The editors of this volume, Ilona Roth and Payam Rezaie, have assembled a valuable collection of chapters providing an excellent overview of a wide range of areas relevant to autism research. The book tackles the challenge of early detection; the complex biology of autism, including genetics (from linkage, to association, to CNVs), the autistic brain (from the perspectives of MRI, DTI, MEG, neuroanatomy and epilepsy) and molecular aspects of autism (from serotonin to oxytocin); the complex psychology of autism (from cognitive models, language, memory and executive function); and the challenge of education in autism.

Autism research is currently enjoying considerable growth, with hundreds of researchers joining in the hunt to understand this important set of conditions. This book showcases some of the best autism scientists in the UK who are contributing to this international effort. The editors are to be congratulated on pulling this collection together, since this will inspire a new generation of autism scientists among contemporary students. The hope is that an anthology of this kind will be produced every few years, so we can track this fast-changing field. This multi-disciplinary book nicely illustrates how autism is a multi-level phenomenon that will need integration across levels. This book exemplifies how each level must be represented and contributes to the bigger picture.

Skeletal muscles are the engines of the body. They account for over a quarter of its weight and the major part of its energy expenditure. They are attached to the bones of the skeleton and so serve to produce movements or exert forces. Hence they are central to such activities as voluntary movement, maintenance of posture, breathing, eating, directing the gaze and producing gestures and facial expressions. Skeletal muscles are activated by motoneurons, as we have seen in previous chapters. Their cells are elongate and multi-nuclear and the contractile material within them shows cross-striations. Hence skeletal muscle is a form of striated muscle. In contrast, cardiac and smooth muscles have cells with single nuclei, and smooth muscles are not striated; we shall examine their properties in Chapters 12 and 13.

Anatomy

Skeletal muscle fibres are multi-nucleate cells formed by fusion of elongated uni-nucleate cells called myoblasts whose respective nuclei become arranged around the edge of the fibre. Mature fibres may be as long as the muscle (Figure 9.1) of which they form part, and 10 to 100 µm in diameter. Bundles of muscle fibres are surrounded by a further sheet of connective tissue, the perimysium, and the whole muscle is contained within an outer sheet of tough connective tissue, the epimysium. These connective tissue sheets are continuous with the insertions and tendons which serve to attach the muscles to the skeleton. An excellent blood supply provides a network of blood capillaries between individual fibres.

Skeletal muscles are innervated by motor nerves. Excitation of the motor nerve is followed by excitation and contraction of the muscle. Thus excitation of one cell, the nerve axon, produces excitation of another cell which it contacts, the muscle fibre. The region of contact between the two cells is called the neuromuscular junction. The process of the transmission of excitation from the nerve cell to the muscle cell is called neuromuscular transmission. This chapter is concerned with how this process occurs.

Regions at which transfer of electrical information between a nerve cell and another cell (which may or may not be another nerve cell) occurs are known as synapses, and the process of information transfer is called synaptic transmission. Neuromuscular transmission is just one form of synaptic transmission; we shall examine the properties of some other synapses in the following chapter.

The neuromuscular junction

Each motor axon branches so as to supply an appreciable number of muscle fibres. Figure 7.1 shows the arrangement in most of the muscle fibres in the frog. Each axon branch loses its myelin sheath where it contracts the muscle cell and splits up into a number of fine terminals which run for a short distance along its surface. The region of the muscle fibre with which the terminals make contact is known as the end-plate. Structures and events occurring in the axon are called pre-synaptic, whereas those occurring in the muscle cell are called post-synaptic.

Autism is an organic neurodevelopmental disorder, the prototypical disorder of the group of conditions known as the pervasive developmental disorders. Genetic findings and general population studies indicate that these types of disorders (commonly referred to as Autism Spectrum Disorders (ASD) or more recently Autism Spectrum Conditions (ASC)), probably occur along a broad continuum of severity. This spectrum of presentations include those individuals with a definable disorder and clear evidence of social impairment and incapacity, qualitatively similar behavioural characteristics in other family members (described as the broader autism phenotype), and a range of more subtle social, communicative and repetitive behaviours in the general population. ASD are no longer considered rare, with a replicated reported prevalence of approximately 1 in 100. With increasing public and professional awareness and an emphasis on the importance of both early recognition and access to so-called ‘early interventions’, there is an expectation of early identification, assessment and diagnosis. This chapter will review the evidence for ASD, the epidemiology and prevalence of these disorders and consider (using the framework of the National Autism Plan for Children) a range of assessment and diagnostic procedures including the use of the best estimate clinical diagnosis for clinical and research practice. Inevitably, the purpose of assessment informs the format and content of the diagnostic process. The chapter will conclude by considering some current diagnostic challenges.

Nervous systems

One of the characteristics of higher animals is their possession of a more or less elaborate system for the rapid transfer of information through the body in the form of electrical signals, or nervous impulses. At the bottom of the evolutionary scale, the nervous system of some primitive invertebrates consists simply of an interconnected network of undifferentiated nerve cells. The next step in complexity is the division of the system into sensory nerves responsible for gathering incoming information, and motor nerves responsible for bringing about an appropriate response. The nerve cell bodies are grouped together to form ganglia. Specialized receptor organs are developed to detect every kind of change in the external and internal environment; and likewise there are various types of effector organ formed by muscles and glands, to which the outgoing instructions are channelled. In invertebrates, the ganglia which serve to link the inputs and outputs remain to some extent anatomically separate, but in vertebrates the bulk of the nerve cell bodies are collected together in the central nervous system. The peripheral nervous system thus consists of afferent sensory nerves conveying information to the central nervous system, and efferent motor nerves conveying instructions from it. Within the central nervous system, the different pathways are connected up by large numbers of interneurons which have an integrative function.

Certain ganglia involved in internal homeostasis remain outside the central nervous system.

Although brain structure in Autism Spectrum Disorders (ASD) has been extensively investigated using magnetic resonance imaging techniques, considerable heterogeneity across studies exists for findings at the level of individual brain structures and regions. An important theme to emerge, however, is of structural alterations within the neural circuit that has become known as the ‘social brain’ – including the amygdala, superior temporal sulcus, fusiform face area and orbito-frontal cortex. Evidence points also to altered structure in the caudate nucleus in association with restricted and repetitive behaviours. Diffusion tensor imaging studies suggest aberrant connectivity between social brain structures and also between these areas and other cortical regions. Important future roles for structural neuroimaging will include longitudinal studies to investigate developmental trajectories in ASD, and efforts to join together neuroimaging and genomic techniques and to relate these findings to neuropathological studies.

Background

The notion that mental illness is a somatic disorder of the brain was put forward in 1845 by Wilhelm Griesinger (Griesinger, 1845), first Professor of psychiatry and neurology in Berlin, and has been actively investigated ever since. The initial work was neuropathological as there existed no means of visualising the brain in life but clear cut results were obtained in some disorders (Alzheimer, 1897; Wernicke, 1881) and where no such findings could be demonstrated as in schizophrenia, work still continued (Dunlap, 1924; Klippel and Lhermitte, 1909).

Muscle cells have become adapted to a variety of different functions during their evolution, so that in other muscle types the details of the contractile process and its control show differences from those in vertebrate skeletal muscles. These final two chapters successively examine the properties of mammalian heart and smooth muscle.

Structure and organization of cardiac cells

Cardiac cells are considerably smaller than skeletal muscle fibres; they are typically up to 10 μm in diameter and 200 μm in length (Figure 12.1). However, adjacent cardiac cells are mechanically and electrically coupled both in a branched and in an end-to-end manner by intercalated disks to give a syncytium through which both electrical activity and mechanical forces are transmitted (Figure 12.1a). Atrial and ventricular myocytes specialized to generate mechanical activity contain contractile elements whose structure is similar to that found in skeletal muscle. Thus they also show thick myosin and thin actin filaments aligned transversely (Figure 12.1b). Cardiac myocytes are accordingly cross-striated in appearance. They similarly contain mitochondria, sarcoplasmic reticulum and transverse tubules. However, the sarcoplasmic reticulum is less developed. In the ventricle, it makes complexes with transverse tubular membrane at dyad rather than triad junctions. In atrial myocytes, the transverse tubular system is considerably less developed, and sarcoplasmic reticulum makes junctions at caveolae in the membrane surface. However, there are additional cardiac cell types with differing specializations that include cells that primarily generate and conduct electrical impulses.

Autism is a neurodevelopmental disorder characterised by impaired social skills, communication deficits and repetitive behaviours. Alterations in a number of neurotransmitter signalling systems and neuroregulatory proteins have been reported in individuals with autism spectrum disorders (ASD). The most compelling evidence seems to suggest an imbalance in excitatory and inhibitory impulses in the premature autistic brain, combined with defects in secondary neurotransmitter systems, resulting in autistic traits. Serotonin, known to be disrupted in ASD, facilitates the release of both reelin and oxytocin, with excessive levels of serotonin resulting in a decrease in reelin and oxytocin. Deficits in developmental growth factors, such as reelin, may regulate or be regulated by oxytocin, thus contributing to both neurodevelopmental arrest and altered social behaviour, characteristic for the autistic spectrum. In this review we therefore concentrate on the role of the serotonin neurotransmitter and the two neuroregulatory proteins (reelin and oxytocin), and evaluate the pharmacological interventions available at the moment, associated with the latter neurochemical changes in autism.

Introduction

Autism is regarded as a heterogeneous neurodevelopmental disorder, characterised by a spectrum of impaired social skills, communication deficits, repetitive behaviour and frequently associated with co-morbid disorders (e.g. obsessive compulsive disorder, epilepsy, Tourette syndrome, attention deficit hyperactivity disorder, tuberous sclerosis and Fragile X syndrome, among others; Gillberg and Billstedt, 2000). A significant number of individuals with autism also show hyperactivity, anxiety and self-injurious behaviours.

This chapter introduces a modern functional neuroimaging method, magnetoencephalography (MEG), and addresses how this technique is being applied to study dynamic brain activity and neural processing in autism. An outline will be given of relevant technical and analytical approaches, before discussing functional systems and presenting important findings associated with autism, using MEG. The focus is directed at aspects of neural processing that are affected in individuals on the autism spectrum, including auditory processing, semantic processing, face processing and theory-of-mind (progressed through study of imitation-related processes linked to activity within the ‘mirror neuron’ system). While MEG is a relatively new tool, the studies available to date lend some support to the notion that autism involves altered cognitive strategies as opposed to cognitive impairments or deficits. In addition, the research on this subject is reviewed, which suggests that MEG may help define and further characterise subclinical epilepsy and epileptiform activity (seizures) in individuals with autism spectrum disorders.

Instrumentation and measurements

Magnetoencephalography (MEG) is one of a range of functional neuroimaging methods that may be applied to the study of autism. It is of interest because it allows changes in activity to be followed dynamically with millisecond resolution, and thus provides direct information on the evolution of processing along neural pathways.

By far the most common method of imaging brain activity is functional magnetic resonance imaging (fMRI).

Memory can be thought of as the capacity of an organism to utilise past experience in order to direct current and future behaviour. Such a capacity entails the registering and recording – the encoding – of that experience in such a way as to enable its subsequent retrieval. Retrieval can be either voluntary or involuntary and the resultant information may or may not form part of conscious awareness. The processes of encoding and retrieval are the result of a range of psychological processes and are in turn influenced by other factors both psychological and physiological. In this respect, study of the patterning of memory processes and the factors that influence their operation can give clues to the wider psychological functioning of the individual. It is in this last respect that the study of memory can enhance our understanding of people with Autism Spectrum Disorder (ASD). ASD is not ‘caused by’ difficulties in memory, but the patterning of memory seen in individuals with ASD can provide clues to underlying cognitive and neuropsychological atypicalities as well as giving us a window onto their inner experiences of the world.

Preliminary remarks

Any discussion of memory in ASD must first emphasise the heterogeneous nature of the conditions that comprise the autism spectrum. An important aspect of this diversity is the distinction between ASD with accompanying intellectual disability (often referred to as ‘low-functioning ASD’ or LFA) and ASD without it (often termed ‘high-functioning ASD’ or HFA), a group that, as here defined, also includes individuals with Asperger's disorder.

Studies of structural language in individuals with autistic spectrum disorder (ASD) are reviewed, and theories of the causes of structural language anomalies and impairments in ASD are presented and discussed. It is concluded that the factors that may contribute to language impairment in individuals with ASD are many and various; that impaired mindreading is always implicated, but that some additional and critical causal factor remains to be conclusively identified.

Introduction

Languages, defined in formal or structural terms, are systems of mainly arbitrary items (e.g. sounds, signs or written letters; morphemes; words) with rules for combining items to convey meaning to others with shared knowledge of the language. Language can be analysed and characterised at the level of grammar (morphology and syntax) and meaning (semantics); and, in the case of spoken language, phonology.

Communication, on the other hand, involves the use of language in social interaction, whether directly in face-to-face talk, or indirectly as in, for example, a recorded phone message or a Last Will and Testament. Thus, language is a means, or method, of communicating. Non-linguistic, or non-verbal, signals including facial expression, gesture, and body language also provide means, or methods, of communicating. Prosody, which involves the use of vocal tone, pitch, rhythm and inflexion during speech also comes under the heading of non-verbal communication. Factors influencing the communicative use of language and non-verbal communication signals in specific instances can be analysed and characterised in the study of pragmatics.

Smooth, unstriated muscle forms the muscular component in the walls of hollow organs such as the gastrointestinal tract, the trachea, bronchi and bronchioles of the respiratory system, blood vessels in the cardiovascular system and the urogenital system. Smooth muscle contracts and relaxes much more slowly than skeletal muscle, but is much better adapted to sustained contractions. The load against which smooth muscle works is typically the pressure within the tubular structures that they line. In organs such as the blood vessels, they are responsible for a steady intraluminal pressure brought about by their tonic contraction. In the gastrointestinal tract, they produce a phasic contraction that propels its contents onward. They also occur in the iris, ciliary body and nictitating membrane in the eye, and are the small muscles which erect the hairs. The functions of smooth muscle in the body are thus diverse. This is reflected in their wide variations in structure and detailed physiological properties, for which this chapter only provides a brief introduction.

Structure

Smooth muscle cells (Figure 13.1) are uni-nucleate, elongated, often spindle-shaped and much smaller than the multi-nucleate skeletal muscle fibres. They are typically 3–5 μm in diameter and up to 400 µm long. Their thick myosin and thin actin filaments are arranged longitudinally in the cytoplasm, but are not aligned transversely. The cells consequently show no visible striations or sarcomeres. The actin filaments are attached in bundles at dense bodies in the cytoplasm, and to attachment plaques at the membrane.

Initiation of movement, whether in the form of voluntary action by skeletal muscle, or the contraction of cardiac or smooth muscle, is the clearest observable physiological manifestation of animal life. It inevitably involves activation of contractile tissue initiated or modulated by altered activity in its nerve supply. An appreciation of the function of nerve and muscle, and of the relationships between them is thus fundamental to our understanding of the function of the human body.

This book provides an introductory account of this important aspect of physiology, in a form suitable for students taking university courses in physiology, cell biology or medicine. It seeks to give a straightforward account of the fundamentals in this area, whilst including some of the experimental evidence upon which our conclusions are based.

This fourth edition includes new material reflecting the exciting discoveries concerning the ion channels involved in electrical activity, the activation of skeletal muscle and the function of cardiac and smooth muscle, reflecting important new developments made in these rapidly growing fields. We are grateful for expert advice and specialist comments from Drs. James Fraser, Ian Sabir and Juliet Usher-Smith, Physiological Laboratory, Cambridge, and Thomas Pedersen, Department of Physiology, University of Aarhus, and continue to benefit from the insight and wisdom left us by the late David Aidley, in these revisions.

The term ‘Autism Spectrum’ currently embraces a cluster of conditions known as Autism Spectrum Disorders or ‘ASD’, that are characterised by impairments in social functioning, verbal and non-verbal communication, together with repetitive and stereotypical patterns of behaviour and interests. Impairments within each of these ‘core’ clinical domains can range in severity from mild to profound, and intellectual disability may be present in more severe cases. The classification of ASD broadly includes classic autism (childhood autism; autistic disorder), Asperger syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) (Levy et al. 2009). Classic autism is frequently diagnosed around the age of 3 (and may be diagnosed as early as 2 years of age) (Baird et al. 2003; Landa, 2008). Asperger syndrome often presents with more subtle symptoms, and is usually diagnosed later on in childhood (frequently around 11 years of age), and occasionally in adults (Howlin and Asgharian 1999; Toth and King 2008).

While the precise causes of autism remain a mystery, prevalence estimates have risen almost exponentially within the last six decades, making autism a major global concern. Initially considered rare, current estimates suggest that as many as 1% of children under the age of 8 years may have an autism spectrum diagnosis (Baird et al. 2006), with boys being diagnosed up to four times more than girls. More than half a million people are thought to be living with autism in the UK alone (National Autistic Society, 2007), and in the US autism is considerably more common today than it was in the 1980s (Yeargin-Allsopp et al. 2003).

There is widespread concern about the apparently growing prevalence of autism, although this increase may be due, in large part, to factors such as changes in diagnostic criteria and ascertainment practices. Public and scientific interest in the causes and fundamental nature of autism has never been stronger. Research in this field has grown exponentially in the last twenty years, with significant financial support in this area provided by Governments, Research Councils and private charities. Studies spanning a whole range of disciplines share the goals of elucidating the core phenomena and underlying aetiology, thereby informing therapeutic interventions, as well as offering valuable insights into normal functioning. Research by individuals and groups in the UK has played a leading role in addressing key unanswered questions about autism, including its causes and psychological substrates, the underlying brain mechanisms, and the most effective ways to work with and support people with autism and their families.

A major conference which we were privileged to organise in 2007, entitled: ‘Autism Research UK: from diagnosis to intervention’ hosted by the Open University and sponsored by the Medical Research Council, Wellcome Trust, Autism Speaks and a number of other organisations, provided an effective backdrop to this book. At this first national meeting of this scope, internationally renowned speakers and chairpersons convened with representatives from the Medical Research Council, the Wellcome Trust, Economic and Social Research Council, National Autistic Society and Autism Speaks for two days of discussion and debate aimed at elucidating ways forward in understanding the autism spectrum and helping affected individuals and their families.

The functioning of the nervous system depends largely on the interactions between its constituent nerve cells, and these interactions take place at synapses. In most cases synaptic transmission is chemical in nature, so that, as in neuromuscular transmission, the pre-synaptic cell releases a chemical transmitter substance which produces a response in the post-synaptic cell. There are a few examples of electrically transmitting synapses, which we shall consider briefly at the end of this chapter.

Acetylcholine is only one of a range of different neurotransmitters. Figure 8.1 shows some of the variety found in the central nervous system. For a long time it was thought that any one cell would only release one neurotransmitter, but several cases where two of them are released at the same time are now known.

Different chemically transmitting synapses differ in the details of their anatomy, but some features are common to all of them. In the pre-synaptic terminal the transmitter substance is packaged in synaptic vesicles. The pre- and post-synaptic cells are separated by a synaptic cleft into which the contents of the vesicles are discharged. There are specific receptors for the neurotransmitter on the post-synaptic membrane.

Just as with the neuromuscular junction, our knowledge of how synapses work was greatly affected by the invention of the intracellular microelectrode. Much of the fundamental work with this technique was performed by J. C. Eccles and his colleagues on the spinal motoneurons of the cat, so it is with these that we shall begin our account of synapses between neurons.