example, being derivatives of interest are compelling, given the estimated the amphetamine-class of stimulant drugs. market for dementia therapy (see Jones et al. 2007). Such disorders are associated with different forms of pathology and so it Cognitive enhancers is likely that there will be a need for different types of medication. However, it is also Considerable interest was aroused in conceivable that a single compound may cognitive enhancers and performance have several possible disease targets, as it enhancing drugs (see also Box 1; and may provide improvements not by Sections 3.1, 3.2, and 3.3) by the Foresight removing a particular pathology but by project. This project made it clear that producing compensatory improvements in there may exist certain drugs with the neuronal systems that are intact. potential ability to enhance cognitive performance, not only in patients with There is no programme in ‘big Pharma’ for cognitive disorders, but also in the normal developing cognitive enhancers for the healthy population (Jones et al. 2007; healthy population; regulatory and legal Academy of Medical Sciences 2008). issues determine this lack of commercial interest. However, ‘cognitive enhancing’ ‘Cognition’ refers to brain processes of drugs may be publicised by word of mental activity including: perception, mouth, the media and the web, often attention, learning, memory, language, leading to considerable ‘off-label’ use, thinking, planning, decision-making and which raises signifi cant issues of cognitive control. Cognition must be regulation for government. A commentary distinguished from overt behaviour, which in Nature by Sahakian and Morein-Zamir is, however, largely a product of cognitive (2007) entitled Professor’s Little Helper processes. Cognitive performance also described the ‘off-label’ use of cognitive depends on other important factors such enhancing drugs such as methylphenidate as arousal level (ie the level of wakefulness) (Ritalin) and modafi nil by University and motivation. Thus, in theory a ‘cognitive students and academics. Many of their enhancer’ may produce its benefi cial conclusions were endorsed by a effects indirectly through effects on subsequent questionnaire issued by the motivation or arousal. (This essay excludes same journal (Maher 2008). consideration of enhancement of other aspects of behaviour such as sexual A compelling consideration for ‘cognitive function or appetite.) enhancers’ is the diversity of candidate

The Royal Society Brain Waves Module 1 I January 2011 I 23 Figure 3 These images show the signal acquired using [18F]fallypride (the radioactive tracer molecule) positron emission tomography following placebo (top row) and oral methylphenidate (Ritalin) (bottom row) in a healthy volunteer, superimposed on a high resolution magnetic resonance image (MRI) acquired from the same volunteer. [18F] fallypride competes with endogenous (naturally produced) dopamine for the binding to dopamine receptors. The signal reduction observed following methylphenidate relative to placebo indicates that the drug increased dopamine levels, leading to less [18F] fallypride binding due to increased competition with endogenous dopamine. (Reproduced courtesy of Natalia del Campo, University of Cambridge.)

PLACEBO 30 25

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mechanisms that are being utilised in structures of the brain such as the cerebral their development. Many compounds, cortex and the hippocampus. including well-known drugs such as Drugs are also being developed as ‘inverse methylphenidate (Ritalin) (see Figure 3), agonists’ that invert the sedative actions of amphetamine, and nicotine exert their related compounds to produce memory- effects by optimising chemical signalling enhancing effects. One such compound by monoamine neurotransmitters (eg has been found to block the amnesia dopamine, noradrenaline, or 5-HT) in brain produced by alcohol, through acting at regions such as the prefrontal cortex. New GABA-activated receptors. Another, compounds, such as the ‘AMPA-kines’ modafi nil, has long been licensed as a work by exaggerating the effect of the fast treatment for narcolepsy, but has also been signalling neurotransmitter glutamate in shown to enhance working memory and neural networks in key ‘cognitive’

24 I January 2011 I Brain Waves Module 1 The Royal Society executive functioning in non-sleep- costs—of such practice (see also deprived volunteers. Intriguingly, it is far Section 3.2). from clear how it produces its cognitive Some aspects of the ‘cognitive enhancing effects and this is a currently a enhancement’ strategy arising from recent subject of great research interest. discoveries in basic neuroscience may ‘Nutraceuticals’ such as vitamins, appear paradoxical at fi rst sight. For supplements and other aspects of dietary example, it may eventually be possible to modifi cation may also produce cognitive help patients with certain disorders such effects, although their precise modes of as post-traumatic stress disorder (PTSD), action are largely obscure. Perhaps anxiety, or drug addiction by treating them predictably, members of the public appear with drugs that seemingly impair to fi nd cognitive enhancement via dietary cognition—by producing selective means less objectionable than by orally amnesias. It is now evident from work on administered drugs, even though they may experimental animals that memories may share common modes of action. be subject to experimentally-induced forgetting if evoked in the presence of The discovery of cognitive enhancing drug certain drugs (so-called ‘memory effects is of particular interest in terms of reconsolidation’). This is also true for the boosting performance in a number of procedure of extinction, whereby a certain different occupations—notably in shift stimulus is no longer followed by its workers, for which controlled trials are expected consequence, a process that already suggesting some benefi t. Another leads to an active suppression of the potential application has been illustrated in normally-evoked behaviour. Extinction can a demonstration of benefi cial effects of be accelerated in the presence of drugs modafi nil in the performance of surgeons, that facilitate the functioning of certain over conventionally-employed stimulants receptors. such as caffeine, which lead to counterproductive hand tremor (Sugden The optimization of behaviour by et al. 2010). pharmacological agents is a complex issue that depends on a balance of cognitive This area is also of signifi cance for enhancement and cognitive suppression. subsequent modules of the Brain Waves It is now crucial that we begin to assess project. There is signifi cant military interest possible costs as well as benefi ts as a in cognitive enhancement. Modafi nil is consequence of treatment with cognitive thought to have been used by the French enhancers, especially long term or chronic army in Iraq in the early 1990s and in 2003 consequences. Relevant considerations the US Air Force authorised its use to have been set out in the Academy of combat fatigue. This use of modafi nil Medical Sciences (2008) report on Brain echoes that of stimulants such as science, addiction and drugs. amphetamine in the Second World War, but today there is much more precise Allied to this scientifi c excitement and information about the benefi ts—and the uncertainty are similar ethical dilemmas

The Royal Society Brain Waves Module 1 I January 2011 I 25 posed by the use of cognitive enhancing drugs targeting the brain (as opposed to drugs by the healthy population. Whilst it ‘riot control agents’)—for law enforcement may not be considered ethically dubious to purposes. This has led to signifi cant aspire to enhance performance, there are controversy and concern, particularly obvious problems in competitive following the use of an aerosolised spray situations, eg examinations or the of an opioid analgesic drug, thought to be workplace. Other ethical issues may 3-methylfentanyl (carfentanil), to break the include the coercive use of such drugs, siege of a Moscow theatre in 2002, which such as to ensure good behaviour in resulted in the death of over 120 hostages juveniles with ADHD (eg in certain schools (see also Section 3.2). This issue will be in the US), or as a compulsory requirement addressed in more detail as part of Module for soldiers. The example of cognitive 3 of the Brain Waves project. enhancers is a main theme of the As in the case of cognitive enhancing burgeoning new subject of ‘neuroethics’ drugs, there are many ways of producing (see Greely et al. 2008) (see Section 3.3). incapacitating effects including mechanisms related to anaesthesia and respiratory depression, as well as more Incapacitating agents general neurotoxicological actions. The Drugs acting on the central nervous former can be produced via a range of system can also be used to incapacitate different mechanisms generated by our humans, primarily for benefi cial purposes, burgeoning understanding of brain such as the use of anaesthetics under mechanisms of consciousness, including highly controlled circumstances for the discovery of new neurotransmitter medical procedures, or the sedation of substances such as orexin. (Saper et al. violent patients. However these drugs have 2005). also drawn the attention of military and police organisations since the late 1940′s for use as chemical weapons. Developers of such incapacitating chemical agents Conclusion The fact that drugs can produce mind- generally aim to target the central nervous altering effects through their chemical system to induce unconsciousness or actions has been known for centuries, but sedation. These weapons are distinct from the excitement of the fi eld in neuroscience ‘riot control agents’, such as ‘tear gas’, is that we can now explain a good many of which cause local irritation to eyes, skin, these actions through our enhanced and the respiratory tract, and have long understanding of the chemistry and been used by police forces around the functioning of the brain. A signifi cant world. realisation is that drugs can have diverse Since the international ban on chemical effects on different aspects of function weapons was agreed in 1993 some (leading obviously to inevitable ‘side- countries have continued to develop effects’); and that these effects will often incapacitating chemical weapons—ie encompass both benefi cial (eg ‘cognitive

26 I January 2011 I Brain Waves Module 1 The Royal Society enhancing’, ‘mood-enhancing’, pain-killing Nutt D, Robbins T, Stimson G, Ince M and and detrimental (physical withdrawal, Jackson A (eds) (2006) Drugs and the neurotoxicity) actions. Thus, it becomes Future: Brain science, addiction and society. important to defi ne in which precise Burlington MA: Academic Press. context a drug is being used, and also to Robbins T, Everitt B, Nutt D (2010) The formulate the cost-benefi t equations in Neurobiology of Addiction; New vistas. both biological and ethical terms. (see also Oxford: Oxford University Press. Sections 3.2 and 3.3). Royal Society (2005) Personalised medicines: hopes and realities. References and further reading Academy of Medical Sciences (2008) Brain Sahakian B and Morein-Zamir S (2007) science, addiction and drugs. London: Professor’s little helper. Nature, Vol 450, Academy of Medical Sciences. pp 1157–1159.

Greely H, Sahakian B, Harris J, Kessler RC, Saper C, Cano G, and Scammel T (2005) Gazzaniga M, Campbell P and Farah M Homeostatic, circadian and emotional (2008) Towards responsible use of regulation of sleep. Journal of Comparative cognitive-enhancing drugs by the healthy. Neurology, Vol 493, pp 92–98. Nature, Vol 456, pp 702–705. Stahl S (2008) Stahl’s Essential Jones R, Morris K and Nutt D (2007) Psychopharmacology: Neuroscientifi c basis Cognition enhancers. In: Nutt D, Robbins and practical application. 3rd edition. T, Stimson G, Ince M, and Jackson A (eds) Cambridge: Cambridge University Press. Drugs and the Future. Amsterdam: Sugden C, Aggarwal R, Housden C, Elsevier. pp 241–283. Sahakian B and Darzi A (2010) Maher B (2008) Poll results: look who’s Pharmacological enhancement of doping. Nature, Vol 452, pp 674–675. performance in doctors. British Medical Journal, Vol 340, p 2542. Mattay V, Goldberg T, Fera F, Hariri A, Tessitore A and Egan M (2003) Catechol-O- Volkow N, Wang G, Fowler J, Logan J, methyl trasferase Val 158-Met genotype Gatley S, Hitzemann R, Chen A, Dewey S and individual variation in the brain and Pappas N (1997) Decreased striatal response to amphetamine. Proceedings of dopaminergic responsiveness in detoxifi ed the National Academy of Sciences, Vol 100, cocaine-dependent subjects. Nature, Vol pp 6186–6191. 386, pp 830–833.

The Royal Society Brain Waves Module 1 I January 2011 I 27 Box 2: Cognitive enhancing drugs Professor Trevor Robbins FRS, University of Cambridge

‘Cognitive enhancers’ are a broad class of drugs from a number of distinct pharmacological classes with diverse molecular mechanisms of action (see Table 1). These may include disease modifying drugs (for example, arresting aspects of Alzheimer’s disease pathology) or compounds that exert specifi c effects on particular chemical neurotransmitter systems. These serve to optimise different aspects of cognitive function, often mediated by different parts of the brain. There is growing published evidence that such actions may range, depending on the compound, from the enhancement of working memory (eg for recalling telephone numbers) or episodic memory (eg for memories of one’s own life) to the augmentation of concentration and the restraint of impulsive urges. These functions may be impaired in many neuropsychiatric patient groups, including those with schizophrenia, attention defi cit hyperactivity disorder (ADHD), addiction, brain damage, or Parkinson’s disease, and are all targets for pharmacological remediation.

Cognitive functioning is powerfully modulated by such factors as motivation and arousal. For example, it is frequently sub-optimal even in healthy individuals as a function of circadian infl uences, fatigue or sleep deprivation. Thus any agent affecting those processes is bound also to also impact on cognition—often benefi cially, although excesses of either motivation or arousal are likely to impair cognition. There are also probable costs as well as benefi ts of effects of cognitive enhancers because of the theoretical diffi culty of optimizing, simultaneously, all of the brain systems that contribute to cognition. Thus what may be good for consolidating long term memory is possibly incompatible with improvements in short term memory. It is also possible that long term use of cognitive enhancers may lead to a reduction of any benefi cial effect, for example, because of the phenomenon of drug tolerance, or because of the possibility of neurotoxic effects of such compounds. However, these factors have not been researched extensively.

Another complicating factor is that, as for many other drug effects, there is considerable individual variability in response and some individuals may benefi t from a dose of a compound that impairs cognitive function in others. Such variability is already known to depend in part on individual genetic variation and this may enhance future programmes directed towards personalised medicine and risk assessment. The issue of cognitive enhancement in healthy individuals has gained considerable prominence on the basis of recent surveys; whilst many so-called cognitive enhancers cannot be obtained by prescription, they are often available via the internet. This raises regulatory issues, to accompany the ethical controversy that exists on the non-medical—‘off- label’—use of cognitive enhancers (see also Sections 2.2, 3.1, 3.2, and 3.3).

28 I January 2011 I Brain Waves Module 1 The Royal Society Table 1: Candidate cognitive enhancing drugs

Mechanism of action Examples

‘Nootropic’ agents (probably acting piracetam, aniracetam, nefi racetam, through effects on cerebral metabolism) oxiracetam, pramiracetam, pipexide Glutamatergic agents (some under clinical ampakines, memantine, D-cyclo- trial) serine, mGLU-R5 potentiators, glyt-1 inhibitors GABAergic (γ-aminobutyric acid) agents inverse GABA receptor agonists eg suritozole; GABA-b receptor antagonists eg NS105 Catecholaminergic agents methylphenidate (Ritalin), atomoxetine, propanolol, bromocriptine, L-Dopa Cholinergic agents nicotine and related nicotinic agonists (alpha-7; alpha4, beta 2) galantamine, rivastigmine, donepezil, choline, lecithin Histamine R3 antagonists ABT-39,ciproxifan ‘Eugeroics’ or atypical stimulants: Modafi nil unknown mechanism, possibly via adrenergic or hypocretin receptors, dopamine reuptake blockade, histaminergic or glutamatergic mechanisms Agents acting on cerebral circulation or vinpocetine, hydergine, phenytoin, calcium homeostasis nifedipine, nimodipine, Idebenone. Hormones and neurohormones dehydroepiandrosterone (DHEA) and DHEA-sulphate, vasopressin Miscellaneous others acetyl-L-carnitine, gingko biloba, ginseng, orotic acid, vitamin E, vitamin B6

Further reading Jones R, Morris K and Nutt D (2007) Cognition enhancers. In: Nutt D, Robbins T, Stimson G, Ince M, and Jackson A (eds) Drugs and the Future. Amsterdam: Elsevier. pp 241–283.

The Royal Society Brain Waves Module 1 I January 2011 I 29 30 I January 2011 I Brain Waves Module 1 The Royal Society 2.3 Neural interfaces and brain interference

Professor Irene Tracey, University of Oxford

Background the brain and this ongoing neural activity is A new branch of neuroscience has evolved decoded and used to predict cognitive over the past decade that is causing intentions (eg plans to perform a considerable excitement. Aimed at movement). In this way they can creating links between the human nervous potentially replace a lost connection to the system and the outside world by outside world. Also, by forming a direct stimulating or recording from neural tissue, connection between the brain and outside it is hoped to bring unprecedented benefi t world, NISs free us from the limitations of for people with sensory, motor or other our bodies. It is this last opportunity that disabilities of brain function. Devices that has captured the public’s imagination. may enable restorations of these functions Devices that can decipher intentions, which are known as brain-machine interfaces to date are generally movement related, are (BMIs), brain-computer interfaces (BCIs), being developed into clinically viable neural prostheses or neural interface systems for patients who are paralysed. As systems (NISs). For simplicity, here the is often the case with advances made in overarching term, NIS, will be used. the medical arena, we are simultaneously NISs can be broadly separated into two seeing these developments penetrate the types—interfaces that input to neural games and toy industries too. Such systems, and NISs that record electrical translation brings knowledge, acceptance activity (output) and use it to predict and normalisation of this extraordinary cognitive intentions. ‘Input NISs’ constitute concept within society. the majority of NISs to date and have Other techniques, sometimes known as already reached widespread clinical ‘brain interference’ devices, and which application. They provide direct electrical include Transcranial Magnetic Stimulation stimulation input to a specifi c part of the (TMS) and Transcranial Direct Current nervous system to restore or improve Stimulation (tDCS), are now widely used in function by altering local neural activity neuroscience research with some clinical (see Box 3). applications (see Box 4). These devices do ‘Output NISs’ are another matter and it is not encode or decode brain signals but these devices that are causing such a stir instead inhibit or excite brain activity to in the scientifi c and clinical communities, produce certain behavioural outcomes. as well as among the general public. They are limited in the specifi city regarding Output NISs record electrical signals from which brain region can be stimulated and

The Royal Society Brain Waves Module 1 I January 2011 I 31 are relatively crude when compared to the neural activity within this area. These precision of NISs. However, they are useful animals demonstrated that they could devices for allowing ‘non-invasive’, wilfully control the activity in their motor controlled manipulation of cortical brain cortex to alter the movement of an regions and as such, they contribute to a independent device. This provided the fi rst more causal understanding of human brain evidence that primates could learn networks, particularly when combined feedback control of neural activity without with other brain imaging tools such as actually performing any bodily movements. functional magnetic resonance imaging These early observations provided the (fMRI) and electroencephalography (EEG) impetus for the following thirty years of (see Section 2.1). research to develop viable NISs for humans (Evarts 1968; Fetz 1969; NIS research is a thriving area of Humphrey et al. 1970). neuroscience that links animal and human neurophysiology research and brings new insight into the neural basis of behaviour and The current state of the science perception. Advancement in NIS technology Two forms of neural interface are possible: heralds new ways for understanding brain function and our understanding of neural i) Open-loop prediction which records coding and representation, plasticity, brain- neural activity from multiple sites to behaviour relationships, as well as the predict behaviour. Open–loop paradigms neurobiology of disease. But what about enable us to learn what features of extending these NISs to other forms of brain neural activity are critical for eliciting the manipulation—aimed at cognitive measured behavioural outcome. We can enhancement or neural ‘modifi cation’ or then record and then decode these. ‘correction’? As these technologies improve, ii) Closed-loop control, which records we are faced with the realisation that a new neural activity to guide a device era has begun in neuroscience and with it controlled by an animal/human that important issues are raised that warrant receives sensory feedback for learning discussion (see Sections 3.2 and 3.3). purposes. Here, the experimental subject can use feedback (eg watching where the external device is moving) to Early studies that provided the modulate neuronal activity on an impetus for NIS developments ongoing basis, so that the accuracy of In the 1960s and early 1970s pioneering the intended outcome (eg the experiments from awake, behaving movement of the device) can be nonhuman primates showed that the improved. In essence, the NIS here activity of neurons within a specifi c brain effectively acts as a virtual mirror to area (the primary motor cortex) was real neuronal activities. directly correlated to specifi c aspects of movement. More importantly, these Closed-loop control is the common movements could be predicted by the approach used in clinical applications, as

32 I January 2011 I Brain Waves Module 1 The Royal Society these largely focus on paralysed patients retain a brain mechanism to generate who require control of an artifi cial limb or movement intentions. All they need is a device via intention, and where feedback way to deliver motor commands from the to improve performance is critical. Patients brain to an artifi cial aid. suffering spinal cord injury, stroke, degenerative disorders and amputation all retain a brain mechanism to generate Potential clinical applications movement intentions. All they need is a A pilot study of the fi rst human long term way to deliver motor commands from the implanted multielectrode array-based NIS, brain to an artifi cial aid or directly to still called BrainGate, is ongoing and so far functioning muscles (called Functional deemed successful (Hochberg 2006). The Electrical Stimulation). NIS records signals from an implant within the part of the motor cortex responsible for Many examples have recently been the arm in patients with severe paralysis, published, often using non-human following injury. They are now able to primates (Truccolo et al. 2010; Velliste et al. move a cursor on a screen and perform 2008; Kipke et al. 2008). Here, recordings grip and transport actions using a robot’s are taken and decoded from many areas of arm. What is astonishing about these the cortex, and used for prediction of results is that years after injury-induced movement or control of an external robot paralysis, normal brain activity was still or device. present in the motor cortex that could be Proof-of-concept studies in rats and non- wilfully modulated. human primates paved the way for Functional imaging studies in humans determining the essential elements for a show that imagined movement produces successful closed-loop NIS. This has now blood-fl ow-related changes similar to those been translated to early stage human produced during real movement, but it clinical trials with considerable success, was assumed that the nature of the and is generating much media and public underlying neuronal activity might be interest (Hatsopoulos and Donoghue 2009; subtly different and not viable for NIS. Hochberg 2006). To enable a patient with From this pilot NIS study, it is apparent severe paralysis to regain control, that the underpinning brain patterns communication and independence would observed are similar whether movement is be a tremendous achievement. imagined or performed. Considering the number of conditions where a disconnection between a healthy Animal studies show that the brain rapidly brain and target muscles produces changes following injury (often in a paralysis but where the patient has a maladaptive way) due to plastic normal capacity for planning and mechanisms, affecting activity in primary imagining movement, this is the fi rst cortical areas. However, recordings in obvious target area of application. Patients various chronically injured patients now suffering spinal cord injury, stroke, challenge this view. Clearly, years after degenerative disorders and amputation all sustaining dramatic injuries the neural

The Royal Society Brain Waves Module 1 I January 2011 I 33 activity is present and capable of being surrounding these fi ndings indicates that harnessed to operate artifi cial devices. the public wants to engage and debate the Such fi ndings are encouraging but perhaps implications of this work (Cruse and Owen surprising and raise questions about how 2010). closely fi ndings in animals are applicable to humans. These results also encourage us to reconsider attitudes towards patients Brain-Body Uncoupling who are severely disabled but have brains One potentially very interesting perfectly capable of encoding behaviour. extrapolation of NISs in the future is in ‘brain-body uncoupling’. As described A decoder must simultaneously collect above, output NISs work because the information on both neural activity and same group of neurons which normally behaviour in order to map one to the other. move a limb can instead be co-opted to This is not possible in patients who have move an artifi cial device. Fascinatingly, in already lost the behavioural component non-human primates it has been observed (eg movement). However, passive visual that these neurons quickly adapt such that observation of a task produces neuronal no or minimal movement of their own responses near identical to those observed limbs occur when moving the device in the when the task is performed. This same manner. The capacity of the brain to knowledge provides us with the concept of disconnect from its body parts and interact ‘mirror-neurons’ (neurons that behave the with the world via artifi cial means has same when a task is observed as when wide-ranging and signifi cant implications. that task is performed) that can be used in the development of NISs bespoke to patients while contributing to a better understanding of the role of such mirror- NISs as tools for neuroscience like neurons in humans. research NISs have a considerable future role in As NIS technologies improve, broader many areas of basic neuroscience applications will become available. For research. NIS and other neuroimaging example, better software in the NIS can studies have taught us that large networks generate smoother movements of external of neurons beyond specialised motor devices, as well as allowing more motor regions are involved in even the simplest control and movement options, which of movements, as many brain areas can might suit severely disabled individuals. encode movement to some extent. These One context where this ability is potentially fi ndings argue against focussing solely on applicable is for patients in vegetative functionally specialised brain regions in states and comas. There has been a lot of order to understand systems behaviour. recent publicity surrounding data from neuroimaging studies showing that Further, NISs offer an opportunity to patients who are in a persistent vegetative understand how the activity of individual state may have wilfully controlled thoughts neurons and the surrounding groups of (Owen et al. 2006). The media coverage brain cells (measured through fi eld

34 I January 2011 I Brain Waves Module 1 The Royal Society potentials) inter-relate in coding More interesting and ethically challenging information. These two types of electrical applications include those producing signals are often studied separately—but long-term modifi cation of the strength of NISs take in both types of information. connections between brain cells. Given that the strength of connections between cells The closed-loop NIS provides an underpins learning and behaviour, NISs unprecedented opportunity to explore could potentially ‘force’ the brain to react in learning in the human brain in the context a certain way to a certain stimulus or ‘learn’ of short-term and long-term improvements. something. However, given our ignorance Because the NIS forms a direct, causal link of the way that memory is structured this between the recorded brain area and seems a distant possibility. behaviour, any behavioural changes can be attributed to changes in neural activity from Technological developments make it the recorded brain area and not possible to implement recurrent NISs in downstream areas (eg spinal cord, higher-order cognitive areas of the brain— muscles)—as these have been removed eg hippocampus, producing what could be from the system. This is not to say that called a ‘cognitive prosthesis’. This could there aren’t changes occurring upstream in cause signifi cant changes in how the brain other brain areas that in turn provide altered operates and functions. inputs to the recorded brain area, but this Such recurrent NIS induced plasticity opens can now be studied using distributed NISs. opportunities for experimentation and clinical translation (eg to facilitate recovery from stroke), but also manipulation and Recurrent NIS and ‘cognitive exploitation (see Section 3.2). prostheses’ There is considerable interest in creating a recurrent NIS system where neural activity Technical challenges and is recorded and processed in real-time to control electrical stimulation of particular opportunities The primary requirements of an NIS for the areas of the brain or muscles through broad range of neuroscience applications other implanted electrodes. The brain are recording and/or stimulating from a could then learn to incorporate this activity number of discrete parts of the brain at into normal function. Initial devices were requisite spatial resolutions for specifi c developed using a ‘neurochip’ that periods of time, safety, usability, reliability, interacts continuously with the brain of a patient acceptance, and cost. A number of monkey, allowing continuous operation electrode technologies are in various during free behaviour and sleep. Future stages of development with wire bundles applications might include using NISs to and arrays being the simplest technology directly control a patient’s paralysed and most widespread type of implantable muscles (instead of an external device) electrodes. Microfabricated electrode where the normal pathway has been arrays (neural probes) are more complex damaged.

The Royal Society Brain Waves Module 1 I January 2011 I 35 but can be customised to meet specifi c direct implantation, and support experiment requirements to have a larger reasonably high brain-based control after ‘design space’. extensive user training. The games and toy industries have leapt into this area realising Technical developments are thus how such devices have captured the progressing that will allow for more public imagination. Early examples are complicated NISs to be stably implanted simple games where participants wear a that will record robustly and reliably for headset, focus on a small ball in a cylinder, many years from different brain areas at the and control the motion of the ball through same time. Wireless transmission of thought. More complex games have information is also a real possibility. In players move a tiny foam ball through a addition, developments in better mini–obstacle course using fans that cause understanding of ‘background’ brain activity the balls to rise. Both toys employ EEG (a may allow for more detailed control of the method of measuring brain activity behavioural output. Rather than controlling a through the scalp, see Section 2.1) and massless, virtual object or physical device utilise a wireless headset equipped with via a controller, it is important to develop sensors that read alpha and beta waves, NISs that can control a system that has relaying signals to the toys. physically realistic dynamics – early results for this are promising. Using more sophisticated developments in neurotechnology, a personal interface for Finally, NISs to date have largely relied upon human computer interaction has been visual feedback. However, incorporating developed by Emotiv. It is described by the other forms of sensory feedback will be company as ‘a high resolution, neuro-signal important, such as tactile and acquisition and processing wireless proprioceptive (sense of the body’s position neuroheadset that uses sensors to collect and movement) sensations. For example, data to detect player thoughts, feelings and an NIS might be able to (artifi cially) expressions and connects wirelessly to a stimulate muscles directly (via functional computer’. Emotiv claims: ‘you can use your electronic stimulation) and receive feedback thoughts, feeling, and emotion to from the body’s network of sensors that dynamically create color, music, and art; it provide proprioception. Or, during brings life changing applications for disabled movement, an NIS could stimulate the patients, such as controlling an electric areas of the brain that elicit tactile and wheelchair, mind-keyboard, or playing a proprioceptive experiences in individuals hands-free game; you can experience the where these are lacking. fantasy of controlling and infl uencing the virtual environment with your mind’. The headset can be linked to software Less / non-invasive NISs and applications by converting detected events extrapolation to the games and from ‘thoughts’ into any combination of toy industry keystrokes: For example, smile detection Non-invasive NISs use brain activity can be linked to characters such as ‘:)’, so recorded from the scalp rather than via that chat applications know when you smile.

36 I January 2011 I Brain Waves Module 1 The Royal Society Less invasive NISs can record from the Fetz E (1969) Operant conditioning of surface of the brain. This requires less cortical unit activity. Science, Vol 163, penetration of the brain than intracortical No 870, pp 955–958. recordings and has a higher spatial Hatsopoulos N and Donoghue J (2009) resolution than scalp based NISs, and The science of neural interface systems. other benefi ts including potential longer- Annual Review of Neuroscience, Vol 32, term stability than intracortical pp 249–266. recordings. Hochberg L, Serruya M, Friehs G, Mukand J, Saleh M, Caplan A, Branner A, Chen D, Conclusion Penn R and Donoghue J (2006) Neuronal NISs exist and are being developed at a ensemble control of prosthetic devices by rapid pace by both the industrial and a human with tetraplegia. Nature, Vol 442, academic sectors with wide-reaching No 7099, pp 164–171. application to basic science, clinical problems and the games and toy industry. Humphrey D, Schmidt E and Thompson W Extrapolation to other fi elds, for example (1970) Predicting measures of motor intelligence and defense agencies, will performance from multiple cortical spike occur in the coming years (see also Section trains. Science, Vol 170, No 959, pp 758– 3.2). At this point no legislation exists to 762. control their use, as in general, devices are Kipke D, Shain W, Buzski G, Fetz E, subject to considerably less stringent Henderson J, Hetke J and Schalk G (2008) approval systems than pharmaceuticals. Advanced neurotechnologies for chronic Nevertheless, the proven track-record of neural interfaces: new horizons and clinical many types of input NISs and early opportunities. Journal of Neuroscience, Vol indications with the more advanced output 28, No 46, pp 11830–11838. NISs suggest that potential benefi ts exceed the potential for ill-use and harm. Owen A, Coleman M, Boly M, Davis M, Laureys S and Pickard J (2006) Detecting awareness in the vegetative state. Science, References and further reading Vol 313, No 5792, p 1402. Cruse D and Owen A M (2010) Truccolo W, Hochberg L and Donoghue J Consciousness revealed: new insights into (2010) Collective dynamics in human and the vegetative and minimally conscious monkey sensorimotor cortex: predicting states. Current Opinion in Neurology, pp single neuron spikes. Nature Neuroscience, 656–660. Vol 13, No 1, pp 105–111.

Evarts E (1968) Relation of pyramidal tract Velliste M, Perel S, Spalding M, Whitford A activity to force exerted during voluntary and Schwartz A (2008) Cortical control of a movement. Journal of Neurophysiology, prosthetic arm for self-feeding. Nature, Vol Vol 31, No 1, pp 14–27. 453, pp 1098–1101.

The Royal Society Brain Waves Module 1 I January 2011 I 37 Box 3: Neural interface systems Professor Irene Tracey, University of Oxford

‘Input Neural Interface Systems (NIS)’ are now widely utilised in medicine. If we consider these input ‘neuroprostheses’ as falling into categories of sensory (eg auditory, visual), motor (eg bladder function), pain relieving (eg spinal cord stimulation) and cognitive (eg Alzheimer’s), it is clear there is widespread need and potential.

Cochlear implants, auditory brainstem implants and auditory midbrain implants are the three main types of auditory prostheses, with the fi rst cochlear implant dating back to 1957 and being the most successful of all three types. Unlike hearing aids that simply amplify sound to send it through the external ear, a cochlear implant has a microphone that receives sound from the external environment and sends it to a processor that digitises the sound, fi lters it into separate frequency bands and then sends these signals to the appropriate region in the cochlear corresponding to these frequencies. Estimates from 2006 suggest that over 100,000 are in use worldwide.

Likewise, a visual prosthesis creates a sense of an image by electrically stimulating nerve cells in the visual system. A small camera wirelessly transmits to an implant, which maps the image across an array of electrodes—stimulating over a thousand locations in the retina to create an image.

For pain relief, spinal cord stimulators are used to stimulate sensory cells in the spinal cord to produce a tingling sensation in the area of a patient’s, which provides pain relief. Again, they are increasingly implanted for intractable chronic pain.

Motor prosthetics are devices that support function of the autonomous nervous system, including an implant for bladder control whereby a device delivers intermittent stimulation which improves bladder emptying. Directly stimulating muscles (functional electrical stimulation) is another means whereby motor prosthetics are used to produce movement of a limb in patients with motor disabilities, and of course cardiac pacemakers would be another related example. Cognitive prostheses, which are discussed in more detail in Section 2.3, aim to restore cognitive function to patients with brain tissue loss due to injury, disease, or stroke by performing the function of the damaged tissue – this can be via ‘input’ NIS or ‘output’ NIS. An example of a common ‘input’ NIS in this domain would be deep brain stimulation for alleviation of Parkinson’s disease related symptoms.

In short, as these many devices become safer, and our understanding of how the brain works increases, our capacity to develop the devices we will see their use increase for the betterment of patients’ quality of life and well-being.

38 I January 2011 I Brain Waves Module 1 The Royal Society Box 4: Transcranial magnetic stimulation Professor Geraint Rees, University College London

Transcranial magnetic stimulation (TMS) is a brain stimulation technique that uses electromagnetic induction to induce weak electrical currents in the brain using a rapidly changing magnetic fi eld. A coil of wire enclosed in plastic is held close to the scalp over the brain area to be stimulated. When a current is passed through the coil, a magnetic fi eld is produced oriented at right angles to the plane of the coil. Magnetic fi elds pass through the scalp and skull and activate nerve cells in the part of the brain underlying the coil. The effect of this activation is to transiently disrupt the stimulated brain areas, and to produce activity in distant brain areas connected to the stimulated areas by neural connections (axons). TMS can both stimulate the underlying brain region to produce a muscle twitch and nullify brain activity by introducing ‘noise’. The effects of stimulation are temporary and there are no long- term side effects, though there is a very small risk of inducing an epileptic seizure during stimulation. This possibility is minimised through adherence to internationally agreed safety guidelines.

TMS belongs to a larger family of non-invasive brain stimulation technologies, including transcranial direct current stimulation (tDCS) where weak electrical currents are passed through the skull through attached electrodes to modulate the activity of neurons in the brain. All of these techniques are commonly used to investigate whether activity of neurons in a particular brain area is necessary for a particular function. If transient stimulation impairs a particular mental process or function, then it can be concluded that the stimulated brain area is causally necessary. TMS can be used to investigate the timing of mental processes, by showing that only stimulation at one particular time during a process is effective at causing disruption. This ability to investigate causality has made it a powerful tool complementary to neuroimaging techniques that are purely observational, and so cannot be used on their own to determine whether a brain area is necessary for behaviour (see Section 2.1).

This ability to change brain activity raises the question of whether TMS might also be capable of deliberately manipulating brain activity and therefore changing thought or behaviour (see Section 3.2). However, there are very signifi cant barriers to this that have not been overcome. While the fi ctional fi lm Eternal Sunshine of the Spotless Mind envisages a future in which a TMS-like device can selectively erase unwanted memories, in reality such memories (as with all thoughts, perceptions and actions) are encoded in the brain at a very fi ne spatial scale and interwoven with other neuronal representations. Because TMS and other techniques necessarily operate at a much coarser spatial scale they cannot effect such selective disruption, even if the desired pattern of neuronal representations was known. Moreover, the effects of these

The Royal Society Brain Waves Module 1 I January 2011 I 39 approaches are transient, lasting a few hundred milliseconds at most, and not permanent. Thus, while approaches to ‘brain reading’ show some ability to decode individual thoughts, perceptions and actions, there is no commensurate non-invasive technique available, either now or in the immediately foreseeable future, that will disrupt or change those patterns of activity selectively.

40 I January 2011 I Brain Waves Module 1 The Royal Society 2.4 A determinist view of brain, mind and consciousness

Professor Wolf Singer, Max Planck Institute for Brain Research, Frankfurt

Background according to a person’s experiences. Progress in brain research allows scientists During the initial development of the brain, to explore the way that the connections which in humans lasts until about the age between neurones in the brain (the of 20, the wiring of the brain undergoes ‘functional architecture’) guides higher major modifi cations and these depend on brain functions such as perception, environmental infl uences. At birth most of reasoning, decision-making, planning and the neurons are already present and have consciousness. These studies indicate that migrated to their fi nal position but many of mental functions are based on neuronal them are not connected yet. Many new processes in very much the same way as connections are formed only after birth and the many other behavioural functions that this outgrowth of connections continues are controlled by the brain. This view is in until adulthood. These newly formed confl ict with our intuitions and requires connections are maintained or reduced, reconsideration of a number of ethical guided by the activity of neurons, and by issues. This essay provides a determinist any external factors that affect neuronal view of behaviour and decision making that activity. Therefore, all interactions with the is not shared by all (see Section 3.3 and physical and socio-cultural environment Box 5). infl uence the fi nal layout of neuronal connections in the brain. These structural modifi cations are complemented by Implicit assumptions lifelong learning processes (which are In their efforts to understand the discussed further in Module 2 of the Brain organisation and function of the brain, Waves project, Neuroscience: implications neuroscientists make a number of for education and lifelong learning). It is assumptions that are taken for granted. For likely that this is a result of existing instance, they consider the nervous system connections being strengthened or to be a specialised organ whose structural weakened depending on use. In this way, and functional features depend on genetic there is ongoing brain modifi cation after and other factors in the same way as for the age of 20. other organs. The general layout of the various centres of the brain and of the The structure of the mature brain is connections among them is specifi ed by therefore determined by three processes: genetic instructions. However, to a much i) Genetic instructions that specify the greater extent than any other organ, the general lay out of the brain; properties of the brain can be modifi ed

The Royal Society Brain Waves Module 1 I January 2011 I 41 ii) Epigenetic shaping of connections that The evidence adapts the brain to its environment Observations suggest that the during development; development of complex nervous systems is the result of a continuous, self- iii) Lifelong adaptation in response to organizing process. Throughout experience. development, close correlations exist Neurobiologists assume that all functions between the maturation of distinct brain of the brain are determined by its structures and the emergence of particular structure and the connections between brain functions. The behaviour of simple neurons (known as the ‘functional organisms can be fully accounted for by architecture’ of the brain). In contrast to the functions of their neuronal networks; the situation for computers, in which and the same is likely to be true for more different hardware components are complex organisms. reserved for different operations such as storage of data and computations, all The close relationship between the functions of the brain are realised by function of brain structures and mental widely distributed networks of neurons phenomena has been demonstrated in and uniquely determined by the functional clinical studies by the loss of specifi c architecture of these connections. This functions after structural damage. More defi nes the fl ow of signals and the recently non-invasive imaging technologies structure of the complex activity patterns (see Section 2.1) have provided that are the basis of brain functions. overwhelming evidence that even our These include not only basic functions most ‘private’ thoughts, decisions and such as the ability to perceive, remember, emotions are preceded by the activation of and act but also higher functions such as defi ned networks of neurons (Frith and the ability to decide, control attention, Frith 2010; Frith and Rees 2004). generate emotions and fi nally to It follows that both subconscious and understand and generate speech, to conscious processes are the result of consciously deliberate and to be aware of neuronal interactions. Our perceptions, oneself as an independent, autonomous emotions, decisions, plans, thoughts, and intentional agent. It follows from this arguments, and value assignments are view that mental phenomena are the shaped by sequences of neuronal states consequence and not the cause of that are causally linked. neuronal interactions. A thought or a decision is the result of preceding computations and therefore cannot per se Conscious versus unconscious infl uence the functioning of neuronal processing networks. The future dynamics of These causally linked brain processes neuronal networks are infl uenced by the determine which of our many mental neuronal activity patterns that underlie the contents actually reach consciousness. thoughts and decisions. Evidence indicates that we are aware of

42 I January 2011 I Brain Waves Module 1 The Royal Society only a tiny fraction of the neuronal that infl uence neuronal activity. One activities that guide and control our decisive condition is the specifi c functional behaviour. Some signals are always architecture of the brain, which varies from excluded from conscious processing, such individual to individual because of as those involved in controlling blood differences in genetic dispositions, glucose levels and kidney function. The developmental imprinting, and experience. same is true for implicit knowledge that The other relevant condition is the determines how we perceive, decide and activation state preceding the moment of react, which we use without being aware decision making. Activation patterns that of the fact that we have it. It is contained in have access to consciousness are the layout of the brain’s functional subjectively experienced as causes or architecture, which in turn is mostly arguments and can therefore be quoted as determined through genetics and shaped reasons for a particular decision. We say during early development without ‘we have decided in this way because . . . conscious control. ‘and then we give the reasons that we are consciously aware of. However, much of In contrast to this implicit knowledge, the activity that actually prepared and knowledge acquired by learning has determined the decision process escapes access to consciousness and can therefore conscious recollection. be subject to conscious deliberation. However, the number of items that can be Imaging studies indicate that there is held simultaneously in consciousness is sometimes a clear dissociation between limited and it is not possible to retrieve the onset of neuronal activity patterns that them ‘at will’. Everybody is familiar with fi nally result in the decision to move a the problem of not being able to recall fi nger and the moment when subjects names or situations that have previous become aware of their intention (Moser been well remembered. et al. 2010; Soon et al. 2008). After having been identifi ed with functional magnetic resonance imaging (fMRI) the neuronal Wrong intuitions activation patterns associated with the The evidence described above contradicts voluntary act to press a key with either the our intuition that we can always freely right or the left hand, subjects are asked to decide what we are going to do next and perform freely paced key presses while which factors we are going to consider their brain activity is measured. In this case when we plan future acts. If mental the onset of activation patterns predicting processes are the consequence of a right or a left hand press can precede by neuronal processes then decisions are the up to ten seconds the subjects’ awareness result of self-organizing neuronal of having decided to press. processes that converge towards the most In this experiment, the instruction is stored probable stable state in the given in working memory, and the motor act (the conditions. These conditions usually key press) is prepared before the subjects comprise a very large number of variables

The Royal Society Brain Waves Module 1 I January 2011 I 43 become aware of what they are going to also Section 2.5). One line of evidence do next. Here, the ‘intention’ is concordant suggests that evidence is accumulated with the action. However, there are also until a particular threshold is reached, and conditions where the real causes of an a decision is then made (Shadlen et al. action dissociate from the reported 2008). This correlates to an increase of intentions. For instance, subjects can be activity in neural circuits representing the instructed to perform a particular action different stimuli. The circuit with the without being aware of having been fastest rise in activity will reach the instructed. When subjects that comply threshold soonest. A different, related are asked why they performed the action, model suggests that decisions are the they reply as if they intended to do so result of competitive interactions between (eg ‘I decided to do this because I wanted neuronal networks representing different to . . ..’). In this case the reported reasons options. This model rests primarily on for a particular action do not match the real behavioural experiments and requires reason, but are experienced as if they had further neurobiological examination been at the origin of the performed action. (Keysers et al. 2008 ). It is likely that most These examples illustrate impressively that of these decision processes do not require only a fraction of the neuronal processes conscious deliberation, or conscious that prepare decisions and guide behaviour recollection of the variables involved). have access to conscious recollection and Conscious decision making appears to that neurobiological processes precede the follow different rules. As consciousness awareness of having reached a decision. has a limited capacity, only a small number of variables can be dealt with. This requires the contents of declarative memory Differences between unconscious (memory that can be recalled) to be and conscious decisions scrutinised sequentially, which takes time. Intuition tells us that there is a difference Moreover, this rational strategy can result between being able consciously to weigh in well adapted solutions only if the arguments and then decide what to do, variables involved are suffi ciently reliable. and acting spontaneously without For most decisions reached in this latter refl ecting consciously different arguments way subjects can correctly report the and possible consequences. This is not relevant arguments. necessarily contradicted by what we know about subconscious processing as Decision processes occurring without described in the section above. The rules conscious deliberations seem to be less governing subconscious and conscious constrained. They can exploit the rich decisions differ (Engel and Singer 2008; database of subconscious heuristics Dehaene 2008). The neuronal mechanisms (problem solving) and therefore can underlying decision making are the subject process many more variables in parallel of intense research and likely to differ and cope better with unreliable and ‘noisy’ depending on the task being done (see variables. Often, these subconscious

44 I January 2011 I Brain Waves Module 1 The Royal Society processes lead to more adapted responses processes are essentially linear. As than the conscious deliberations, in linear processes cannot account for the particular if there is little time for the processes that we ascribe to ourselves and preparation of a decision, if multiple others, we postulate the existence of an interdependent variables have to be intentional agent that is not fully considered simultaneously and if the determined by the neuronal machinery. reliability of these variables is low. Linear deterministic systems behave like reliable clocks. They cannot self-organise, Usually, subconscious decisions result in cannot be creative and their future immediate action. However, they may also behaviour is fully determined by initial be inhibited by simultaneously occurring conditions. Their trajectories can only be conscious deliberations. In this case the changed by external forces. In contrast, we solutions presented by the subconscious experience ourselves and others as and conscious decision mechanisms need creative, and able to take new courses not be congruent. We experience this without perceivable external infl uences. dissociation when we say that we have However, if one accepts that the brain is a decided after having carefully scrutinised complex self-organizing system with non- all arguments but that the outcome linear dynamics, an independent somehow does not feel right. Vice versa intentional agent is dispensable. All certain decisions are felt to be absolutely characteristics attributed to such an agent right even though they are considered are emergent properties of non-linear, self- entirely irrational. Thus, both the organizing systems, such as the brain. subconscious and the conscious decision mechanisms are equally relevant in determining future behaviour. Both are Potential consequences for our based on neuronal processes that infl uence in a causal way future states of legal systems The neurobiological evidence reviewed the brain but they follow somewhat above is incompatible with the view that a different rules. person, at the moment of having reached a decision, could have decided otherwise. Why is intuition in confl ict with However, this assumption is said to be at the base of our legal systems and the neurobiological evidence? justifi cation for attributing responsibility to We tend to feel that there is an agent in a person and sanctioning deviant our brain that is at any time free to make a behaviour. Consequently, it could be decision that overrides that of the argued that if this premise is false, persons deterministic neuronal machinery. There are not responsible for their actions and are at least two reasons for this. First, we therefore exempt from sanctions. The are only aware of the results of the original assumption implies a separation neuronal processes in our brain, and not of between an intentional agent (the person) the mechanisms of these processes. and the mechanics of the nervous system Second, we tend to assume that these

The Royal Society Brain Waves Module 1 I January 2011 I 45 that are required for the execution of the much more severe, even though the agent’s orders. What would be the deviant behaviour, the ‘subjective guilt’, consequences if one abandoned this was exactly the same. traditional dualist approach and adhered to the interpretations suggested to us by modern neuroscience? Would this require a Attenuating conditions change of legal practices or only a revision What light does neurobiological evidence of the interpretation of deviant behaviour? shed on the attribution of mitigating These issues, and others discussed below, neurological factors? It is unlikely that this will be considered as part of Module 4 of would change anything if the purpose is to the Brain Waves project on neuroscience, fi nd out how likely it is that anyone else responsibility and the law. would have done the same thing in the same circumstances. To determine this, it The view that a person is responsible for would be necessary to examine the what she or he does (meaning that they options available at the moment of the are the causal agent) is not invalidated by decision, and the extent to which the neurobiological evidence, because all subject was able to fully exploit the brain authorship remains with the deciding and mechanisms required for reaching the acting person. How about the measures decision. This comprises evaluation of taken to prevent deviant behaviour or to dependencies from external pressure, from protect society from harm? Should they be internal constraints such as addictions or modifi ed in view of the evidence that the compulsory drives, the time available for a delinquent, in the moment of his or her decision and the ability to rely not only on action was unable to decide otherwise? subconscious heuristics but also on conscious deliberations. Conscious deliberation is attributed particular Punishment and confi nement signifi cance because most of the social Punishment is an evidence-based means imperatives that have been acquired of prevention because of its educative and through education are amenable to deterrent effect. Constraining freedom is conscious processing. likely to remain as a means of protecting others. Punishment also seems to fulfi l a Viewed from a neurobiological perspective, second function, in satisfying the human this does not assume anything about ‘free need for justice. Legal systems do not will’ because it only examines how far the seem to only sanction the amplitude of behavioural dispositions or character traits deviance but also the severity of the of a person exhibiting deviant behaviour consequences of deviant behaviour. differ from the normal distribution. If most Crossing a red light without causing an of the human beings raised in a particular accident may lead to a temporary loss of cultural context would have acted in the the driver’s license. However, if the same way given the conditions, sanctions consequence is a severe accident with are moderate because attenuating factors casualties, the punishment tends to be will prevail. In contrast, if the conclusion is

46 I January 2011 I Brain Waves Module 1 The Royal Society that under the given circumstances the imperatives get stored, or they may have deviant behaviour has to be considered as led to abnormally weak control extremely far from the norm, sanctions are mechanisms for the inhibition of actions. usually drastic. The same abnormalities may have been caused by developmental mishaps, Brain research posits that behavioural insuffi cient installation of moral imperatives dispositions, character traits and the through education, or defi cient inhibitory decision mechanisms available to a person mechanisms due to lack of training during are determined by the functional brain maturation. If all these features of the architecture of the person’s brain. Is it then functional architecture are actually in the that legal systems in practice evaluate the normal range, then one would have to extent to which the functional architecture assume temporary abnormalities in the of a law breaker’s brain deviates from the system’s dynamics, for instance caused by normal distribution and adjusts sanctions metabolic disturbances, or by some highly accordingly? If this were a commonly unlikely but still possible deviations of the accepted stance, would it interfere much brain’s dynamics. with the common practice of sanctioning deviant behaviour or would it only lead to a Even though none of these abnormalities more empathic attitude towards persons are detectable with currently available who happen to end up at the negative tail methods this does not detract from the of the normal distribution? conclusion that there must have been a neuronal cause for the deviant behaviour The following simple thought experiment is whatever its exact nature. Thus, members meant to illustrate this point. If a person of our society who had the misfortune to has committed what is considered to be possess a brain which ended up at the cold blooded murder in order to obtain negative end of a normal distribution some benefi t and a tumour is discovered in should have our empathy. But does this his frontal lobe, extenuating conditions may exempt our society from its duty to protect be granted. One might argue that this all its members and to defi ne what is tumour disrupted the pathways that link tolerable and what is not? the storage site of moral values with the inhibitory centres that would normally prevent the fatal action. From a References and further reading neurobiological point of view, however, one Engel C and Singer W (Eds) (2008) Better might argue that any person capable of than Conscious? Decision Making, the committing such a crime must always have Human Mind, and Implications for some abnormalities in the functional Institutions. Strüngmann Forum Reports. architecture of his or her brain, even if this Cambridge, MA: MIT Press. abnormality is not detectable with current technologies. Genetic dispositions could Frith U and Frith C (2010) The social brain: have limited the storage capacity of the allowing humans to boldly go where no networks in which moral values and other species has been. Philosophical

The Royal Society Brain Waves Module 1 I January 2011 I 47 Transactions of the Royal Society B, Vol Moser E, Corbetta M, Desimone R, 365, No 1537, pp 165–176. Frégnac Y, Fries P, Graybiel A, Haynes J, Itti L, Melloni L, Monyer H, Singer W, von Frith C and Rees G (2004) Brain Imaging: der Malsburg C and Wilson M (2010) The Neural Correlates of Consciousness. Coordination in brain systems. In: Von der Oxford: Oxford University Press. Malsburg C, Phillips W and Singer W Dehaene S (2008) Conscious and (Eds). Dynamic Coordination in the Brain. nonconscious processes: Distinct forms of From Neurons to Mind. Strüngmann evidence accumulation? In: Engel C and Forum Reports. Cambridge, MA: MIT Singer W (Eds) Better than Conscious? Press, pp 193–214. Decision Making, the Human Mind, and Shadlen M, Kiani R, Hanks T and Implications for Institutions. Strüngmann Churchland A (2008) Neurobiology of Forum Reports. Cambridge, MA: MIT decision making: An intentional Press, pp 21–49. framework. In: Engel C and Singer W (Eds) Keysers C, Boyd R, Cohen J, Donald M, Better than Conscious? Decision Making, Güth W, Johnson E, Kurzban R, Schooler L, the Human Mind, and Implications for Schooler J, Spelke E and Trommershäuser J Institutions. Strüngmann Forum Reports. (2008) Explicit and implicit strategies in Cambridge, MA: MIT Press, pp 71–101. decision making. In: Engel C and Singer W Soon C, Brass M, Heinze H and Haynes J (Eds) Better than Conscious? Decision (2008) Unconscious determinants of free Making, the Human Mind, and Implications decisions in the human brain. Nature for Institutions. Strüngmann Forum Reports. Neuroscience, Vol 11, pp 543–545. Cambridge, MA: MIT Press, pp 225–258.

48 I January 2011 I Brain Waves Module 1 The Royal Society Box 5: The biological becomes personal: philosophical problems in neuroscience Dr Sarah Chan and Professor John Harris, University of Manchester

Early historical beliefs notwithstanding, we recognise the brain as fundamental to shaping who we are, our personality and personal identity. Consider the still- hypothetical prospect of whole-brain transplantation: most people would probably regard this as whole-body transplantation (and not as a brain transplant). Nevertheless, and despite modern scientifi c understanding of the brain, the philosophical relationship between brain, body, mind and identity remains elusive.

The inherently problematic nature of this can be explored through two related but conceptually distinct questions: ‘Am I my mind?’, and ‘Is my mind my brain?’ Clearly, ‘we’ are not just our brains or our minds: our sense of identity is closely associated with our physical bodies; our experience of the world, though expressed in one form as brain activity, necessarily includes the phenomenon of embodiment. Equally, however, the brain-transplant thought experiment illustrates that selfhood is not solely attached to the body. This is refl ected in social and clinical attitudes towards ‘brain death’ and current philosophical thinking on ‘personhood’ (Radin 1982; Harris 1985). But are we then embodied minds—a mind within a body—or is embodiment itself an essential element of mind? Moreover the relationship between the physical and mental properties of the human organism is philosophically problematic. Neurobiology attempts to explain mental processes and the workings of the mind in terms of physical neuronal processes in the brain. But is mind (mental) merely a property of brain (physical); can all mental states be reduced to physical phenomena? Against such reductionist approaches, we might argue that mental states are not simply physical phenomena, any more than a poem is simply words on a page (see also Section 2.4).

The mind-body problem has been the subject of extensive philosophical inquiry since long before the brain was recognised as the organ responsible for thought. Yet although we can now relate states of mind to physical ‘states of brain’, that does not resolve the fundamental philosophical questions (Ryle 1969).

Despite the perhaps inextricable entanglement of our physical, mental and psychological natures, it is evident that much of what we see as our ‘selfness’ is brain- dependent. This raises, however, further questions that assume new signifi cance in light of neuroscience. For example, am I still the same person when my brain changes—through injury or disease, the infl uence of drugs or surgery, or simply experiences and the passing of time? Again, we may now be able to observe, understand, and even affect the physiological basis of these changes more directly.

The Royal Society Brain Waves Module 1 I January 2011 I 49 However, this provides no simple answers to such questions but throws them into sharper relief.

The idea that mind and self have biological foundations has profound implications for our understanding of free will and responsibility. If all our desires and impulses to act can be reduced to neurochemistry, how can ‘we’ be responsible for our actions or choices? Studies showing that decisions manifest physically in the brain even before one is consciously aware of the decision being made, for example, throw into question our usual assumption that it is the conscious mind that exercises free will. And if we do not have free will, if our brains are deciding for us, then can we truly be responsible for our actions? Responsibility implies volition and intention, not just causation; there is a difference between doing something intentionally and unintentionally, yet both involve causation and consequences and both have correlated brain states. The origin and explanation of free will and of intent, however, remain open to debate (see also Section 2.4).

This applies not only to our everyday understanding of moral responsibility but also to the concept of legal responsibility. When we hear the defence ‘My brain made me do it’, how should we respond? Neuroscience may radically change our concept of criminal and legal responsibility, and the way we react to wrongdoing (Greely 2006). This topic will be explored in Module 4 of the Brain Waves project on responsibility and the law.

References and further reading Dennett D (1969) Content and Consciousness. London: Routledge.

Greely H, The Social Effects of Advances in Neuroscience: legal problems, legal perspectives. In: Illes J (ed), Neuroethics: Defi ning the Issues in Theory, Practice and Policy. Oxford: Oxford University Press.

Harris J (1985) The Value of Life. London: Routledge.

Radin M (1982) Property and Personhood. Stanford Law Review, Vol 34, p 957.

Ryle G (1969) The Concept of Mind. London: Hutchinson.

50 I January 2011 I Brain Waves Module 1 The Royal Society 2.5 Reward, decision-making and neuroeconomics

Professor Wolfram Schultz FRS, University of Cambridge

Background engage positive emotions such as joy, and Recent work in behavioural neuroscience produce hedonic feelings. Rewards has examined how humans and animals support elementary processes such as make economic decisions about gains and eating, drinking and sex, and engage losses. This research is based conceptually individuals in such diverse behaviours as on animal learning theory and economic novelty seeking, foraging, trading on stock choice theory. It investigates how markets and social interactions. By individual neurons in animals and brain contrast, punishments have largely regions in humans process information opposite effects to rewards, inducing about gains (rewards) and losses avoidance learning, negative emotions (punishments) and use this information to such as fear, and feelings of displeasure. make economic choices. As animal work Obtaining rewards and avoiding forms an important part of this research, punishments is crucial for individual and investigations are more frequently directed gene survival. at reward than punishment. The fi eld also incorporates data from brain lesions and pharmacological Aims of neuroeconomics: manipulations of neurotransmitters. perspective of neuroscience The term ‘neuroeconomics’ refers to The neuroscientist wants to know how the the neurobiological basis of economic brain works, notably how it organises the decision making. It combines economic behaviour that is crucial for the survival of choice theory with neuroscience in the organism and its genes. What does the order to understand the neuronal basis neuroscientist expect from for economic decisions. For review neuroeconomics? articles see Glimcher et al. 2008 and Schultz 2008. Theoretical concepts The functions of rewarding and punishing Economic choice theory provides outcomes are not defi ned by specifi c important defi nitions of decision variables sensory receptors but are inferred from and valid decision models. A decision their infl uence on behaviour. Rewards are process can be broken down into its objects or events that induce approach different components, which is essential learning (positive reinforcement in animal for designing well controlled behavioural learning theory), serve as arguments for tasks. The impact of rewards and economic (value-related) decisions,

The Royal Society Brain Waves Module 1 I January 2011 I 51 punishments is quantifi ed by gains and Aims of neuroeconomics: losses in subjective value, called utility, perspective of economics which can be assessed by revealed choice The behavioural economist wants to know preferences. In general, outcomes are how humans make economic decisions in variable and uncertain. Outcomes are order to survive best in a competitive therefore adequately described by world with limited resources. The recent probability distributions, which are fi nancial crisis has shown that many characterised by their expected value and aspects of everyday life and world risk. ‘Risk’ refers to the uncertainty of the economics depend on the risk-taking outcome, rather than simply the chance of behaviour of a few individuals. What does losing. The term ‘ambiguity’ denotes the economist expect from uncertainty when probability distributions neuroeconomics? are incompletely known. Risk and ambiguity infl uence decision making by impacting on the subjective value of risky Biological plausibility outcomes. Behavioural economics has established theoretical concepts for individual decision making. Identifi cation of neuronal signals Behavioural tools for particular theoretical decision variables Economics has developed behavioural and would demonstrate its biological analytic tools to assess crucial components plausibility, inform decision models, allow of choice behaviour. Examples are the deconstruction of whole decision following: processes and identify crucial steps that • the Pest procedure (Parameter might possibly go wrong. estimation by sequential testing) assesses values of unknown relative to known outcomes; Identifying brain states related to suboptimal decision making • the defi nition of subjective value by Controlled, quantitative assessments of Expected Utility Theory; anomalies in decision making may help to • the impact of risk on outcome characterise patterns of inconsistent, valuation and choices; suboptimal, ‘irrational’ choices. Such choices may constitute normal biological • the weighting of outcome probabilities, phenomena that may not be easily loss aversion and reference dependent changed without explicit policies. coding by Prospect Theory; Suboptimal choices would become more • the role of past experience in updating understandable if physical, neurobiological, predictions of outcomes; and correlates were found. • the identifi cation of ‘irrational’ choices Reward systems show subjective rather of suboptimal outcomes. than objective value coding. Nevertheless,

52 I January 2011 I Brain Waves Module 1 The Royal Society humans tend to make irrational choices, particular in situations for which our brains which do not maximise the expected have not (yet) evolved. monetary utility of the outcome. Such irrational behaviour is observed often when emotions are involved. For instance, in the Current state of neuroeconomic ultimatum game, one player proposes how research: how the factors that to divide a given amount of money. The infl uence decisions are second player either accepts the offer and represented in the brain both players get their share, or rejects it The neuroeconomic investigation of reward and both players receive nothing. Rejection and punishment is based on the of any non-zero offer in this game is understanding that outcomes are defi ned economically irrational; it is attributed to by their value and by the risk with which the sense of or outrage. Receiving fair they occur (see Schultz 2006). The brain’s offers activates the insular and prefrontal reward (or gain) system includes the cortex, suggesting a neurobiological dopamine system, orbitofrontal cortex, correlate for this emotion. Future striatum, amygdala and other cortical and economic theory might attribute an subcortical structures in the brain. economic value to this emotion and Punishment (or loss) is processed in similar generate new value functions with which structures, with the exception of the choices involving emotions can become dopamine system which is concerned optimal and thus ‘rational’. In this way, more with reward than punishment (see neuroeconomics may lead to new also Section 2.2). normative theories that provide valid explanations of consistent choices across a wider range of human and animal choice Value behaviour than current utility and prospect The value of a particular outcome depends theory. on the type of outcome, its magnitude and its probability. Reward neurons code We assume that brains evolved to assure reward value by graded fi ring, increasing the survival of genes and their carriers in or decreasing activity. Later rewards, most situations. Assuring survival in all which are subjectively valued less possible, however unlikely, situations (temporal discounting), induce lower value would require extra brain matter and responses, suggesting subjective rather function that would make brains less than objective value coding. Neurons code effi cient and their carriers less value relative to explicit references in all competitive. The existence of visual major reward structures. This neuronal illusions demonstrates the boundaries property may underlie reference- imposed by such effi ciency principles. dependent reward valuation which is a Even with new normative theories of central tenet of prospect theory. Prefrontal economic decision making, exceptional value responses show distorted responses circumstances may remain in which to reward probability in line with prospect economic choices will be inadequate, in theory.

The Royal Society Brain Waves Module 1 I January 2011 I 53 Risk and ambiguity options are represented in the brain. These Reward neurons encode risk separately studies are based on a number of theories from value (see Schultz et al. 2008). (see also Section 2.4), for example: Prefrontal risk signals differ between risk avoiders and risk takers. Risk reduces value signals in risk avoiders and increases Reinforcement learning theory value signals in risk takers. Thus, individual The ultimate behavioural consequence of a risk attitudes may refl ect variations of decision is an action. Each possible action prefrontal function. Some neuronal leads to a particular outcome which has responses are stronger for ambiguity specifi c value, and the action leading to (uncertainty of an outcome when the the highest value is selected. Neurons probability of distribution of its occurrence track the outcome values of the individual is not known) than for risk. actions (‘action value’). Rational decision makers select the action producing the highest action value. This action is the Predictive learning result of a competition between neurons Predictions contain information about the carrying different action values. value and risk of future outcomes and are necessary for making informed decisions. Theories of evidence accumulation Neurons in all reward respond to stimuli Neuronal activity in parietal and frontal that predict reward value, and some cortex develops gradually as evidence neurons respond to stimuli that predict about the values of the available options risk. Predictions are acquired and updated accumulates. So-called diffusion-race through experience when the actual models conceptualise how the fi rst option outcome differs from the predicted reaching a threshold is chosen (see Gold outcome (prediction error). Dopamine and Shadlen 2007). neurons signal prediction errors for reward value during learning. The insular cortex signals prediction errors for risk. Current state of neuroeconomic research: social decisions Current state of neuroeconomic One of the great promises of neuroeconomics is the use of formal tests research: how one possible for studying neuronal processes underlying action is selected from multiple social interactions, including the role of options emotions in decision making. We decide what to do in a particular situation by assessing the relative values of different responses. Current work in Apes and monkeys neuroscience aims to determine the way in Behavioural work on nonhuman primates which the different variables and choice identifi es ‘rational’ maximisation without

54 I January 2011 I Brain Waves Module 1 The Royal Society regard for others in the ultimatum game. • Dictator game: The player splits a Neurophysiological work on monkeys uses received endowment with another economic games against computer player. The game tests fairness and opponents, showing activity related to aversion to inequity; subjective preferences and past actions • Ultimatum game (described above): and rewards. However, the extent to The game tests fairness, inequity which monkeys perceive such games as a aversion and outrage; social activity is unclear. Ongoing neurophysiological work on interacting • Trust game: The amount of money one monkeys investigates basic processes player gives to another player is such as video game competition and multiplied by the experimenter. The reward observation. other player gives back an amount which is multiplied again, and so forth. The game tests trust, reciprocation, Outcome observation in humans cooperation and fairness; Human social economic neuroimaging • Prisoner’s dilemma: Rewards are studies employ straightforward situations assigned to two players depending on such as observation of reward and their cooperation with each other. If punishment received by others. For the fi rst player cooperates but the example: second player ‘betrays’ his/her, the fi rst • The effect of reward on the striatum is player receives the worst possible relative on the reward received by outcome and the second player the others; best, thus tempting the second player. If both cooperate or both betray each • Seeing another person making errors other, they receive intermediate in predicting a reward whilst learning outcomes, which are higher for the same task activates the striatum; cooperation than betrayal. The game • Observing another person receiving tests cooperation against defection painful stimuli activates a neuronal and self-interest: correlate for empathy in the cingulate • Public goods game. Players can put and insular cortex; goods into a pot to be split between • Following the behaviour of others in the group. The game tests prosocial the valuation of outcomes activates the attitude, cooperation, altruism and striatum. defection. Several brain activations are observed in such studies (see Frith and Singer 2008). Games in humans Many socially and emotionally positive Human studies often use formal economic situations activate the brain’s reward games to standardise and measure system, including fairness in the ultimatum emotions. The most popular tools are: game; cooperation in prisoner’s dilemma;

The Royal Society Brain Waves Module 1 I January 2011 I 55 reciprocation and intention to trust in the appalling murder or terrorism) can be trust game; and altruistic punishment of overvalued in the brain (the rewarding players who were uncooperative in the nature of novelty), a factor that might trust or prisoner’s dilemma game. contribute to resources being diverted Donations to charities activate the from issues that affect the majority of the striatum, despite one’s own money loss. population. Activations in the amygdala correlate with The encouraging news is that social the trustworthiness of faces (see Figure 4); cooperation activates the reward centres correspondingly, lesions of the amygdala of the brain that are involved in plasticity reduce the recognition of trustworthiness and learning. As we understand more of faces. Many aversive situations activate about the processing of reward in the the brain’s punishment system in the brain, it may be possible to infl uence our anterior cingulate and insula, including own brains and those of future generations receiving unfair and likely unacceptable to reward the things that are actually offers in the ultimatum game. In line with rational for us in the longer term. its cognitive control functions in behaviour, the prefrontal cortex is activated when unfair offers in the ultimatum game are Individual variations in how our brains rejected. process reward Variations in brain function across individuals appear inevitable given the Policy questions complex nature of the brain. As our Neuroeconomics is starting to uncover the understanding of individual neurobiological basis for the properties of neurobiological variations in reward economic valuations and decisions. In processing (both natural and pathological) some cases, these valuations lead to daily increases, we can unpack the economic choices that could be disadvantageous to consequences of these variations. Early individuals and society. By increasing our indications highlight possible roles for this understanding of these processes we may variation in reward processing in very be able to fi nd means to avoid their diverse areas: detrimental consequences. • risk avoidance and anxiety disorders; We know that certain reward values are coded ‘inaccurately’ in the brain. For • risk seeking (an area where the example, we know that the reward behaviour of a few individuals may processes in the striatum tend to discount impact economically on the majority); the values of future rewards (temporal • obesity; value discounting). This may be a factor that leads us to invest less in provisions for • drug addiction (both pathological the future (such as education, healthcare infl uences of drugs on reward signals or pensions) than we ‘should’ do. Similarly, and natural variation); and events of low probability (such as an • gambling.

56 I January 2011 I Brain Waves Module 1 The Royal Society Figure 4 When you recognize a familiar face the parts of the brain highlighted in orange on this functional magnetic resonance image (fMRI) light up. In this case ‘lighting up’ means there is increased blood fl ow to the areas that are working hardest. Functional MRI allows these regions to be visualized. They can then be superimposed onto a 3D reconstruction of the brain to get a precise picture of the location of those regions. (Reproduced courtesy of Mark Lythgoe and Chloe Hutton, University College London.)

Neuromarketing In addition, a recent study on wine tasting A practical application of neuroeconomics shows that the same wine elicits a concerns consumer behaviour. Demand stronger reward value signal when its price for goods can be infl uenced by several information is infl ated. These data suggest factors, many of which impact on the a neurobiological basis for the infl uence of reward system of the brain. Neurons in all external infl uences such as pricing on reward structures respond to stimuli that subjective valuation. Furthermore, studies predict rewards, and these can be show that the brain values rewards relative conditioned in a Pavlovian manner without to external references, such as the current the active participation of the subject. For economic situation and the rewards of example, reward predictions stimulate social partners. This may explain in part dopamine neurons, and the stimulation of why the wealthy are not necessarily any dopamine neurons in rats induces happier than those less well off. approach behaviour and learning. Understanding more about these reward predictive stimuli could help us appreciate References and further reading the biological foundations of individual Frith C and Singer T (2008) The role of consumer behaviour and perhaps even social cognition in decision making. intervene when this behaviour becomes Philosophical Transactions of the Royal detrimental. Society B, Vol 363, pp 3875–3886.

The Royal Society Brain Waves Module 1 I January 2011 I 57 Glimcher P, Caterer C, Fehr E and Schultz W (2008) Neuroeconomics. Poldrack R (2008) Neuroeconomics: Philosophical Transactions of the Royal Decision making and the brain. London: Society B, Vol 363, pp 3765–3886. Academic Press. Schultz W, Preuschoff K, Camerer C, Gold J and Shadlen M (2007) The neural Hsu M, Fiorillo C, Tobler P and Bossaerts basis of decision making. Annual Review of P (2008) Explicit neural signals refl ecting Neuroscience, Vol 30, pp 535–574. reward uncertainty. Philosophical Transactions of the Royal Society B, Schultz W (2006) Behavioral theories and Vol 363, pp 3801–3811. the neurophysiology of reward. Annual Review of Psychology, Vol 57, pp 87–115.

58 I January 2011 I Brain Waves Module 1 The Royal Society 3 Neuroscience and society

The Royal Society Brain Waves Module 1 I January 2011 I 59 60 I January 2011 I Brain Waves Module 1 The Royal Society 3.1 Benefi ts and opportunities

Professor Barbara J Sahakian, University of Cambridge

Background children to learn in schools. This will lead Neuroscience is of growing importance in to evidence-based programmes of the 21st century given the rapid individualised or personalised learning. technological advances in this area and This area, termed ‘educational their impact on society. For example, neuroscience’, is addressed in depth in neuroscience is critical to the Module 2 of the Brain Waves project, understanding of the brain in health and Neuroscience: implications for education disease and in developing more accurate and lifelong learning. diagnosis and new treatments across the Other areas of neuroscience too will fl ourish, lifespan. To illustrate, cognitive training including those that intersect with social treatments are under development for sciences and genetics, such as studies on disorders such as attention defi cit whether, and under what conditions, we hyperactivity disorder (ADHD) (see choose prosocial over antisocial or non- Figure 5) and substance abuse, and drugs cooperative behaviour. The intersection of that protect the nervous system from neuroscience with information technology degradation are being developed for will expand and further develop, including Alzheimer’s disease. Recent innovative neural interface systems, neuroprosthetics proof of concept studies for drugs such as and functional Magnetic Resonance ketamine and scopolamine suggest that it Imaging (fMRI) feedback (see Sections 2.1, might be possible to treat patients for 2.3 and Box 3). depression effectively and very rapidly. Deep brain stimulation is another area For neuropsychiatric disorders and also for which continues to develop rapidly for brain injury, cognitive enhancing drugs are treatment for neuropsychiatric disorders, being used and further developed to including depression, obsessive improve functional outcome, quality of life compulsive disorder and Parkinson’s and wellbeing (see also Section 2.2 and disease. This involves surgically implanting Box 2). This area of research in a medical device that stimulates specifi c neuroscience raises important neuroethical parts of the brain. Similarly, stem cell issues, such as the increasing use of so- research applied to the treatment of called ‘lifestyle drugs’ including ‘smart neuropsychiatric disorders continues to drugs’ by healthy people. The neuroethics progress (see Section 2.3 and Box 4). of this and other areas is discussed in more detail in Section 3.3 (see also Section 3.2).

During the next decade, there will be Application to policy marked advances in the use of Certain areas of neuroscience will be neuroscience in education in helping important for public health policy. For

The Royal Society Brain Waves Module 1 I January 2011 I 61 Figure 5 This image shows a) in green: major white matter tracts generated from a population of 32 subjects-16 healthy volunteers and 16 adult patients with attention defi cit/ hyperactivity disorder (ADHD) b) in red: regions where these tracts were found to be abnormal in ADHD patients compared to controls and c) in yellow: regions of reduced white matter density in ADHD patients compared to controls. A, b and c are overlaid on a high resolution brain template acquired with magnetic resonance imaging (MRI). (Reproduced courtesy of Natalia del Campo, University of Cambridge.)

example, early deprivation and poverty, in interaction with genetic predisposition, are key factors in future mental health problems. Interventions are needed to counteract the effects of these factors. It is essential to develop the brain’s resilience to damage by promoting mental as well as physical health from an early age. It is also important to stress that certain behaviours have positive impacts on both mental and physical health, and these behaviours should be promoted accordingly. For instance, exercise stimulates the prevented, while others could be treated development of nerve tissue in some effectively before they develop a chronic, regions of the brain (Olson et al. 2006). relapsing or progressive course. Furthermore, new insights into underlying Another example is the importance of early mechanisms, coupled with the use of detection and treatment, as well as the more selective cohorts in clinical trials, is need for new treatments, for essential for the development of effective neuropsychiatric disorders, such as drugs in Alzheimer’s disease. depression and Alzheimer’s disease. For example, genetic, cerebrospinal fl uid (CSF) Strong links should be fostered between and blood, cognitive and neuroimaging academia and industry to allow valuable biomarkers can play an important part in collaborations to facilitate drug early identifi cation of these disorders. This development and evaluation. As we move would enable some disorders to be further into the 21st century, it is important

62 I January 2011 I Brain Waves Module 1 The Royal Society to develop novel treatments, drug-based to deliver better and more effective and otherwise, based on symptoms rather treatments. Translational medicine—the than the specifi c diagnosis. For example, it process of turning biological discoveries would be more productive to focus on into drugs and medical devices that will symptoms, such as impulsivity, across help patients—is a UK strength. In diagnostic categories (such as mania, addition, these partnerships could ADHD and substance abuse) or specifi c promote the development of cognitive functions (eg impaired episodic pharmacogenomics, the discipline behind memory) irrespective of disease diagnosis how genes infl uence the body’s response (Sahakian et al. 2010; MRC 2010). To to drugs. This might lead to a illustrate this, a treatment that reduces ‘personalised medicine’ approach to impulsive behaviour may do so whether a mental wellbeing, with individuals being person has a diagnosis of ADHD or given treatments tailored according to substance abuse. Similarly, a treatment for their genotype (see also Section 2.2). certain memory problems may be useful Other novel approaches to understanding for improving cognition and functional and treating brain diseases will include outcome in both mild Alzheimer’s disease synapse proteomics. Irregularities in the and fi rst episode schizophrenia. sets of synapse proteins (chemicals in the Symptoms, such as impulsivity, refl ect junctions between nerve cells) cause genetics and underlying neurobiology and particular clinical symptoms shared are therefore more likely to be tractable between diseases. This provides a novel targets for treatment, compared with a route for the pharmaceutical industry, heterogeneous category from diagnostic since ‘blockbuster’ drugs that have large manuals. markets and are useful in many individuals Industrial partnerships could promote the can be developed. Sets of synapse development of biomarkers and proteins can be targeted by drugs that neurocognitive training research, as well should be useful in the treatment of as novel drug development. Proof of multiple diseases. concept studies with ketamine and The discovery of hundreds of new synapse scopolamine indicate novel areas for the proteins also provides a new set of pharmaceutical industry to pursue which potential drug targets. For example, to would result in great benefi ts for patients date, by far the greatest effort of with depression (Berman et al. 2000; pharmaceutical companies has been on Zarate et al. 2006; Drevets and Furey the neurotransmitters (chemicals that send 2010). Unlike the currently used selective a signal from one nerve cell to the next) serotonin reuptake inhibitors (SSRIs), with and their receptors and uptake systems. which depressed patients take weeks to These comprise less than 10% of all show improvements, new drugs with synapse proteins, which leaves the other different mechanisms work very rapidly. In 90% to investigate. This provides an addition, small molecule drug design is of investment opportunity. The study of growing importance as it holds potential molecular functions at synapses and their

The Royal Society Brain Waves Module 1 I January 2011 I 63 importance in behaviour is rapidly Imaging (MRI), it may prove especially developing. Synapse proteomics will be of valuable (Wells et al. 2010). Moreover, the increasing importance in genomic technique has proved benefi cial in diagnostics of brain diseases. For instance, restoring visual function in mice (Lagali from data on genetic disorders that affect et al. 2008) and so has applicability to the nervous system, it was found that over treating forms of human blindness. 130 brain diseases are caused by Optogenetic therapy also holds promising mutations in synapse proteins (Bayes and potential for the treatment of neurological Grant 2009; Fernandez et al. 2009). It is diseases. The technique has now been already clear that autism, schizophrenia used in the study of Parkinson’s disease and bipolar disorder involve dozens of where it can be used to investigate how synapse proteins. This further emphasises symptoms are produced by different the important point that future diagnostics pathways in the brain (Kravitz et al. 2010). will be likely to involve careful clinical A recent study in Nature (Kravitz et al. phenotyping (classifi cation of observable 2010) indicated in a mouse model of characteristics) using, for example, Parkinson’s disease that regulation of cognitive testing and brain imaging, but motor behaviours by optogenetic control also genetic diagnosis. was possible and that a modulation of circuitry may represent an effective Other novel neuroscientifi c approaches to therapeutic strategy for ameliorating motor understanding and treating defi cits in patients with Parkinson’s neuropsychiatric disorders, such as disease. While optogenetic techniques Parkinson’s disease, exist. For example, hold great promise for translational studies there are highly innovative techniques to aid understanding of neural using optics to control neural activity mechanisms in neuropsychiatric disease, it (Gradinaru et al. 2010). These techniques remains to be determined whether these allow for the control of cellular activity by techniques can be used in humans. exposure to light. Specifi c cells can be excited or inhibited by different wavelengths of light, a technique that is Opportunities both spatially and temporally precise. The prospect of new technologies and new These optogenetic methods (an emerging treatments for neuropsychiatric disorders fi eld that combines optics and genetics to and brain injury for the benefi t of patients, probe neural circuits) have been society and the economy is extremely demonstrated to be effective in many exciting. Many opportunities for their species and are likely to have wide commercialisation exist, including those applications in the future (Boyden et al. described above. These may be developed 2005). Optogenetics has been used to through public-private partnerships in investigate synaptic connections within some instances. neuronal networks (Petreanu et al. 2007) and synaptic plasticity (Zhang et al. 2008). Important innovation in the area of Used alongside Magnetic Resonance neurocognitive activation (cognitive

64 I January 2011 I Brain Waves Module 1 The Royal Society training) could be exploited commercially in health and disease to ensure the UK is for the benefi t of society relatively rapidly. economically competitive and that our This is an important new technique which society fl ourishes. Therefore it is could easily be exploited through the UK unfortunate that there has been a recent Games Industry. It could be used in withdrawal of some drug companies, entertainment games for training impulse including UK-based ones, from the or cognitive control in children and development of new drugs for the adolescents with ADHD or substance treatment of psychiatric disorders (Miller abuse problems. It could also be used for 2010) (see also Sections 2.2 and 3.2). training episodic memory in elderly people Two actions which might stimulate central with amnestic mild cognitive impairment nervous system (CNS) research and (aMCI), the onset stage of Alzheimer’s development enterprise are: i) to extend disease. Klingberg (2010) has the patent life of a new drug for psychiatry demonstrated the power of the technique to ensure that the enormous development by showing that training on a working costs are taken into account; and ii) to memory task is associated with changes in make new mental health treatments a brain activity in specifi c regions of the priority by speeding access and brain, as well as changes in the densities development of new drugs/products for of certain types of receptors in healthy mental health, as is done for HIV/AIDS. people. Therefore this technique could be useful for young and old healthy people, in A more diffi cult problem to solve is the addition to those with neuropsychiatric sensitivity of ‘accepted outcome disorders and brain injury. The challenge measures’ to change and early stage for the games industry or other markets is disease, such as those used by the US to transform this training from a chore into Food and Drug Administration (FDA) and a fun and enjoyable activity. European Medicines Agency (EMA). This is particularly true where early detection is Other areas provide fi nancial opportunities important and where neuroprotective for neuroscientifi c development, although drugs can be given. Treatments, including the gain to society is unclear, such as pharmacological ones, need to be given neuromarketing (see Section 2.5). Studies early—before the patient has marked in this area have used decision making and impairments in occupational and social purchasing paradigms together with fMRI functioning and reduced quality of life and technology to indicate, for example, that a wellbeing. (The standard diagnostic preference for the drink Coke may be manuals require a decline and impairment infl uenced by brand image rather than by in social and occupational functioning for a the taste itself. diagnosis of dementia). Therefore this challenge may lead to an opportunity to innovate the drug development process, Challenges and solutions for instance targets for treatment may Neuroscience is coming of age and can be become closely related to genetics and successfully applied to important problems neurobiology (eg impulsivity, episodic

The Royal Society Brain Waves Module 1 I January 2011 I 65 memory) rather than diagnostic categories effective in long-term studies, policy (eg schizophrenia, ADHD) (see Sahakian change might allow these to be marketed et al. 2010). Another challenge is the true through the usual routes. This would translation of Proof of Concept studies to reduce potential harms of current internet Phase 3 clinical trials, as it is diffi cult to purchase of these ‘smart drugs’ and may replicate exactly the methodology used in be of particular aid to certain groups in these two stages. Finally, other challenges society such as elderly people (see also for research studies include extensive Sections 2.2, 3.2 and Box 2). bureaucracy (such as paperwork for Furthermore, there is a global market for research and development funding, ethical adaptive learning technologies. Marketing reviews, and intellectual property rights e-books and TV programmes are thus far protection) and the reluctance of research an unexploited area. These types of sponsors to tolerate risk. initiatives can have importance for lifelong Other European opportunities in response learning. Education and learning are to this need to ‘repair’ the CNS research known to enhance cognitive reserve, and and development enterprise may include: better cognitive function is associated with funding via organisations such as the better wellbeing (Beddington et al. 2008). Innovative Medicines Initiative (IMI),a Both science and technology and higher partnership between the European levels of cognitive abilities and education Community and the European Federation are linked to increased prosperity (eg of Pharmaceutical Industries and increased gross domestic product) (see, Associates (EFPIA); grant funding from the eg, Royal Society 2010; Rindermann 2008). EU via the national research councils; Furthermore, investment in mental health development of a capability cluster in has provided substantial economic benefi t mental health; and increased integration in the past and should continue to do so in between disciplines, particularly psychiatry the future (Health Economics Research and neurology. Group, Offi ce of Health Economics, RAND Europe 2008).

Neuroscience can provide us with the tools Conclusion to make the most of our minds and also In summary, there are extensive the necessary platform for an economically opportunities for neuroscience to competitive and fl ourishing society. Now it contribute evidence-based advice to is up to us as neuroscientists, the policymakers, health professionals, the government and society to transform this private sector and the public. Public potential into a reality. engagement in neuroscience is a rapidly growing area. ‘Smart drugs’ or cognitive enhancing drugs (eg modafi nil) and their benefi ts for healthy people have been of References and further reading Bayes A and Grant S (2009) keen interest. If these drugs are shown by Neuroproteomics: understanding the the pharmaceutical industry to be safe and

66 I January 2011 I Brain Waves Module 1 The Royal Society molecular organization and complexity of Health Economics Research Group, Offi ce the brain. Nature Reviews Neuroscience, of Health Economics, RAND Europe (2008) Vol 10, pp 635–646. Medical Research: What’s it worth? Estimating the economic benefi ts from Beddington J, Cooper C, Field J, Goswani U, medical research in the UK. London: UK Huppert F, Jenkins R, Jones H, Kirkwood T, Evaluation Forum. Sahakian B and Thomas S (2008) The mental wealth of nations. Nature, Vol 455, Klingberg T (2010) Training and plasticity of pp 1057–1060. working memory. Trends in Cognitive Sciences, Vol 14, pp 317–324. Berman R, Cappiello A, Anand A, Oren D, Heninger G, Charney D and Krystal J Kravitz A, Freeze B, Parker P, Kay K, (2000) Antidepressant effects of ketamine Thwin M, Deisseroth K and Kreitzer A in depressed patients. Biological Psychiatry, (2010) Regulation of Parkinsonian motor Vol 47, No 4, pp 351–354. behaviours by optogenetic control of basal ganglia circuitry. Nature, Vol 466, Boyden E, Zhang F, Bamberg E, Nagel G pp 622–626. and Deisseroth K (2005) Millisecond- timescale, genetically-targeted optical Lagali P, Balya D, Awatramani G, Münch T, control of neural activity. Nature Kim D, Busskamp V, Cepko C and Roska B Neuroscience, Vol 8, No 9, pp 1263–1268. (2008) Light-activated channels targeted to ON bipolar cells restore visual function in Drevets W and Furey M (2010) Replication retinal degeneration. Nature Neuroscience, of scopolamine’s antidepressant effi cacy Vol 11, pp 667–675. in major depressive disorder: A randomized, placebo-controlled clinical MRC (2010) MRC Review of Mental Health trial. Biological Psychiatry, Vol 67, No 5, Research - Report of the Strategic Review pp 432–438. Group. London: Medical Research Council.

Fernandez E, Collins M, Uren R, Miller G (2010) Is Pharma running out of Kopanitsa M, Komiyama N, Croning M, brainy ideas. Science, Vol 329, pp 502– Zografos L, Armstrong J, Choudhary J and 504. Grant S (2009). Targeted tandem affi nity Olsen A, Eadie B, Ernst C and Christie B purifi cation of PSD-95 recovers core (2006) Environmental Enrichment and postsynaptic complexes and schizophrenia Voluntary Exercise Massively Increase susceptibility proteins. Molecular Systems Neurogenesis in the Adult Hippocampus Biology, Vol 5, p 269. via Dissociable Pathways. Hippocampus, Gradinaru V, Zhang F, Ramakrishnan C, Vol 16, pp 250–260. Mattis J, Prakash R, Diester I, Goshen I, Petreanu L, Mao Y, Sternson S, Svoboda K Thompson K and Deisseroth K (2010) (2009) The subcellular organization of Molecular and cellular approaches for neocortical excitatory connections. Nature, diversifying and extending optogenetics. Vol 457, pp 1142–1145. Cell, Vol 141, pp 1–12.

The Royal Society Brain Waves Module 1 I January 2011 I 67 Rindermann H (2008) Relevance of cortical neurons and astrocytes with MRI education and intelligence at the national at .9.4T. (abstract). level for the economic welfare of people. Zarate C, Singh J, Carlson P, Brutsche N, Intelligence, Vol 36, pp 127–142. Ameli R, Luckenbaugh D, Charney D and Royal Society (2010) The Scientifi c Century: Manji H (2006) A randomized trial of an securing our future prosperity. RS Policy N-methyl-D-aspartate antagonist in document 02/10. treatment-resistant major depression. Archives of General Psychiatry, Vol 63, Sahakian B, Malloch G and Kennard C No 8, pp 856–864. (2010) A UK strategy for mental health and wellbeing. The Lancet, Vol 375, pp 1854– Zhang F, Prigge M, Beyrière F, Tsunoda SP, 1855. Mattis J,Yizhar O, Hegemann P and Deisseroth K (2008) Red-shifted Wells J, Walker-Samuel S, Marina N, optogenetic excitation: a tool for fast Figueiredo M, Teschemacher A, Spyer M, neural control derived from Volvox carteri. Gourine A, Kasparov A, and Lythgoe M Nature Neuroscience, Vol 11, pp 631–633. (2010) In-vivo optogenetic activation of

68 I January 2011 I Brain Waves Module 1 The Royal Society 3.2 Risks

Professor Steven Rose, The Open University

Background Section 2.4) with Chan and Harris on the The rapid advances in neuroscience of the other in this volume (see Section 3.3). past decades, and those that can be Some distinguished neuroscientists anticipated in the near and mid-future, celebrate such a reduction of mind to brain bring with them not merely new (eg Crick 1994) whilst some philosophers knowledge of how the brain works, with view it with foreboding (eg Habermas profound implications for humanity’s 2003). I take neither view. Instead I would understanding of itself, but also actual and argue that any genuine increase in potential technologies with associated knowledge of brain processes and their benefi ts and risks. Both have been widely pre- and post-natal development can only discussed in the media. This section is enrich our understanding of ourselves. Nor concerned to balance the risks against the can such increased knowledge replace or perceived benefi ts discussed more diminish the insights into what it is to be extensively in other sections (see eg human that come from philosophy, the Section 3.1). social sciences or the humanities— although these disciplines will need to take the fi ndings of neuroscience into account, Is increased knowledge of the just as neuroscience will need to respect brain itself hazardous? these other perspectives and Some argue that increasing knowledge of understandings. Here, therefore, there brain mechanisms and their relationship to should only be benefi ts, providing one can such deeply personal and private pick one’s way through the ‘over-hyping’ characteristics as memory, cognition, of apparent neuroscientifi c claims and the emotion and even consciousness, risks attendant prophesies of doom that so diminishing our sense of having attract media attention. independent agency and free will. We will be nothing other than neuronal machines, driven by the complex fi ring patterns of the Neurotechnoscience cells in our brains, themselves the Technosciences involve research inevitable product of the interplay between enterprises in which the old distinctions genes and environment during our between science and technology have development. broken down. It is not just that one cannot say where the science stops and the This interpretation is itself vigorously technology begins, but that the two are contested among philosophers and inseparable, each both driving forward and neuroscientists—compare for instance, the being driven by the other. And it is as a views of Singer on the one hand (see technoscience that the risks and benefi ts

The Royal Society Brain Waves Module 1 I January 2011 I 69 of advances in the study of the brain may unequivocal and replicable genetic be seen as more fi nely balanced. To judge markers have been identifi ed. Rather, the these requires refl ecting not merely on the modern techniques of genome wide potential of developments discussed in the association studies (GWAS) suggest that previous sections, but also on the there may be tens or even hundreds of intentions and goals of those who fund genes which, individually or in them—primarily the State, pharmaceutical combination and varying from individual to companies, medical charities, individual, may affect the risk for the supranational organisations such as the disorder. Under these circumstances, the European Commission, and the military. In benefi ts of genetic testing of an individual awarding funds each organisation will have for the predisposition may well be specifi c ends in view, and these must be outweighed by the risks of false diagnosis taken into account as we consider their (either positive or negative) with its implications (see also Section 3.4). consequent implications for how a person plans his/her life. Even when a relatively certain genetic diagnosis can be made, as Policy issues in the case of HD, experience has shown Neurogenetics and the that many of those known to be at risk of pharmaceutical industry the disease decline the test, preferring Many neurological and psychiatric uncertainty, especially where there is no disorders run in families, and in some effective treatment, as is still the case cases genes have been identifi ed that for HD. increase the probability of a person having Some commercial companies offer tests a particular disorder (see also Section 3.1). for one of the genetic risk factors for AD, Huntington’s disease (HD), which results in the gene ApoE4, but this practice worries increasing motor and mental incapacity in both genetic counsellors and ethicists, as a middle life, is a single gene disorder where positive result is indicative only of a both the gene and its biochemical and potential risk factor and provides little cellular consequences are well known and guidance as to how one should live one’s predictable. The same is true for rare forms life, whilst adding to a person’s burden of of Alzheimer’s disease (AD), which strike in anxiety such that every small slip in mid-life rather than, as in most cases, older memory may be taken as a warning of the age. There are also known genetic risk impending onset of the disease. factors for the more common forms of the Nonetheless in an unregulated or only disease, but these are probabilistic rather lightly regulated biotechnological than predictive. economy, the availability of such tests is The situation is less clear for the common likely to increase substantially in the psychiatric disorders such as depression coming years (see eg Collins 2010). or schizophrenia, whose mode of One of the major goals for transmission is obscure and for which, neuropharmacology must be to develop despite decades of research, no

70 I January 2011 I Brain Waves Module 1 The Royal Society drugs to treat or alleviate these conditions. For psychiatric diagnoses such as Both the record and the prospects are schizophrenia and depression, the mixed. In the case of AD, even though the situation is less optimistic. Despite earlier triggering events for the disease are hopes and claims, the newer generation of unknown, the biochemical cascade that selective serotonin reuptake inhibitor drugs leads to the accumulation of plaques and (SSRIs) to treat depression have turned tangles and the death of neurons is well out, when widely prescribed, to be little understood, providing many potential more effective that the earlier ones in targets for drug action. Whilst the present treating what the World Health generation of drugs is not very effective, Organization has categorised as a there are several promising new worldwide epidemic of depression. developments. Most such drugs are aimed However, people’s responses to the drugs at slowing the cognitive decline are very variable, and one hope, though characteristic of AD. In this sense the not yet realised, is that GWAS might make drugs are cognitive enhancers (see also it possible to identify subsets of the Section 2.2, 3.1 and Box 2). The benefi ts population who could benefi t most from of such drugs—at the least in enabling any of the different classes of drugs that AD sufferers to maintain a longer period are available, Nonetheless, it is perhaps in of independent living—are clear. However, recognition of these diffi culties, and the as they do not prevent the inexorable sheer seeming intractability of the problem neurodegeneration that the disease that, as mentioned by Robbins and entails, some have questioned whether Sahakian (see Sections 2.2 and 3.1), living with the knowledge of that fate several of the major pharmaceutical rather than benign neglect is always companies have abandoned their drug benefi cial. discovery programmes for these disorders, whilst retaining those for frank There is some evidence that drugs like the neurological conditions such as AD or statins, used to control cholesterol levels, Parkinson’s Disease (Miller 2010). and folic acid may be marginally neuroprotective, as are ‘brain exercises’ on the ‘use it or lose it’ principle (see also Section 3.1). There have also been very Drugs for social control? recent claims to have identifi ed a ‘marker’ The US Diagnostic and Statistical Manual molecule, present in cerebrospinal fl uid (DSMIV), regarded as the psychiatrists’ that can predict the onset of the disease bible, is currently undergoing revision, but before any behavioural indications of its a category of disorders that is likely to onset. The benefi ts that would accrue from remain in one form or another is that developing a truly protective agent against which relates not to relatively clear-cut neurodegeneration would be enormous, psychiatric conditions but those concerned even when set against the risks of the with an individual’s behaviour—conditions widespread prophylactic drug taking over such as (in the current classifi cations), many years. conduct disorder, oppositional defi ance

The Royal Society Brain Waves Module 1 I January 2011 I 71 disorder and, attention defi cit hyperactivity criteria for what is or is not acceptable disorder (ADHD). changed? Or might the problem lie less in the brain of the child and more in the The frequency with which such diagnoses parenting practices or social environment? are being made has increased dramatically over the past two decades. ADHD (then There is a more general issue at stake here, called minimal brain dysfunction), and that is the use of drugs as a means of considered to affect no more than one in social control. Whilst there are several hundred children in the UK in the undoubtedly children who could benefi t 1980s, is now estimated to be present in from the drugs, such medicalisation of from 1–5% of children—mainly boys— behaviours regarded as outside the norm, between 6 and teenage. The diagnosis is to use Chan and Harris’ term (See Section based primarily around a child’s unruly, 3.3), may turn out to be an example of disobedient or inattentive behaviour at what Stirling categorises as missed school and home. There are no opportunity or forced tramlines (see unequivocal neurological or neurochemical Section 3.4). By focussing on the individual markers to correlate with the diagnosis. and positing that the source of his or her There are, however, pharmaceutical distress lies in some molecular disorder in approaches to correcting or modifying the brain, we may miss the broader social these behaviours, most notably the public health context (from economic amphetamine-like drug methylphenidate insecurity to poor schooling or inadequate (Ritalin). parenting) that affects the brain and makes the distress manifest. In focussing on ‘a Ritalin prescriptions in the UK have pill for every ill’ do we risk moving towards increased from around 2000 a year in the what a neurophysiologist once referred to early 1990s to approaching 600,000 a year (approvingly) as a ‘psychocivilised society’— today, though with very marked regional and what, less approvingly, Aldous Huxley variations. Ritalin and related drugs wrote about in Brave New World? certainly make a child calmer in class, less troublesome to teachers and parents. More immediately, in the US, where the However, the long-term effects of the use of Ritalin has been more widespread drug, on a growing child’s brain and for far longer than in the UK, the FDA has behaviour, have not been fully assessed. called attention to the extent to which it is being widely traded amongst An unanswered question is why a disorder schoolchildren on the grounds that its considered rare several decades ago attention-enhancing effects are an aid to should now be diagnosed with such study and preparing for exams. As frequency. Did it exist unrecognised earlier, discussed by Robbins (see Section 2.2), a with children being called naughty or number of respondents—predominantly delinquent rather than as having a brain from the US—to a survey conducted by disorder? (The increase in autism Nature amongst its readers as to whether diagnoses over the decades is a they use cognitive enhancers also reported comparable example). Have society’s

72 I January 2011 I Brain Waves Module 1 The Royal Society that they had or currently still used Ritalin exception is magnetoencephalography in this way. (MEG). Barring the usual problems with all scanning techniques—of both false Ritalin is of course not the only drug to be positives and false negatives—the clinical considered as a cognitive enhancer (see benefi ts to neurosurgery and neurology Section 2.2 and Box 2). A wide variety of scarcely need stressing. The only risk agents with very different mechanisms of seems to be the general one: that modern action have been proposed, mainly on the medicine and clinical practice sometimes basis of animal experiments and often seem to substitute diagnosis for without good evidence as to their effects treatment—as for instance in the use of in humans, to act as cognitive enhancers, MRI scans to detect spinal disc injury as a giving rise to much ethical debate (see substitute for, or addition to, clinical Section 3.3) and media speculation. judgement even when surgical intervention Concern has been expressed over whether is not contemplated. the use of such drugs outside a medical context confers an unfair advantage on Similarly, at fi rst glance the neural their users in competitive examinations. interfaces discussed by Tracey (see Section Should such ‘steroids for the brain’ be 2.3 and Box 3) would seem only benefi cial, regulated as in sport? Even if it were in their potential to compensate for loss of possible—and the wide availability of sensory or motor abilities—though their Ritalin for purchase via the web suggests military applications are more disturbing. that it would be diffi cult—would it be However, the science fi ction possibilities of appropriate? How different, ethically, is the such prostheses—as described for deliberate and voluntary taking of a example by Gibson (2000)—open the cognitive enhancer to employing a tutor or prospect of a dystopic world of enjoying the educational advantages that, cyberpeople: part human, part engineered, in a profoundly unequal society such as refl ecting in fi ction Habermas’s concerns Britain, come with class and income (Rose, (see also Section 3.3). 2002)? There are, however, two main areas in which developments in imaging techniques raise immediate social Imaging and neural interfaces concerns. Both relate to the consequences As discussed by Rees (see Section 2.1), of living in an increasingly security- and once they had moved beyond the surveillance-obsessed society. Could brain experimental province of physicists, imaging be a further step down the path virtually all modern neuroimaging pioneered by the ubiquitous CCTV techniques were developed with cameras and national DNA databases— diagnostic aims in mind: Computed Axial that is, as a further restriction on an Tomography (CAT or CT), Positron individual’s privacy? Might brain imaging Emission Tomography (PET), Magnetic provide an internal surveillance of our Resonance Imaging (MRI) and functional thoughts, emotions and intentions to add MRI (fMRI) are examples. Perhaps the

The Royal Society Brain Waves Module 1 I January 2011 I 73 to the external surveillance of the of both legal and illegal drugs, and many cameras? Not Brave New World but 1984 other potentially relevant experiences. updated? Although there have been claims that it is possible to detect propensity to Claims that brain imaging (‘Brain psychopathy, based on psychological and Fingerprinting’) could serve as an updated even biological measures in young form of lie detection have been treated children, whether useful predictive brain with some scepticism by the imaging differences could be found prior to crime, community (See Box 1), but a number of conviction and imprisonment is simply not commercial companies now offer devices known. Furthermore, even if such claiming to do just this, mainly based on predictions could reliably be made, it is a the measurement of evoked response cardinal principle of law that intentions or potentials—an application of the predispositions in the absence of acts are electroencephalography (EEG) technique not crimes—unless we are truly to move discussed by Rees (see Section 2.1). The towards a 1984-type category of ‘thought company websites suggest their use to crime.’ The argument that individuals ‘at detect whether someone ‘is a terrorist’ or risk’ should be scanned and subjected to has visited ‘terrorist training camps’ as an appropriate remedial or control regime, well as in the courts to help determine and the individual could choose whether guilt or innocence. The use of such to be subject to it rather than coerced, fails techniques has been admitted into trials in on the grounds both that any such brain India and the US, though not so far in the fi ndings are likely to include many false UK (Rose 2006). These issues will be positives, and a lack of knowledge about addressed in more detail in Module 4 of just what would constitute an appropriate the Brain Waves project on neuroscience, remedial regime. It is doubtful whether responsibility and the law. there would be any added value provided Of at least as great concern are the by a brain scan above that given by suggestions that brain imaging can provide standard psychiatric evaluation. a prospective diagnosis of a person’s More directly interventive are the potential for criminal activity or expanding applications of transcranial psychopathic violence. There have been magnetic stimulation (TMS) (see Box 4). claims that MRI or fMRI could detect TMS has been proposed as a potential characteristic differences in brain therapeutic approach to mitigate the structures or neural activity between effects of neurological conditions such as incarcerated men convicted of murder or Parkinson’s, to alleviate depression, or as other violent crimes and either non-violent an alternative or adjunct to cognitive criminals or ‘normal’ people. However a behaviour therapy in obsessive/ major problem with such studies is that compulsive disorders. In these senses it they are post-hoc. The violent murderers would seem to carry a similar balance of studied have been in prison, often for long benefi ts and possible risks as do periods of time, have a history of the use pharmacological interventions. However,

74 I January 2011 I Brain Waves Module 1 The Royal Society the declared interest of the US military The use of any toxic chemical, including (see below) in exploring the uses of TMS neuroactive chemicals such as nerve as a method of thought and behaviour gasses, as weapons of warfare is control, though still in the realm of basic prohibited in international law by the research and even science fi ction, raises Chemical Weapons Convention. However, the same issues of privacy versus social the Convention allows for the use of long- control and manipulation discussed standing ‘riot control agents’—‘tear above. gasses’ such CN and CS that cause local irritation of skin and mucous membranes— for ‘law enforcement including domestic The military and riot control’. It is into this grey area neurotechnoscience between ‘police’ and ‘military’ deployment Military interest in neurotechnoscience is that some countries have sought to directed towards two general goals: introduce incapacitating chemical improving the effi ciency of one’s own weapons with central affects on the brain forces, and diminishing that of an enemy. to induce unconsciousness or sedation. Most available information comes from the The fi rst use of incapacitating chemical US, where the military and its research weapons was in Moscow in 2002 when organisations such as the Defence Russian Special Forces stormed a theatre Advanced Research Projects Agency to release hostages taken by Chechen (DARPA) have a long record of funding militants. A derivative of the opioid work in this area, and where information is fentanyl was pumped into the theatre with much more freely available than in other the intention of incapacitating the militants more secretive states. Current concerns before the troops stormed the building— centre on two areas: psychoactive but the drug killed over 120 of the chemicals; and behaviour modifi cation via hostages (Davison 2009). Concerns have brain stimulation. These issues will be been raised of the risk such weapons’ addressed as part of Module 3 of the Brain development poses to the international Waves project on neuroscience, confl ict ban on chemical weapons (see also and security. Section 2.2).

Psychoactive chemicals: Pharmaceuticals Physical methods: Other basic research to improve the performance or motivation efforts aim to investigate the potential for of one’s own military have a long history affecting the brain and central nervous (from hashish to marijuana and system using different powers, amphetamine) and widespread use. For frequencies, and pulses of electromagnetic example during recent confl icts it is radiation. These would join emerging reported that US pilots were supplied with directed energy weapons, including lasers Modafi nil to improve alertness and and the so called ‘Active Denial System’, a concentration during long fl ights (see also new weapon that projects a millimetre Section 2.2). wave beam of radiation to heat the skin with the aim of causing a burning

The Royal Society Brain Waves Module 1 I January 2011 I 75 sensation without permanent damage which neuroscience could or should be (Davison 2009). This weapon has recently pursued is now, whilst policy makers and been installed on trial in a Los Angeles society at large still have time to consider prison. Whether one judges the availability the potential developments and how, and of such techniques as a benefi t or a risk to what extent, they may be directed or depends on whether one sees them as controlled (see also Section 3.4). The preventing unwanted social disorder or further ‘downstream’ the technologies increasing the power of a militarised State have moved, the harder such choices to control citizens. will be.

Of more direct military signifi cance has been the research conducted over several References and further reading decades under DARPA contracts to Collins F (2010) The Language of Life: DNA develop ‘distance’ methods to control or and the revolution in personalised medicine. manipulate brain and thought processes, HarperCollins. in the past by high intensity microwave beams and more recently by magnetic Crick F (1994) The Astonishing Hypothesis: pulses through TMS (Rose 2006). Despite the scientifi c search for the soul. London: the claims by some groups in the US that Simon and Schuster. they have been unwittingly subject to such experiments by the military, the evidence is Davison N (2009) ‘Non-lethal’ Weapons. that at present the available technology Basingstoke: Palgrave Macmillan. requires that the individual be placed Gibson W (2000) Neuromancer. Voyager. directly into the appropriate equipment. Thought control at a distance remains in Habermas J (2003) The Future of Human the realm of science fi ction. Nature. Cambridge: Polity Press. Miller G (2010) Is Pharma running out of brainy ideas? Science, Vol 329, pp 502– Conclusion 504. Many of both the benefi ts and the risks of advances in neuroscience still lie in the Rose S (2002) Smart drugs: do they work? future. Some we can anticipate, others will Are they ethical? Will they be legal? Nature be unintended or unforeseen. Much Reviews Neuroscience, Vol 3, pp 975–978. neuroscience is still ‘upstream’ of Rose S (2006) The 21st Century Brain: application. However the time to consider Explaining, mending and manipulating the and make choices about the directions in mind. London: Vintage.

76 I January 2011 I Brain Waves Module 1 The Royal Society 3.3 Neuroethics

Dr Sarah Chan and Professor John Harris, University of Manchester

Background questions relating to participation in ‘Neuroethics’ is a term that has gained neuroscience research, or concerns prominence over the last decade to regarding risk in relation to experimental describe ethical issues arising in relation to technologies. Aside from these, however, various advances in neuroscience (Dana neuroscience does challenge us to Centre 2002; Illes and Raffi n 2002; Farah contemplate the brain and its relationship 2005). The kinds of technologies that to the mind in new ways. Our increasing provoke neuroethical concerns include understanding of brain function as a neuroimaging techniques such as biological phenomenon leads us to functional magnetic resonance imaging reconsider profound philosophical (fMRI) (see Section 2.1), the use of questions about free will, responsibility, pharmacological agents to alter brain identity, and the nature of consciousness. function (see Section 2.2), neurosurgery Although the questions themselves may and other physical interventions (see be age-old, neuroscience both encourages Section 2.3). In addition, basic research in us to revisit them and casts them in a new neuroscience continues to expand our light—though not necessarily one that knowledge of the biological basis for the illuminates the answers any further (see brain’s functioning and for the mental, Section 2.4 and Box 5). psychological and behavioural correlates Additionally, neuroscience is likely to have of neurobiological phenomena (see also far-reaching social implications. The way in Sections 2.4 and 2.5). This raises further which we constitute ourselves and other ethical and philosophical challenges as to persons as ‘neurological subjects’ the implications of these fi ndings and how (Cunningham-Burley 2010) inevitably they should be interpreted and used. affects our understandings of ourselves As with many new areas of technology and our relationships with others. For and the sub-fi elds of ethics that have example, clinical and social attitudes developed in association with them, the towards mental illness have evolved emergence of neuroethics as a specifi c considerably over the last century, area poses the question: are the associated infl uenced by our changing understanding ethical issues novel and distinct from of the neuroscientifi c aspects of general ethical concerns raised in the psychiatric conditions and the consequent context of medicine, health care and perception of mental disorders as rooted in biotechnology? physical pathology (see also Section 3.2).

Some of the issues related to neuroethics There are also diffi cult and in some cases are common across many areas of urgent questions about how we ought to biomedical technology: for example, make use of the knowledge and the

The Royal Society Brain Waves Module 1 I January 2011 I 77 technologies emerging from this fi eld, in legal understanding of what it is to be contexts ranging from health care to the conscious, or a moral agent? (See also legal process and even political or social Section 2.4.) control (see Sections 2.4, 3.1, and 3.2). Whether or not this is the case, The ethical concerns and social changes neuroimaging does have some ethical engendered by neuroscience and all it consequences in its application, including entails will require extensive consideration ramifi cations for diverse areas of medical with respect to policy and regulation: how ethics. For example, in relation to end of are we to manage and respond to these life decisions: recent research shows that concerns and changes? How can and patients previously thought to be in a should we guide the uses of neuroscience permanent vegetative state actually in the public interest? demonstrate some level of brain function suffi cient to express (and therefore This essay presents a brief overview of the presumably to have) preferences. This issues at the forefront of neuroethics as it result provoked intense debate over has developed to date and highlights some whether treatment protocols for such that require further attention and others patients should be revised to take that may emerge in the near future. Lastly account of their newly-discovered capacity this essay will identify some current for some level of thought or at least priorities for policy consideration and reaction. suggest an approach to ethical policy- making in neuroethics. Privacy concerns Foremost amongst the concerns raised Neuroimaging about neuroimaging technologies is the Neuroimaging technologies such as fear that the use of neuroimaging to ‘read positron emission tomography (PET) and minds’ may lead to unacceptable fMRI enable us, in a manner of speaking, infringements of personal privacy and civil to ‘see’ mental processes in terms of the liberty. At present, given the primitive state architecture and activity of the brain. (See of the technology, such concerns are Section 2.1) This has certainly increased probably overblown. Neuroimaging, scientifi c knowledge of the brain as a although it may be able to detect general biological organ but does not fully answer mental states such as emotion and even, philosophical and human or personal at a rudimentary level, more specifi c questions about conscious thought and conceptual/thought patterns, currently it the nature of mind. For example, we now cannot be used to determine precisely the have a scientifi c understanding of the content of thoughts. Insofar as it can neurological processes involved in moral currently be interpreted to form general reasoning and can observe some of the conclusions about individuals or biological correlates of the mental tendencies within a population, it is little phenomenon of consciousness—but will different to other physical indicators of this produce a deeper philosophical or

78 I January 2011 I Brain Waves Module 1 The Royal Society mood or mental state (see also Sections Genetic neuroscience 2.1 and 3.1). Those seeking to map and explore the novel territory of neuroethics have often made reference to the genomics era and the Forensic uses congruent evolution of genethics to address Of more concern is the danger that the ethical and social implications of genetic possibilities currently offered by science as a paradigm for the development neuroimaging may be misinterpreted and of neuroscience and neuroethics. As well as thus misapplied, overstretching the current clear parallels between the two, there are capabilities of the technology and leading degrees of overlap: the intersection of to false assumptions being made about genetics with neuroscience, for example in the extent to which brain states may behavioural genetics, multiplies the possible constitute ‘windows on the mind’. This is ethical dilemmas. particularly worrying in the forensic Already in a number of instances, context, for example neuroimaging lie behavioural genetics has raised novel detectors (see Section 2.1 and Box 1). An issues: the correlation of particular sets of attitude of scientifi c reductionism to chromosomes with aggressive personality forensic uses of neuroscience might lead types has led to at least one legal attempt to a one-dimensional legal approach which at a ‘genetic defence’ (Farahany and would be less likely to serve the Burnet 2006) for criminal behaviour, while requirements of justice or due process. the discovery of specifi c genes thought to Overly scientistic approaches to subjective be associated with risk-taking and fact-fi nding disregard the many complex aggression, in connection with racial factors that feed into legal and judicial genotyping, may reinforce unwarranted decision-making. A rigorous and and unwanted social attitudes towards contextualised understanding of certain racial groups (Wensley and King neuroscience and its place within social 2008) (See also Section 3.2). structures such as the law is required to avoid such pitfalls. This topic will be addressed as part of Module 4 of the Brain Waves project on neuroscience, New medical applications responsibility and the law. Probably the biggest area of medical application in neuroscience has been the This is one area for the cautionary shaping development of psychopharmacological of policy, both regarding direct uses and to agents to alter various aspects of brain help develop understanding on the part of function (see Section 2.2 and 3.1). publics and policy-makers. Scientists too Psychoactive drugs such as have an important role to play in this antidepressants are becoming process, through communication but increasingly widely used; many drugs without exaggeration and with a realistic provide effective relief for conditions attitude towards what is possible currently which previously represented serious and in the near future. impairments.

The Royal Society Brain Waves Module 1 I January 2011 I 79 Electrochemical or physical interventions that enables commercial operators to sell may also have therapeutic effects: for products more effectively is also a form of example, deep brain stimulation to treat mind manipulation.) Another worry is that diseases such as Parkinson’s has been knowledge of neuroscience may be used highly successful in a number of cases to create new incapacitating chemical (see Box 4). Neurosurgery may alter brain agents—a form of neurochemical warfare function as a side-effect of removing (see Sections 2.2 and 3.2). These issues harmful growths such as tumours, or may will be addressed in Module 3 of the Brain aim to achieve alterations in function Waves project on neuroscience, confl ict through physical intervention. and security.

Other possibilities include neural interfaces The dilemma in relation to many of these to enable humans (or indeed other neuroscience applications, as with many animals) to control electronic or robotic new scientifi c advances, is that the devices—something that has immense selfsame technologies or knowledge used possibility in terms of prosthetic for the benefi cial medical treatments applications (see Section 2.3 and Box 3). described might also be used for harmful Yet these developments also lead us to purposes. How we should deal with the question the biological nature of the so-called ‘dual use’ problem is one of the human body and, perhaps, to redefi ne serious issues facing not just neuroethics what we consider to be human. When but science ethics as a whole (see also machines are as much a part of ‘us’ as our Section 3.4). own bodies the boundary between the biological and mechanical becomes blurred. And when we consider the extent Medicalising the mind to which we already depend on machines There is one concern over dual-use for our everyday existence—computers, technologies that we would argue is electronic devices, modes of transport—it misdirected: not just their alternative or becomes apparent that perhaps the ‘dual’ use to cause harm, but their use to modern human is already part-machine. cause too much good—in other words, to enhance as well as to cure. Neuro- enhancement carries its own set of Harmful uses cautions to be considered, as will be These promised new technologies also discussed—however, simply doing more have potential downsides (see also Section good should not in itself be a problem. 3.2). Some have speculated that The perception that enhancement is wrong psychopharmacology may be used in a while treatment is right relates to another, harmful way to achieve mind control or more subtle but more signifi cant manipulation of minds to suit some ulterior consequence of neuroscience: the motive. (Drugs are not the only medicalisation of the mind (see also possibility—it might argued that Section 3.2). The scientifi c defi nition of a advertising and the psychological research

80 I January 2011 I Brain Waves Module 1 The Royal Society biomedical model of the ‘healthy’ brain decisions about it for themselves. This is and by extension the ‘healthy’ mind is perhaps of particular concern with respect constructed in opposition to mental illness to mental health and neuroscience. The and psychiatric disorder, where health and construction of medical norms for mental normality are the binary opposite of and psychological attributes may be seen disease and dysfunction. to exclude and devalue the abnormal, thereby dictating what constitutes an This characterisation of certain conditions ‘acceptable’ way to think and to be. as abnormal or pathological affects our perception of self and of others. It may be There is also a further concern related to stigmatising to be classed as mentally ill; the development of new therapies. The the translation of neuroscience into normativity of medicine provides diagnostic psychiatry criteria, and the legitimation for those interventions effect this may have on people must take designated as ‘medical therapies’, aimed account of the possibility of harmful at curing ‘disease’. But this phenomenon effects on those who are diagnosed. On may be capitalised upon in reverse: by the other hand, the understanding of redefi ning the state of disease, an apparent mental illness in terms of physical moral need, not to mention a market, is pathology might reduce feelings of created for new therapies. Some have personal responsibility and attribution of speculated that the rise in availability and blame for what can then be interpreted as range of psychoactive drugs is due at best an unfortunate accident of biology rather to overdiagnosis or a broadening of than purely mental and a fl aw intrinsic to diagnostic categories, and at worst to the the self. Receiving a neuroscientifi c creation of new diseases to encourage diagnosis may be something of a relief, not uptake of new marketable products (see only because it affords what appears to be Section 3.2). concrete and hence a feeling of control, but because it allows separation of the ill/ diseased state of the body part ‘at fault’, Neuro-enhancement and the negative values associated with Perhaps the question we ought to ask this state, from the self. about all neurotechnologies is not whether they constitute a medical therapy for a Medicine and its conception of health recognised dysfunction or disease, but provides a tremendous normative force whether in and of themselves they have that is often seen as stipulating the proper some benefi cial effect, regardless of how and improper uses of technologies we classify them. It is certainly true that (Fukuyama 2002; Habermas 2003). many of the new treatments available have However, there is the danger that ascribing huge potential to improve function—and excessive normative weight to a medically- yet they have often been criticised for determined concept of health risks precisely that: for being ‘enhancements’ removing the power of individuals to rather than ‘treatments’. evaluate their own condition and make

The Royal Society Brain Waves Module 1 I January 2011 I 81 Cognitive enhancement Along with these drugs come fears that we Cognitive enhancement is one of the will become a population of lotus-eaters oldest forms of human enhancement and constantly bathed in a sea of drug-induced one of the most valued. Improving euphoria and contentment, and concerns cognitive powers and capacities is one of about authenticity of emotion and the quintessential human activities: tool- experience, once we can control our using, social organization, speech, written emotions and the way in which we react to language, and more recently universal experience through the application of formal education and the use of suitable chemical modifi ers (see also computers, are all dramatic enhancers of Section 3.2). It might even be argued that cognition and knowledge acquisition. there is something inherently wrong in Chemical cognitive enhancers (see also seeking to alleviate distress and negative Section 2.2 and Box 2) may now provide emotions through artifi cial means, that we us with another means by which to seek as humans have a need for suffering This the same end (Chan and Harris 2006; argument, though, is in many ways Greely et al. 2008; Foresight Mental Capital analogous to arguments about hard work and Wellbeing Project 2008). While many as a virtue in other areas of enhancement are rightly concerned that our powers (Kass 2003), and is susceptible to the same might outstrip our ability or willingness to criticisms (Harris 2007). control their harmful effects, the paradox will remain that cognitive enhancement is also the most promising option we have to Moral enhancement? prevent or remedy potential harms caused One topic that has received recent (Rees 2004; Perrson and Savulescu 2008; attention is the possibility of moral Harris 2011). enhancement: that alongside the other mental and psychological capacities we might improve upon, it may also be Mood enhancement possible to ‘make us better people’ in Many of the psychoactive drugs available another sense, through enhancing our today in the medical context and the ability to act in a moral way. This idea recreational context—or sometimes seems plausible and perhaps appealing at both—are what might be termed ‘mood fi rst glance: morality in the sense of enhancers’ (see Section 2.2). This could ‘goodness’ is perceived as a desirable mean that they enhance mood either in the quality and something for which we sense of heightening whatever emotions should strive. As science begins to the user is experiencing, or in the sense of examine the biological foundations of improving mood towards some ‘better’ morality, for example through identifying state however this may be defi ned: by regions of the brain that appear to be personal preference, by medical involved in moral decision-making or normativity or by moral philosophy, exploring the evolutionary origins of moral among others. behaviour, it is tempting to think that

82 I January 2011 I Brain Waves Module 1 The Royal Society morality is something that can be easily points out that certain strong emotions, identifi ed, isolated and improved. Along including aversions, are an essential and these lines, some have argued not only even desirable part of certain valuable that enhancement is a moral imperative motives or attitudes to others. Could we in but that the greatest imperative is toward short have the sorts of feelings that are moral enhancement (Perrson and appropriate and possibly necessary to Savulescu 2008). morality if we did not feel strong aversion, for example to someone who deliberately Upon closer examination, however, this and unjustifi ably injured those we love? apparently simple proposition is highly problematic. Ethical expertise1 is not being The space between knowing the good and better at being good, rather it is being doing the good is a region entirely better at knowing the good and inhabited by freedom. Without the understanding what is likely to conduce to freedom, good cannot be a choice and if the good. Those with the insight, freedom disappears along with it goes sympathy, empathy and knowledge to virtue. have formed clear ideas of what might conduce to the good are not necessarily better at making the world a better place, Machine minds? for a number of familiar reasons. One group of technologies that are not always considered within the scope of Some of these are to do with the problem neuroethics, but perhaps should be, is of ‘akrasia’ or weakness of will, one form computer science and especially artifi cial of which was brilliantly summarised by intelligence (AI). The modern idea of George Bernard Shaw when he defi ned artifi cial, machine-based intelligence has virtue as ‘insuffi cient temptation’. A bigger been around for over 50 years, and as problem is that the sorts of traits or machines become ever more capable, the dispositions that seem to lead to bad possibility of creating a computer that can conduct are also the very same ones ‘think for itself’ seems increasingly required not only for virtue but for any sort plausible. of moral life at all. Efforts to create AI have produced so- This problem was effectively articulated by called AI computers that can solve intricate Peter Strawson in a famous essay entitled mathematical problems, perform complex ‘Freedom and Resentment’ (Strawson search operations and, famously, play 1960). Strawson was concerned not with chess. There is as yet no evidence that any moral enhancement but with the problem of these think in the way ordinary humans of free will; in the course of combating do, but it is undeniable that AI is becoming some absurd forms of determinism he increasingly sophisticated and perhaps one day they will. 1 In this section we follow lines taken by John Harris in the introduction to his Enhancing Evolution Another related area of research is Princeton University Press, Princeton and Oxford Paperback Edition 2010. computer-based brain simulation. Simple

The Royal Society Brain Waves Module 1 I January 2011 I 83 modelling of neurobiological systems is Manifesto 2009). Not only has it been already possible and plans to create a shown that current mechanisms for simulation of the entire brain are in proprietising innovation may have adverse progress. The question is whether a consequences for the progress of science computer that simulates the whole human through restricting the openness with brain to a suffi ciently realistic degree which scientists feel they can would become, in some sense, a human communicate about their research (Royal mind or indeed any other sort of mind. We Society 2003), but commercialisation, might be reluctant to give a ‘human’ label through altering the balance of incentives to a non-biological entity lacking any of the for innovation, may actually change the physical attributes by which we normally course of science itself—not necessarily identify humans; yet if it were able to think for the better (Chan, Sulston and Harris like us, ought we not to recognise it as one forthcoming). of us? This harks back also to the Another issue is how we ought in general philosophy of mind problems outlined to regulate the use of emerging above: would a computer that simulated technologies (see Section 3.4). While risk the physical workings of a brain also be and safety are quite rightly the foremost thus a mind, though not housed in a concerns in relation to introducing new human body? biomedical technologies, it does not follow When would we say that a computer had that the rational approach to managing risk become conscious? How would we know, is to limit their use only to circumstances and what would or should we do about it? where the likely benefi t is so vast as to The issues we face with AI refl ect those justify unequivocally the fuzzy, unquantifi ed raised by neuroethics with respect to our risk that we fear. If benefi ts of whatever own brains and minds: how do we sort are possible, they perhaps should— quantify consciousness, and what is its and undoubtedly will—be sought after. To moral signifi cance? take again the example of chemical cognitive enhancers, if it proves that ‘healthy’ adults can benefi t from these, we Policy concerns in neuroethics should be pro-active about assessing risk in There are a number of pressing policy these circumstances rather than hiding concerns in neuroethics today. Perhaps the behind over-restrictive regulation (see also foremost relates to the increasing Section 2.2 and Box 2). commercialisation, not just of As discussed, the issues encompassed neuroscience but of science in general. In within neuroethics range from largely relation to neuroscience and to other theoretical philosophical questions to technologies, we need to be aware of the immediate practical concerns regarding effect that proprietary intellectual property possible improper uses of present rights has on the entire process of technology. While the latter self-evidently scientifi c discovery as well as access to the require addressing, it is important to fruits of this process (The Manchester

84 I January 2011 I Brain Waves Module 1 The Royal Society remember that the role of ethics Farahany N and Bernet W (2006) particularly relating to policy and regulation Behavioural Genetics in Criminal Cases: is not simply reactive and restrictive but Past, Present and Future. Genomics, should be forward-thinking and facilitative Society and Policy, Vol 2, No 1, pp 72–79. where needed. The aim of science ethics Regarding the case of Stephen Mobley. should be to ensure that science is done Foresight Mental Capital and Wellbeing as best it can be and also does the best it Project (2008) Final Project Report. London: can, to improve lives and increase the Government Offi ce for Science. welfare of persons. This will be achieved not merely through preventing misuses, Fukuyama F (2002) Our Posthuman Future. but by guiding the direction and London: Profi le Books. application of science to bring about Greely H, Sahakian B, Harris J, Kessler R, benefi cial outcomes as well as avert Gazzaniga M, Campbell P, and Farah M harmful ones. (2008) Towards responsible use of cognitive enhancing drugs by the healthy. References and further reading Nature, Vol 456, pp 702–705. Chan S and Harris J (2006) Cognitive Habermas J (2003) The Future of Human regeneration or enhancement: the ethical Nature. Cambridge: Polity Press. issues. Regenerative Medicine. Vol 1, No 3, Harris J (2007) Enhancing Evolution. pp 361–366. Princeton NJ: Princeton University Press, Chan S, Sulston J, and Harris J Chapter 7. (forthcoming) Ethical Incentives for Harris J (2011) Moral Enhancement Innovation. In: Stiglitz, J et al. (eds) and Freedom, Bioethics, Vol 25, No 2, Intellectual Property Rights: Legal and pp 102–111. Economic Challenges for Development. Oxford: Oxford University Press. Illes J and Raffi n T (2002) Neuroethics: an emerging new discipline in the study of Cunningham-Burley S (2010) Engaging brain and cognition. Brain and Cognition, with neuroscience: examining neurological Vol 50, No 3, pp 341–344. subjectivity and what this means for debates about enhancement technologies Kass, L (2003) Ageless Bodies, Happy (conference paper at ‘Beyond The Body: Souls. The New Atlantis. Spring. Perspectives on Enhancement’, 9–11 April Perrson I and Savulescu J (2008) The perils 2010, Manchester). of Cognitive Enhancement and the Urgent Dana Centre (2002) Neuroethics: Mapping Imperative to Enhance the Moral Character the Field. Brainwork, Special Issue. of Humanity. Journal of Applied Philosophy, Vol 25, No 3, pp 162–177. Farah M (2005) Neuroethics: the practical and the philosophical. Trends in Cognitive Rees M (2004) Our Final Century. London: Science, Vol 9, No 1, pp 34–30. Arrow Books.

The Royal Society Brain Waves Module 1 I January 2011 I 85 Royal Society (2003) Keeping Science Wensley D and King M (2008) Scientifi c Open: the effects of intellectual property responsibility for the dissemination and policy on the conduct of science. London: interpretation of genetic research: lessons Royal Society. from the ‘warrior gene’ controversy. Journal of Medical Ethics, Vol 34, No 6, Strawson P (1960) Freedom and pp 507–509. Resentment. Proceedings of the British Academy, Vol 48, pp 1–25.

The Manchester Manifesto (2009) Available at: http://www.isei.manchester. ac.uk/TheManchesterManifesto

86 I January 2011 I Brain Waves Module 1 The Royal Society 3.4 Governance of neuroscience: challenges and responses

Professor Andy Stirling, University of Sussex

Over past decades, global debates over the energy, medical and material science: nature, pace and direction of research and Levels of knowledge that are suffi cient for innovation have yielded important lessons a technology to meet initial narrow concerning the governance of new practical goals, are rarely suffi cient to technologies. We can identify three broad predict the full range of eventual indirect lessons and seven more specifi c impacts. ‘syndromes’. From these, we can extract Initial visions for many technologies three principles for the ‘social appraisal’ of entirely failed to appreciate wider neuroscience and neurotechnology. The consequences, both benefi cial and lessons of past technologies are all the adverse. On the positive side, for example, more clear and emphatic for being hard- are wireless broadcasting, won in protracted high-stakes semiconductors, lasers or the World Wide controversies, like those over nuclear Web. More negatively, there are examples power, hazardous chemicals, and GM like asbestos, various chemicals (eg DDT, foods. Yet received wisdoms, prevailing PCBs, TBT, and CFCs), thalidomide and values and incumbent interests can retail use of ionising radiation. In all these obscure many key features of these cases, narrow initially-prioritised benefi ts lessons. The challenge is compounded are now generally held to be signifi cantly because some details may be ambiguous, outweighed by unforeseen and unintended with different contexts and interpretations negative impacts. A vast array of other suggesting contrasting policy implications. examples occupy intermediate positions in As a result, there are dangers that some this spectrum like the urban automobile, familiar but readily-avoided mistakes may nuclear power, industrial agrochemicals, be repeated in the fi eld of neuroscience and genetically modifi ed crops. In each of and technology. If society is to maximise these areas there is active debate over prospects for realising the many positive their complex, pervasive, and intertwined potentials in this area—and minimising benefi ts and impacts (ESTO 1999; EEA risks—then it is crucial that these lessons 2001; Stirling 2009). be heeded (EEA 2001; Voß et al. 2006). For good or ill, several of what turned out to be the most signifi cant side effects of Three lessons many new technologies lay well beyond Lesson one the bounds of initial quantifi cation (or even One lesson is taught by cumulative imagination). Indeed, conventional experiences in areas like agriculture, regulatory efforts at anticipation and prior

The Royal Society Brain Waves Module 1 I January 2011 I 87 appraisal were in many cases so infl uential scientifi c and powerful industry circumscribed and rudimentary that a or government bodies, provides no realistic range of implications was typically guarantee that these technologies will fi nally appreciated only by learning through actually come to be established in the actual pursuit of the technologies envisaged forms. themselves in the real world. A resulting A classic example of this is provided by the dilemma is that awareness of our ignorance case of nuclear power. This is not a may actually increase with growing partisan point. Despite current renewed knowledge and experience. Here, it is a interest, there remain serious questions particular feature of neuroscience that— over the relative scale of the future irrespective of its possible applications—an promise of nuclear power when compared increase in such knowledge may in itself be with alternative low-carbon energy hazardous (see Section 3.2). options. Yet in the thirty years after the Neuroscience challenges many deeply Second World War, nuclear power was held convictions around the nature of ‘free almost universally expected in mainstream will’ (see Sections 2.4, 3.3 and Box 5). The scientifi c, industry and government circles more we think we understand human to present a complete and ubiquitous agency, the more diffi cult it becomes to energy source from the 1990s onwards. sustain the necessary fi ctions around its From famous early prognoses that nuclear exercise. As science is translated into electricity would be ‘too cheap to meter’, technology, an expanding array of confi dent predictions of exponential global economic, institutional and political growth rates for this technology were commitments compounds exposures to persistently made by supposedly neutral the consequences of ignorance. Incentives and authoritative scientifi c bodies right up grow to interpret ‘absence of evidence’ as until the 1980s—long after the actual pace ‘evidence of absence’ of harm—leaving us of development was stalled and moving systematically more vulnerable. This places into reverse. In reality, construction rates a high premium on provision for early and for new global nuclear capacity dipped thorough ‘social appraisal’ of the potential almost to zero in the 1990s and presently applications and implications of remain signifi cantly smaller than that of neuroscience. Rather than seeking to avoid wind power—with the discrepancy tending political debate, we should fi nd ways to to increase (Wiliams and Edge 1996; Leach make this as rigorous, comprehensive and et al. 2010). critical as possible (Wynne 1992; EGSG Experience with nuclear power is 2007; Leach et al. 2010). recounted here, because the passage of time has allowed some sense of perspective. In fi elds like neuroscience, Lesson two there has accumulated insuffi cient A second lesson is that: Enthusiastic and experience to determine the validity of highly visible championing of some specifi c some of the more ambitious aspirations new family of technologies by the most

88 I January 2011 I Brain Waves Module 1 The Royal Society and claims. Already, however, there are possible in the real world. Nor does it grounds for caution concerning the ‘over- diminish the essential role of science in hyping’ of certain possible neuroscience opening up and driving forward many new applications. It has become clear, for possibilities. The point is that the particular instance, that benefi ts of genetic testing directions taken by innovation in a fi eld like must be qualifi ed by recognising the neuroscience are powerfully shaped by signifi cance of associated risks (no matter social, as well as material, factors. This is how small) of false diagnosis. Likewise, true even of long-established consumer hopes for a transformative new generation products like the QWERTY keyboard or of drugs to treat depression have thus far VHS videos. Even in highly competitive turned out to be unfulfi lled (see also markets, these technologies came to Section 3.2). In the same way that early global domination, despite being widely expected trends in uptake of GM foods in seen as inferior to possible (even existing) Europe can now be seen to have been alternatives. The same is true of destined for frustration, so these tentative infrastructures like narrow (rather than experiences suggest grounds for caution broad) gauge railways, AC (rather than DC) over exaggerated claims and aspirations. or centralised (rather than distributed) electricity supply, submarine-derived Elsewhere in the life sciences—for civilian nuclear power reactors, early example with monoclonal antibodies and petrol-driven internal combustion engines genome sequencing—we have become (compared to contemporary steam and quite familiar with the dynamics of ‘hype electric technologies, which might feasibly cycles’ generated by privileged parochial have been advanced to similar effect) and interests. This points to the ever-present current general urban dependency on the possibility that even the most authoritative automobile (Williams and Edge 1996; expectations for any given application of EGSG 2007; SPRU 2009). neuroscience will fail to be fully realised— at least on initially stated timescales. Each of these cases demonstrate how Again, this presents an imperative for economic and political power structures, deeper, more comprehensive and critical property rights, income distributions, social appraisal and political debate (Voß dominant values, and incumbent market et al. 2006; SPRU 2009). interests can help ‘lock in’ certain innovation pathways and ‘crowd out’ others. Resource constraints, path Lesson three dependencies, learning effects and scale A third—even more crucial—lesson is that: economies in a fi nite world, all mean that The particular paths followed by scientifi c and our global society cannot equally realise technological developments in any given area the full potential of all feasible and viable are not pre-determined by nature. innovation trajectories. Whether deliberately or blindly, societies choose This insight does not deny that physical which paths to follow or not. Looking reality and technical feasibility impose forward, we see examples in choices highly demanding constraints on what is

The Royal Society Brain Waves Module 1 I January 2011 I 89 between particular low carbon energy or possibilities for innovation, by pursuing sustainable agriculture pathways. Likewise instead alternative trajectories that later within neuroscience—and between leave these practically unrealisable. For neuroscience and alternative applications— instance, this is widely seen as true of those innovation pathways that we end up locked-in global water supply pursuing will typically represent only a infrastructures—which militate against small subset of those that were initially more effi cient and environmentally potentially viable. Which direction we go in benefi cial institutions and practices. depends as much on political as on Likewise, neuroscientifi c interventions in technical choices. This is why social areas like attention defi cit hyperactivity appraisal of neuroscience research and the disorder (ADHD), cognitive enhancement, regulation of associated technologies or brain interference may foreclose should pay as much attention to driving possibilities of alternative institutional or intentions and goals and associated power behavioural provision (see also Section structures as to claimed benefi ts and 3.2). Here as elsewhere, it could emerge supposed risks. Are these for military or that potentially preferable ‘open source’ civilian ends; northern or southern policies or practices are eclipsed by greater markets; public or private applications; IP- enthusiasm of existing research and intensive or open-source development? innovation systems for IP-intensive (SPRU 2009; Leach et al. 2010). neuroscience-specifi c applications (EGSG 2007).

Seven syndromes From these three lessons, there emerges a Missed opportunities series of seven more specifi c ‘syndromes’ A particular economy may fail to gain to look out for in the governance of desired leadership in a successfully neuroscience and technology. These anticipated developmental direction, with interact, but each may be distinguished in benefi ts accruing instead to competitors its specifi c causes, symptoms or making different choices at earlier stages. remedies. For ease of recall, each is There are many historic examples of this, labelled below with a simple phrase. An including what are conceded on all sides appreciation of these interweaving to have been misconceived British choices dynamics in knowledge, technology and in the 1960s of nuclear reactor design. encompassing society is essential to any Again, this is as true of different robust design for associated governance applications within the fi eld of intervention (Leach et al. 2010). neuroscience as of possible non- neuroscience alternatives that a general prioritising of science-based approaches Foregone Futures might obscure. For instance, there are Global society as a whole may fail to fulfi l queries whether the driving objectives of the benefi ts of some particular set of UK neuroscience research appropriately

90 I January 2011 I Brain Waves Module 1 The Royal Society balance preventive public health or regulatory appraisal, to explicitly examine individualised private health? (see also power relations and vested interests within Section 3.2) Does a ‘preventive’ focus rest research and innovation systems, the on practices that address entire greater the exposure to this syndrome populations (implying collective public (SPRU 2009). provision) or proprietary products targeting specifi c sub-populations (implying more readily privately-appropriable revenues)? Convenient blinkers Either way, structural shifts in global Choices among possible technological markets may signifi cantly affect the pathways may be further impeded or prospects for differing patterns of misguided by the contrived invisibility of neuroscience research (see also Section unforeseen, or unintended, side effects. 3.1). These may substantively affect Conventional risk assessment focuses on a competitiveness in presently undetermined typically rather limited set of outcomes. ways (Williams and Edge 2006). These are circumscribed by the remits of regulatory institutions (eg on health rather than equity) and by what can be Forced tramlines documented and quantifi ed in currently- This is like ‘foregone futures’, but can play accredited evidence. These out globally or locally. In contrast to institutionalised blinkers may create further reduced competitiveness from historical or vulnerability to strategic manipulation of politically innocent decision-making, this the kind occurring in ‘forced tramlines’. In syndrome is exacerbated by the deliberate this way, society may be presented with an exercise of power within research and unbalanced picture of the most attractive innovation systems. Either way, economies alternatives. By the time gaps or bias may be forced by narrow incumbent becomes evident, it may be too late easily interests incorrectly to anticipate and to change course. commit to a particular innovation Examples of this syndrome may be seen trajectory, that turns out in actuality to be retrospectively in persistent global inferior to contrasting alternatives. An dependencies on technologies like fossil example is the early neglect by the fuels and carcinogenic and stratospheric centralised UK power generating system of ozone-depleting halogenated large national renewable energy hydrocarbons. These short-sighted capabilities and resources. In similar ways, attitudes towards what are now there are possibilities that current driving acknowledged to be prohibitive health or motivations behind neuroscience research environmental effects have thus (such as pursuing ‘rents’ on IP or contributed to systematic neglect of enhanced military applications), may ‘lock superior substitute technologies. In this in’ to certain research and innovation way, there are dangers that neuroscience pathways. The greater the diffi dence research in areas like incapacitating displayed in research governance or chemical weapons (see Sections 2.2 and

The Royal Society Brain Waves Module 1 I January 2011 I 91 3.2) and other forms of manipulation or See no evil interference with brain function may yield A particular technology may realise its side effects not only in direct use, but also initial promise, but this very feasibility may in less visible indirect ways. Crucial here is itself create opportunities for deliberate or that the mere existence (even positing) of inadvertent misuse. This raises the very some of these technologies may—even simple and familiar challenge of without tangible physical effects—exert contending (sometimes perverse) human certain kinds of indirect social impact. intentions. Although readily foreseeable in Falling outside the conventional scope of the same terms as benign uses, malign regulatory attention, there is currently no applications are typically understated in effective provision for the taking of regulatory assessment, sometimes for responsibility for these kinds of wider legal reasons. Yet easily anticipated effects implications (Wynne 1992). may be of a magnitude that seriously jeopardises overall benefi ts. This is exemplifi ed by the paradox that military Shared delusion aims are at the same time so prominent A particular technological pathway, and so under-scrutinised in global despite being widely adopted, may still research. Roughly one third of worldwide fail to achieve the expected (or promised) human effort in research and innovation is aims on any reasonable timescale. This devoted—directly or indirectly—to refi ning may be entirely independent of ways to perpetrate premeditated organised countervailing pressures or competing violence. Yet the prospect of violent innovations. It may be seen, for instance, intentions is often regarded as an irrelevant in experience hitherto with nuclear factor in appraisal of supposedly ‘neutral’ fusion power. Here, the expected technologies. With an uncertain proportion commercialisation horizon has remained of world neuroscience research directed at a steady three decades or so for the towards military ends, the picture here is past fi fty years. Yet commitments are particularly obscure (see Section 3.2). sustained on a roughly constant scale However, this ‘see no evil’ syndrome has irrespective of this, over periods that see long been acute with ‘dual use’ entire cycles in the rise and fall of other technologies in the nuclear, biological, and technologies. Where a signifi cant chemical sector and is now frequently proportion of current investment in raised of transgenics and synthetic biology. neuroscience rests on some of the more Misuse even of ostensibly non-military colourful ‘magic bullet’ claims made on applications of neuroscience may hold behalf of applications in fi elds like profound security implications, for instance cognitive enhancement (see Section 2.2 in prospects of ‘remote brain imaging’, and Box 2), national security or criminal ‘brain fi ngerprinting’ and ‘transcranial justice (see Sections 3.2, 3.3 and Box 1), magnetic stimulation’ (Voß et al. 2006) (see then it would be prudent to keep a wary Section 3.2 and Box 4) Some of these eye open for prospects of this kind of issues will be addressed as part of syndrome (Leach et al. 2010).

92 I January 2011 I Brain Waves Module 1 The Royal Society Module 3 of the Brain Waves project on complex and intractable. Yet there does neurosience, confl ict and security. exist a well developed body of understanding and practice suggesting a series of practical policy responses. Unwise aspirations Although there are no panaceas, these This syndrome raises a familiar and may offer important ways systematically to innocent human foible: wishful thinking. A maximise potential benefi ts and minimise particular technology may deliver on its adverse impacts. This is despite the fact professed aims, but these may themselves that what constitutes a ‘benefi t’ or ‘impact’ turn out to be questionable. For instance, it may be uncertain or contested (ESTO is precisely the success of visions of 1999; EEA 2001; EGSG 2007). affordable autonomous individual mobility Perhaps the best way to express these that have led to domination of the urban responses is through three principles for automobile and associated pollution and ‘social appraisal’ of neuroscience and gridlock. Despite undoubted benefi ts of neurotechnology: responsibility, increased material affl uence, similar precaution and engagement. These move concerns are voiced about intensifi cation beyond narrow, technical, of ‘the consumer society’. Such issues compartmentalised notions of ‘risk may also arise in neuroscience. For analysis’, ‘regulatory assessment’ or instance, a companion section in this ‘ethical deliberation’. They allow ‘social volume (see Section 3.2) asks whether appraisal’ to develop in ways that enhanced memory faculties in old age are transcend entrenched institutional and actually preferable to ‘benign neglect’? cultural divides. In particular, they equally Private provision for expensive forms of avoid the perils of cornucopian notions of cognitive enhancement may also seriously ‘foresight’ and apocalyptic ideas of aggravate social inequalities (see also ‘precaution’. They help navigate a path Sections 3.2 and 3.3). Such innovation between technocratic forms of ‘expert pathways may be judged problematic not analysis’ and the more romantic because of ‘side effects’, but in terms of aspirations to ‘public participation’. Going the intended aims themselves. Concerns beyond organisational remits and formal compound even if—especially if—these procedures, these principles are shared innovations turn out to be ‘successful’. responsibilities of a range of actors and In neuroscience and technology, as practices—not just ‘regulators’ or elsewhere, ‘we should be careful what ‘decision makers’. Rather than sidelining we wish for’ (EGSG 2007). critical politics, they actively promote more mature political debate. Taken together, they offer more rigorous and Three principles democratically accountable paths for the Taken together, these challenges for the pursuit of neuroscience and governance of neuroscience and neurotechnology (Voß et al. 2006). neurotechnology may seem dauntingly

The Royal Society Brain Waves Module 1 I January 2011 I 93 Responsibility within research and innovation systems Governance of neuroscience and (Voß et al. 2006). neurotechnology should be demonstrably In research prioritization and funding, as independent from vested institutional, well as innovation, development and economic and political interests. These regulation, measures should be enacted include academic disciplines, networks to avoid the undue privileging of and institutes. Rather than treating neuroscience over other socially feasible appraisal as the exclusive preserve of and benefi cial applications. For instance, specialist expertise (including ethics and appraisal should explicitly and social science), this requires open, symmetrically compare an array of diverse proactive, accountable and transparently alternative technology and policy options political oversight of innovation systems and potential substitutes for each and regulatory structures. It should be neuroscience application. This should recognised in various ways that begin with prioritised societal needs, rather developers, regulators, and scientists than favoured ‘solutions’ in search of themselves are responsible and applications. It should also afford accountable for the indirect and comparable attention to organizational and ‘unanticipated’ impacts of neuro- behavioural innovations, as well as IP- innovations as well as their directly intensive scientifi c or technology-based foreseeable effects. For instance, this may options. Greater value might be placed on raise issues around the additive or diversity in research and development synergistic effects of neuroscience portfolios, such as to provide a variety of applications in combination with other complementary options for addressing technologies, as well as possibilities for each focal problem. This involves a inadvertent or malign misuse. premium on increased international Deliberation over such issues should take collaboration and co-ordination in place at the earliest ‘upstream’ stages in neuroscience research (EEA 2001; innovation and policy processes, thus SPRU 2009). helping foster more benign pathways before ‘lock-in’ occurs. It should include account of industrial trends and cumulative Precaution behavior (as often missed in case-by-case Rather than simply assuming claimed regulation of individual applications). It benefi ts, regulation of neuroscience and should scrutinise the reversibility, ‘agility’ neurotechnology should require and ‘resilience’ of associated institutional justifi cation of the social aims of or industrial commitments in the event of neuroscience applications and their negative experience. The more reversible alternatives. This helps address otherwise the commitments, the more relaxed might opposing concerns, in that developers are be the attitude to approval. Above all, such concerned that regulation tends deliberation should explicitly refl ect on the systematically to neglect the importance of implications of the exercise of power benefi ts, while critics are concerned at

94 I January 2011 I Brain Waves Module 1 The Royal Society credulous acceptance that supplier dynamics between unconditional approval advocacy equates with legitimate societal of ‘safe’ innovations or irrevocable benefi t. In examining pros and cons, ‘banning’ of questionable products. Where appraisal should go beyond probabilistic residual uncertainties remain over methods, to scrutinise a wider range of otherwise favourable innovations, then uncertainties, sensitivities and scenarios these may be addressed by deliberately- than is normal in risk assessment or cost- designed provision for liability, benefi t analysis. It should deliberately responsibility or product stewardship search for ‘blind spots’, gaps in knowledge (ESTO 1999; EEA 2001). and divergent scientifi c views of a kind not conventionally publicised by expert advisory committees. In specialist Engagement deliberations as in public communications, Principles of responsibility and precaution it should be clearly emphasised that should be implemented in research and ‘absence of evidence’ is not ‘evidence of innovation governance in a fashion that is absence’ of harm (ESTO 1999). subject to open, accessible and democratically-accountable public Where evidence is lacking, appraisal engagement. There exists a wide variety should attend to proxies of possible harm of methods, procedures, and institutions as well as manifest harm itself. For for facilitating this. Different approaches instance, rapid dissemination or eventual will be appropriate in contrasting contexts. ubiquity of a neuroscience innovation are But certain basic features span the not in themselves hazardous, yet remain differences. For instance, design and relevant to the scale of possible implementation of governance procedures unforeseen harm. Rather than presuming should draw on relevant non-expert ‘proof’ to be singular or self-evident, knowledge and experience as well as a appraisal should deliberate over levels of diversity of specialist expertise. Depending proof, who should bear the burden of on context, this requires regulation to go persuasion and who should resource the beyond the most immediately-implicated gathering of evidence and conduct of neuroscience disciplines to include analysis. It should openly acknowledge patients, families, teachers, healthcare that such matters are intrinsically value- staff, consumers and local communities. based and therefore political in nature. Although specialists are often also all Treating them more explicitly and distinctly, these things, their engagement specifi cally offers to improve both democratic and with neuroscience and technology issues professional accountability. is conditioned by their roles as Likewise, appraisal should avoid over- specialists—involving interests and reliance on glamorous theoretical evaluative perspectives as well as modeling at the expense of scientifi cally technical knowledge. This is as true of less-rewarding (yet crucial) monitoring and social scientifi c and ethical expertise, as it surveillance. This also helps defuse the is of the natural science and engineering otherwise polarised ‘all-or-nothing’ political specialisms (EGSG 2007; Stirling 2008).

The Royal Society Brain Waves Module 1 I January 2011 I 95 Particular attention should be paid to the decision makers a plurality of equally- interests and perspectives of ‘stakeholder reasonable possible policies—each with groups’ who hold themselves to be their associated conditions for adoption. It possibly affected, whether or not these is in this way that public engagement of all groups are formally organised or kinds can avoid itself becoming a recognised. The point here is to engage ‘technical fi x’—and inform and enrich with a diversity of relevant values and (rather than subvert) democratic politics. interests—including those of academic Only through ‘plural and conditional’ institutions, research networks and signals to policy, may public engagement specialist disciplines. As has been simultaneously support both scientifi c demonstrated in regulatory experience like rigour and democratic accountability in the that with bovine spongiform governance of neuroscience (Stirling 2008; encephalopathy (BSE), even apparently Leach et al. 2010). uninformed and spurious sensibilities like the ‘yuk factor’ can sometimes contain important intuitions. If considered in a References and further reading measured fashion rather than rejected as BIS (2009) Stilgoe J (ed), The Road Ahead: irrational, such considerations can be Public Dialogue on Science and Technology, indirectly informative, or serve to prompt Department for Business, Innovation and valuable attention to otherwise neglected Skills. London: HMSO. issues. The point here is not simply to foster ‘trust’, ‘credibility or ‘acceptance’, EEA (2001) Gee D, Harremoes P, Keys J, but substantively to infl uence the nature MacGarvin M, Stirling A, Vaz S, and and direction of the scientifi c and Wynne B Late Lesson from Early Warnings: technological pathways that are pursued. the precautionary principle 1898–2000. Copenhagen: European Environment To this end, public engagement means Agency. being as rigorous in asking questions in social appraisal of neuroscience, as in EGSG (2007). Expert Group on Science deriving the answers. It is only in this way and Governance (Felt U, Wynne B, that there can be confi dence over the Callon M, Goncalves M, Jasanoff S, institutional frameworks and procedures Jepsen M, Joly P-B, Konopasek Z, May S, through which appraisal and governance Neubauer C, Rip A, Siune K, Stirling A, and are undertaken. Here, the point is not that Tallachini M (2007) Science and public engagement delivers apparently Governance: taking European Knowledge simple prescriptive fi ndings to policy Society Seriously, Report to the European making—with the task of decision makers Commission DG Research. then reduced merely to accepting or ESTO (1999) European Science and rejecting. Depending on the context, the Technology Observatory, On Science and role of public engagement may lie more in Precaution in the Management of ‘opening up’ a diversity of possible Technological Risk: Volume I—a synthesis choices, or in conveying to political report of case studies. Seville: European

96 I January 2011 I Brain Waves Module 1 The Royal Society Commission Institute for Prospective Stirling A (2009) Science, Precaution and Technological Studies. the Politics of Technological Risk: converging implications in evolutionary Leach M, Scoones I and Stirling A (2010) and social scientifi c perspectives. Annals of Dynamic Sustainabilities: Technology, the New York Academy of Sciences, Vol Environment, Social Justice. London: 1128, pp 95–110. Earthscan. Voß J, Bauknecht D and Kemp R (eds) SPRU (2009) Scrase I, Stirling A, Geels F, (2006) Refl exive Governance for Sustainable Smith A and Van Zwanenberg P, Development. Cheltenham: Edward Elgar. Transformative Innovation: A report to the Department for Environment, Food and Williams R and Edge D (1996) The Social Rural Affair. Brighton: University of Sussex, Shaping of Technology. Research Policy, Science and Technology Policy Research. Vol 25, pp 865–899.

Stirling A (2008) Opening Up and Closing Wynne B (1992) Uncertainty and Down: power, participation and pluralism Environmental Learning: reconceiving in the social appraisal of technology, science and policy in the preventive Science Technology and Human Values, Vol paradigm. Global Environmental Change, 33, No 2, pp 262–294. pp 111–127.

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