To what extent is the autistic spectrum disorder a condition of nature?

Mariia Safonova

Safonova Mariia

To what extent is the au.s.c spectrum disorder a condi.on of nature?

1. Introduc2on

Au2s2c spectrum disorder (ASD) is a term used to describe a group of neurodevelopmental condi2ons, being characterised by specific diagnos2c features that are referred to as the “triad” of au2sm . These include impairment of social development and communica2on, alongside 1

narrow interests and repe22ve behaviour.

1.1. History of Au2sm

Austrian pediatrician Hans Asperger, who in 1944 first published a defini2on of what currently is known as Asperger Syndrome, first employed the word “au2sm” in its modern sense. He iden2fied a dis2nct paJern of behaviour, calling it “au2s2c psychopathy”, implying that diagnosed children developed self-focused personality. These children displayed “a lack of empathy, liJle ability to form friendships, one-sided conversa2on, intense absorp2on in a special interest and clumsy movements” . Asperger was convinced that thoroughness in studying a 2

par2cular maJer in childhood is likely to manifest as a talent during adulthood.

At the same period, child psychiatrist Leo Kanner recognised some of his pa2ents as having so-called “au2s2c aloneness”, meaning that they have liJle interest in people. Moreover, he noted that they usually had language delays and learning difficul2es. It is, however, no2ceable that prac2cians had opposing accounts of au2sm, with Kanner describing more severe disability than Asperger. This incident gave rise to the assump2on regarding au2sm as consis2ng of different categories – a view prevailing in psychiatry un2l 1994, when it was replaced by the spectrum view. Dr Lorna Wing proposed the spectrum premise, which aided recogni2on of both mild and severe cases of au2sm . This paradigm shiS may be an explana2on for the fact that au2sm 3

became more common now (1 in 100) than it was 30 years ago (4 in 10,000) – more sub-types have been classified as a part of au2s2c spectrum rather than being a separate mental health condi2on.

1.2. Diagnos2c Criteria

The fiSh edi2on of the Diagnos2c and Sta2s2cal Manual of Mental Disorders (DSM) is universally employed in order to diagnose poten2al sufferers of Au2s2c Spectrum Disorder. The DSM has been periodically reviewed and updated since it was first published as there has been con2nuous new research conducted that changed the prevailing approach in recognising mental health issues. Regarding au2sm, the main difference between the fourth and fiSh edi2ons is the

Baron-Cohen, S. Au#sm and Asperger Syndrome (United States: Oxford University Press Inc., New York, 2008), p. 1

10.

McGuinness, S. ‘History of Au#sm’ hJp://www.au2smuk.com/home-page/history-of-au2sm/ [accessed on 30 2

November 2016].

Baron-Cohen, S. Au#sm and Asperger Syndrome (United States: Oxford University Press Inc., New York, 2008), p. 3

21.� 1

replacement of term ‘Asperger’s syndrome” by the new category of Au#sm Spectrum Disorder Level 1, without accompanying intellectual or language impairment , which is summarised in the 4

Table 1.1. This change results in ASD being viewed as dimensional (or spectral) rather than categorical, which is consistent with current research as well as clinical prac2ce.

Table 1.1. : Levels of severity in ASD . 5

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1.3. Weaknesses behind the DSM

Despite universal acknowledgment of the DSM, employment of these criteria as the main diagnos2c tool has its own limita2ons. To start with, DSM criteria are applied through observa2on of the sufferer as well as self-report techniques (i.e. interviews and ques2onnaires). Although observa2on is a convenient way of assessment, it involves subjec2ve interpreta2on by the prac22oners. In order to make a valid diagnosis, different psychiatrists must come to a consensus when assessing a par2cular individual. Being enclosed in the framework of specific behavioural categories, specialists can easily overlook features that could be crucial for future decision. That said, inter-observer reliability between different psychiatrists is likely to be poor, resul2ng in either false posi2ve or false nega2ve diagnosis . Moreover, self-report techniques 6

AJwood, T. The Complete Guide to Asperger’s Syndrome, (United States and United Kingdom: Jessica Kingsley 4

Publishers, 2015), p. 9.

Carpenter, L. ‘DSM-5 Au2s2c Spectrum Disorders’, February 2013.5

Flanagan, C. et al. AQA Psychology for A-level Year 2, (Illuminate Publishing Ltd., 2016), p. 73.6

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could lead to untruthful responses (i.e. social desirability bias) even though both sufferers and their rela2ves are strongly encouraged to provide informa2on that is only based on their own experience.

The validity of DSM is challenged by the co-existence of two mental health condi2ons, which in specialist literature is referred to as co-morbidity. For instance, some individuals with ASD also commonly suffer from specific language impairment . This phenomenon calls into ques2on the 7

validity of classifica2on since these disorders might be viewed as a single psychiatric condi2on.

1.4. Features of ASD

One approach to understanding Au2s2c Spectrum Disorder is considering two opposite ends of the con2nuum: with classic au2sm, also eponymously referred to as Kanner’s au2sm, on the lower end and Asperger’s syndrome – on the higher end. It is important to note that opposite ends of the spectrum represent cogni2ve abili2es of diagnosed individuals rather than severity of the condi2on (i.e. higher end of the spectrum implies one has outstanding abili2es, and vice versa). These condi2ons share certain diagnos2c features such as repe22ve behaviour and lack of social development. Nevertheless, these characteris2cs are also employed for an explana2on of differences between the two, which are reflected in the Table 1.2.

Table 1.2. : Features involved in ASD

Social difficul.es - Extreme lack of interest in other people; - Atypical eye contact; - Limited reciprocity (no dialogues); - Difficul2es predic2ng what someone may think or feel; - Difficul2es knowing how to react to another person’s

behaviour; - Difficulty reading other people’s emo2onal expressions

(e.g. posture); - Difficulty accep2ng that there might be various

perspec2ve to one maJer; - Lack of empathy.

C o m m u n i c a . o n abnormali.es

- Echolalia* (i.e. echoing somebody’s speech); - Neologisms* (i.e. using idiosyncra2c words instead of

conven2onal names for things); - Literal understanding of speech; - Language delay*; - Using speech inappropriately for the social context.

Tomplin, B. ‘Co-morbidity of au2sm and SLI: kinds, kin and complexity’, Interna#onal Journal of Language and 7

Communica#on Disorders, 2011, vol.46, p. 127-137.� 3

1.4.1. Social difficul2es

Main social impairments of children diagnosed with classic au2sm include limited communica2on in general alongside rare and inconsistent eye contacts that may involve either making no eye contact or staring inappropriately at the interlocutor. Although unusual eye contacts are oSen detected in Asperger’s syndrome cases, these do not comprise the main body of diagnos2c criterion. Compared to classic au2sm, these cases are more complex, with individuals having liJle sense of what is socially appropriate (i.e. lack of social awareness) as well as possessing a dis2nct manner of talking at people rather than to them (i.e. inability to maintain a dialogue). Moreover, they have a tendency to prefer adults than peers for communica2on, which is a method used to gain knowledge about a special interest men2oned in Sec2on 1.4.3.

1.4.2. Language and auditory percep2on

The main difference between classic au2sm and Asperger’s syndrome is the age of speech produc2on onset alongside language comprehension . Typically, children with classic au2sm are 8

characterised by delayed speech development, with some individuals not evolving any speech and hence being non-verbal. Although Asperger’s syndrome may involve delayed onset of speech, these pa2ents develop other conspicuous features in terms of language abili2es. The child may unfold sophis2cated vocabulary at an early age, oSen including specific terminology related to area of curiosity. Moreover, these individuals are likely to employ expressions associated with the speech of an adult. In some children, ar2cula2on is over-precise, with some words being pronounced as they are wriJen rather than spoken. This may be explained by

Repe..ve behaviour and narrow interests

- Hand-flapping*; - Spinning of the body*; - Obsessional interests; - Highly repe22ve behaviour; - Severe tantrums at disrup2on to rou2ne; - Unusual memory (e.g. some cases involve impaired short-

term memory); - Insis2ng on sameness.

Other features that cannot be meaningfully categorized

- Areas of below-average IQ or learning difficul2es*; - High risk of epilepsy*; - Self-injury*; - Hypersensi2vity to sensory s2muli; - Clumsy movement; - Impaired auditory percep2on; - Gastrointes2nal dysfunc2ons*.

*More typical of classic au2sm than Asperger syndrome

Baron-Cohen, S. Au#sm and Asperger Syndrome (United States: Oxford University Press Inc., New York, 2008), p. 8

11. � 4

limited 2me spent in interac2ons with peers, in succession leading to the possibility of social exclusion.

As well as that, speech of individuals diagnosed with Asperger’s syndrome can be characterised as being monotonous or flat. It may also have an unusual stress paJern , with pa2ent being 9

unable to convey implicit informa2on and oSen putng an emphasis on every word in a sentence. This feature of language development is referred to as prosody.

In addi2on, a vast majority of au2s2c individuals possesses a distor2on of auditory percep2on. Pa2ents with ASD experience difficul2es with focusing on one person’s voice in case of background noise . They are unable to discriminate auditory data, which results in paying 10

aJen2on to all of the available sounds and voices instead of focusing on an important one. It is an issue with the faulty processing of informa2on rather than a hearing problem.

1.4.3. Repe22ve behaviour and narrow interests

Repe22ve behaviour in classic au2sm usually includes children being involved in physical ac2ons such as hand flapping or spinning of the body, which can be recursively performed for an extensive period . Specialists consider these ac2ons as means of relaxa2on or reducing level of 11

anxiety. On the contrary, in individuals with Asperger’s syndrome this feature manifests as an obsessional interest of unusual nature. Having found a par2cular area of curiosity, a child will me2culously aJempt to develop detailed understanding of it. Due to DSM limita2on discussed in 1.3., an individual displaying repe22ve behaviour might be mistakenly diagnosed with Obsessive-Compulsive Disorder (OCD), which is characterised by certain repe22ons to suppress unpleasant intrusive thoughts. However, the person with ASD seems to enjoy the ac2on, meaning that it is not egodystonic and not necessarily indica2ve of OCD . 12

1.4.4. Insis2ng on sameness

Resistance to change, also referred to as insis2ng on sameness (IS), is undoubtedly intrinsic to both ends of the spectrum. Even a slight interference or change to a rou2ne is likely to trigger violent tantrum in children with classic au2sm, or, in case of Asperger’s syndrome, an episode of reac2ve depression.

1.4.5. Cogni2ve abili2es

Shriberg, L., Paul, R., McSweeney, J. and Klin, A. ‘Speech and prosody characteris2cs of adolescents and adults with 9

high-func2oning au2sm and Asperger syndrome’ Journal of Speech, Language and Hearing Research, 2001, vol. 44, p. 1097-1115.

Alcantara, J., WeisblaJ, E., Moore, B. and Bolton, P. ‘Speech-in-noise percep2on in high-func2oning individuals 10

with au2sm or Asperger’s syndrome’ Journal of Child Psychology and Psychiatry, 2004, vol. 45, p.1107-1114.

‘Au#s#c Spectrum Disorder’, hJps://www.nimh.nih.gov/health/topics/au2sm-spectrum-disorders-asd/11

index.shtml?utm_source=rss_readersutm_medium=rssutm_campaign=rss_full [accessed on 3 December 2016]

Baron-Cohen, S. ‘Do au2s2c children have obsessions and compulsions?’ Bri#sh Journal of Clinical Psychology, 12

1990, vol. 28, p. 193-200. � 5

Another major difference between classic au2sm and Asperger’s syndrome is intellectual ability of such individuals that is usually measured as the Intelligence Quo2ent (IQ). Pa2ents diagnosed with classic au2sm usually score well below average on an IQ test, which implies they could be characterised as having severe learning difficul2es. On the contrary, pa2ents with Asperger’s have dis2nc2ve learning abili2es that include no2cing details and remembering facts in a systema2c manner. However, these individuals oSen experience problems with quick aJen2on shiSing, resul2ng in inability to effec2vely engage in class ac2vi2es. Despite having excep2onal long-term memory , their working memory is impaired, making sufferers unable to manipulate informa2on 13

relevant at the present moment.

1.5. Nature versus nurture debate

Nature vs nurture debate in the human sciences concerns the extent to which behaviour and experience are produced by individual’s nature or nurture. The nature side of the debate originates from assump2ons made by early na2vists such as Rene Descartes, who suggested that all human characteris2cs are governed by heredity. Currently, nature concerns the view that one’s phenotype (i.e. observable characteris2cs) is solely shaped by their genotype (i.e. gene2c cons2tu2on), with environmental factors having from insignificant to no effect. One measure employed to assess the extent to which a certain trait has gene2c origin is called the heritability coefficient. Its numerical value ranges from 0.0 to 1.0, where obtaining coefficient of 1.0 implies that phenomenon studied is en2rely gene2cally determined. In contrast, the nurture side of the debate subscribes to the no2on that environmental forces govern any human behaviour. To be precise, the term ‘environment’ refers to any influence that is non-gene2c in its origin. This may range from pre-natal exposures to dietary influences. Empiricists that support the nurture side believe that infants are born as ‘blank slates’, with environment shaping them in succession.

Prac2cally, nature and nurture are so closely intertwined that it is impossible to view them as separate arguments without losing meaningfulness. For example, it is rather difficult to determine the causal origin of concordance rates in twin studies as twins share both their genes and their environment. Therefore, researchers currently employ approaches that consider an interac2on between nature and nurture rather than viewing them as opposite sides of the debate. For instance, ae2ology of mental health condi2ons such as schizophrenia is viewed as an interplay between genes and environment. The diathesis-stress model suggests that, in case of gene2c predisposi2on to schizophrenia, the condi2on itself will only manifest in case of harmful trigger presence, referred to as stressor. This model produces more holis2c explana2on of psychiatric disorder, considering both nature (i.e. gene2c predisposi2on) and nurture (i.e. harmful trigger). However, is not currently applied to other mental health disorders such as au2sm since more research is necessary to be carried out in order to test its explanatory power.

1.6. Explana2ons of au2sm

AJwood, T. The Complete Guide to Asperger’s Syndrome, (United States and United Kingdom: Jessica Kingsley 13

Publishers, 2015), p. 246. � 6

Theories providing poten2al explana2on of ASD ae2ology are sub-divided into three broader categories: neurobiological, gene2c and environmental. First group involves dysfunc2on of neuronal circuits, ac2vity of neurological structures, atypical brain development or impaired neurochemical func2oning. Second group includes determining candidate genes for au2sm that can subsequently lead to neurobiological dysfunc2on alongside aJemp2ng to detect gene polymorphisms. Last group draws aJen2on to environmental risk factors such as pre-natal experiences as well as influences of medical interven2ons such as vaccina2on or taking an2bio2cs. In this project, I have chosen one explana2on from each broader group in order to determine the extent to which each contributes to ASD development.

2. Mirror neurone theory

Mirror neurone theory of au2sm suggests that specific neuronal circuit involved in imita2on and empathy is impaired in individuals with ASD. This dysfunc2on explains lack of capacity to understand other’s inten2ons and feelings in individuals diagnosed with au2sm.

2.1. Discovery

Rizzolat and his colleagues (1991) detected a specialised circuit of neurones in ventral premotor cortex while studying neural representa2on of motor movements in monkeys. Unlike other motor neurones, these neurones discharged both when the monkey performed a simple goal-directed motor ac2on (e.g. reaching for food) and when it observed another monkey or human performing a similar motor ac2on . As this subset of nerve cells reflected acts performed by 14

another in the observer’s brain, they were named mirror neurones.

Researchers tested whether mirror neurones of ventral premotor cortex, also referred to as F5 area, discharge when a monkey does not observe an ac2on explicitly, but receives a dis2nct auditory s2mulus associated with it. For example, a monkey was first presented with a simple motor act such as breaking a peanut shell, followed by dis2nc2ve sound. Subsequently, the monkey was presented by the sound alone. Electrodes connected to the monkey’s brain detected ac2vity in F5 neurones during both experimental condi2ons. This suggests that mirror neurons comprehend motor ac2ons on a nonvisual basis (e.g. auditory representa2on) . 15

2.2. Mirror system in humans

Later research using positron-emission tomography (PET) showed that the observa2on of goal-directed motor acts ac2vated the inferior parietal lobule (IPL) and ventral part of premotor

Rizzolat, G. and Fabbri-Destro, M. ‘Mirror neurons: from discovery to au2sm’ Experimental Brain Research, 2010, 14

vol. 200, p.223-237.

Rizzolat, G., Fogassi, L. and Gallese, V. ‘Mirrors in the Mind’ Scien#fic American, 2006, p. 54.15

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cortex, forming parieto-frontal mirror system in humans . It is endowed with the mechanism 16

that translates motor acts performed by others into a format generated by observers whilst they perform similar acts. As mirror circuits were detected in a range of neurological loca2ons, they are likely to act as templates for various processes such as imita2on, ac2on and inten2on understanding as well as empathy (i.e. ability to encode one’s feelings).

2.2.1. Evidence for mirror systems involved in imita2on

Buccino et al. (2004) used event-related fMRI to test par2cipants during four ac2ons: (1) observing guitar chords played for a professional guitarist, (2) a pause following observa2on, (3) aJempt to perform the observed chords, and (4) rest. It was found that the neuronal circuit linked with imita2on consists of the inferior parietal lobule (IPL) and the inferior frontal gyrus (IFG) , which is thought to control movement. This circuit is ac2vated both during observa2on of 17

guitarist playing chords and during performance by observer, sugges2ng that a system of mirror neurones is involved in imita2on and thus learning from it.

2.2.2. Evidence for mirror systems involved in empathy

Observing another person experiencing a certain emo2on leads to cogni2ve processing of this informa2on, which at the end results in a conclusion about what the other is feeling. It may also lead to sensory input being mapped on the motor structures producing the reciprocal experience of that emo2on in the observer. Tania Singer and her colleagues at the University College London found the match between experienced and observed emo2ons in terms of pain . In their 18

experiment, par2cipants received a mild pain produced by electrodes placed on their hands and then observed their test partner experience the same s2mulus. Both condi2ons s2mulated anterior insula, which is involved in pain responses, and anterior cingulate cortex shown in Figure 2.1. This supports the assump2on that humans comprehend powerful nega2ve emo2ons through mapping mechanisms.

Rizzolat, G. and Craighero, L. ‘The Mirror Neuron System’ Annual Review of Neuroscience, 2004, vol. 27, p.16

169-192.

Buccino, G. et al. ‘Neural circuits underlying imita2on learning of hand ac2ons: an event-related fMRI study’ 17

Neuron, 2004, vol. 42, p.400-404.

Rizzolat, G., Fogassi, L. and Gallese, V. ‘Mirrors in the Mind’ Scien#fic American, 2006, p.60.18

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Figure 2.1. : Structures of the brain impaired in ASD . 19

2.3. Mirror systems as an explana2on of social impairment in ASD

A set of symptoms such as lack of empathy and capacity to understand feelings and inten2ons of other people appear to be related to func2ons governed by mirror circuits. It has been, therefore, proposed that dysfunc2onal mirror systems in ASD may explain some of the difficul2es experienced by these individuals . 20

2.3.2. Evidence for impaired mirror systems in ASD

In order to demonstrate mirror circuit dysfunc2on in children with ASD, researchers employ electroencephalogram (EEG), which measures electrical ac2vity of the brain. It is known that EEG component called µ-wave is suppressed when one makes a voluntary motor movement. Moreover, this component is also blocked in the event when an individual observes someone else perform the same ac2on. Therefore, it was suggested that µ-wave provides non-invasive pathway for monitoring mirror system ac2vity.

Oberman and her colleagues studied 13 children with ASD and 13 typically developing (TD) children that acted as a control group. During the first condi2on, par2cipants watched a stranger opening and closing their right hand. In the second condi2on, par2cipants performed the same ac2on with their own hand . It was found that, as summarised in Figure 2.2, children with ASD, 21

Ramachandran, V. and Oberman, L. ‘Broken mirrors’ Scien#fic American, 2006, p. 65.19

Williams, JHG, Whiten, A., Suddendorf, T. and PerreJ, DI. ‘Imita2on, mirror neurons and au2sm’ Neuroscience and 20

Biobehavioural Reviews, 2001, vol. 25, p. 287-295.

Oberman, L., Ramachandran, V. and Pineda, J. ‘Modula2on of mu-suppression in Children with Au2sm Spectrum 21

Disorders in Response to Familiar or Unfamiliar S2muli: the Mirror Neuron Theory”, Neuropsychologia, 2008, vol. 46, p. 1558–1565.

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compared to TD children, do not show µ-wave suppression during the observa2on of motor acts performed by others. However, µ-waves were suppressed normally during ac2ve movement produced by ASD individuals themselves. This data supports the assump2on that ASD sufferers develop dysfunc2onal mirror circuits, which subsequently produce social difficul2es.

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Figure 2.2. : µ-wave suppression in ASD compared to TD children.

2.4. Evalua2on of the mirror neurone theory as an explana2on of ASD

One strength of the mirror neuron theory is that it is supported by vast amount of research studies employing highly controlled procedures as well as technological advances such as func2onal MRI, electroencephalography and positron-emission tomography. Use of laboratory experiments ensures rigour in control for extraneous and confounding variables that could easily distort the results, decreasing the internal validity of data and thus leading to wrong conclusion being made. Employment of control group that is closely matched to experimental group ensures that data obtained only reflects variability in neurological development between typically developing and ASD individuals rather than any other par2cipant variables. For example, there is strong evidence from fMRI study in favour of a deficiency in mirror system in ASD. Changes in flow of oxygenated blood were measured in high-func2oning children with ASD and matched control subjects while they were observing and imita2ng emo2onal expressions . The results 22

displayed significantly weaker ac2vity in inferior frontal gyrus (IFG) in children with au2sm. Moreover, ac2vity level was found to be nega2vely correlated to symptoms severity – lower levels of ac2vity in IFG result in social impairment experienced by ASD individuals.

However, the mirror neurone system might not be the only explana2on behind ac2on understanding. A candidate region for this process alterna2ve to mirror circuits is the superior temporal sulcus (STS). Neurones in por2ons of the STS give response to a variety of ac2ons in a

DapreJo, M. et al. ‘Understanding emo2ons in others: mirror neuron dysfunc2on in children with au2s2c 22

spectrum disorder’ Na#onal Neuroscience, 2006, vol. 9, p. 28-30. � 10

way that appears more sophis2cated than that found in mirror neurones . STS neurones 23

discharge in response to voluntary motor ac2ons such as walking towards or away, head turning and arm movements. Moreover, region of parieto-frontal cortex that is thought to contain mirror neurones, projec2ng to ventral premotor cortex (F5), was found to receive impulses from STS . 24

This research sugges2on challenges the theory of mirror systems as an explana2on of social difficul2es in ASD since F5 governs its ac2vity. Therefore, it might be dysfunc2onal STS that produces a lack of capacity to understand other’s inten2ons in ASD.

As well as that, both suppor2ng and contradic2ng evidence is derived from experiments that employ limited sample size of both experimental and control groups. In this case, small sample size is not representa2ve of target popula2on consis2ng of ASD and TD individuals, meaning findings obtained cannot be reliably generalised across world popula2on. Data collected might be affected by inves2gator bias in sampling rather than atypical development. That said, the mirror neurone theory cannot be accepted or rejected on the basis of available research, which implies that this area lacks large-scale inves2ga2ons.

Finally, mirror neurone theory cannot be accepted as universal explana2on for ASD as it doesn not account for some core diagnos2c features referred to in Table 1.2. For instance, repe22ve behaviour and gastrointes2nal dysfunc2on appear to have en2rely different mechanisms behind them since they cannot be meaningfully explained by mirror neurone theory.

3. Gene2c explana2ons of au2sm

The ul2mate goal of human gene2c studies is directed towards the iden2fica2on of the rela2onship between genotype and phenotype. In short, genotype is the gene2c cons2tu2on of an organism that describes all the alleles that it possesses. Phenotype describes any observable characteris2cs, reflec2ng an interplay between the genotype and the environment. For a mental health condi2on such as ASD, the primary aim of gene2c studies is to iden2fy genes, oSen referred to as candidate genes, which might be responsible for predisposing individuals to au2sm. As well as that, researchers make aJempts to determine the extent to which ASD can be characterised as inherited condi2on, calcula2ng concordance rates between both monozygo2c (iden2cal) and dizygo2c (non-iden2cal) twins . 25

PerreJ, D.I. et al. ‘Visual analysis of body movements by neurones in the temporal cortex of the macaque monkey: 23

a preliminary report’ Behavioural Brain Research, 1985, vol. 16, p. 153-170.

Rizzolat, G. and Craighero, L. ‘The Mirror Neuron System’ Annual Review of Neuroscience, 2004, vol. 27, p.24

169-192.

Bailey, A. et al. ‘Au2sm as a strongly gene2c disorder: evidence from a Bri2sh twin study’ Psychological Medicine, 25

1995, vol. 25, p. 63-77. � 11

3.1. Candidate genes approach

Candidate gene approach suggests that gene muta2ons cause a considerable component of phenotypic varia2ons. Candidate genes is a conven2onal term for genes that regulate the developmental processes of the inves2gated traits, in both direct and indirect ways . REELIN 26

(RELN) and SEROTONIN TRANSPORTER (5HTT) have displayed significant associa2on with ASD.

3.1.1. REELIN polymorphism

REELIN codes for specific protein that coordinates neuronal migra2on during development of central nervous system (CNS) in foetus. REELIN is selected as a candidate gene for ASD since it maps to 7q22 - genome region displaying linkage to au2sm in several genome scans . Several 27

polymorphisms have been detected, with one main varia2on being studies for associa2on to ASD. A variable length GGC is repeated, being located in the 5’ untranslated region prior to the start codon. Longer lengths of alleles (i.e. where GGC is repeated) have been demonstrated to produce slower rates of protein synthesis, subsequently resul2ng in cerebellar hypoplasia (underdevelopment) that is typical of ASD phenotype. Cerebellar hypoplasia, which is displayed in Figure 3.1., leads to coordina2on impairment such as clumsy movement in individuals with au2sm.

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Figure 3.1. : Brain with cerebellar hypoplasia (shown inside the yellow box) compared to healthy control (le_)

Persico et al. (2001) studied the GGC repeat employing both case-control method (96 pa2ents and 186 control subjects) and the family-based transmission disequilibrium test (TDT) on 176

Zhu, M. and Zhao, S. ‘Candidate gene iden2fica2on approach: progress and challenges’ Interna#onal Journal of 26

Biological Sciences, 2007, vol. 3, p. 420-427.

Interna2onal Molecular Gene2c Study of Au2sm Consor2um. ‘A full genome screen for au2sm with evidence for 27

linkage to a region on chromosome 7q’ Human Molecular Gene#cs, 1998, vol. 7, p. 571-578.� 12

families . Both samples were characterised by significant associa2on between au2sm and GGC 28

repeat length. In the case-control study, longer alleles of GGC repeat (11 and more repeats) were detected with higher frequency in au2sm-affected popula2on (17.9%) compared to healthy control (9.1%). These findings were replicated on a family-based associa2on analysis on a different sample, with over-transmission of longer alleles in affected individuals. Thus, individuals with ASD possess longer alleles of the GGC repeat.

3.1.2. SEROTONIN TRANSPORTER (5HTT) polymorphisms

The 5HTT is a protein characterised by high affinity for the neurotransmiJer serotonin (5-HT) that transports 5-HT across the axoplasm (axon membrane) through ca2on-exchange pump, located on the pre-synap2c terminals. The 5HTT gene is located on region 17q11, having at least four single nucleo2de varia2ons in the non-coding sequence. An inser2on/dele2on polymorphism situated on the 5’regulatory region has been found to affect transcrip2on in cell lines. This polymorphism has short and long alleles, with the laJer displaying three-fold increase in basal ac2vity (i.e. func2oning at rest) . Hyperserotonemia (increased levels of serotonin) has been 29

detected both in samples of whole blood and urine of ASD individuals . As well as that, more 30

recent brain imaging studies concluded that serotonin synthesis rates are atypical in ASD pa2ents . 31

3.2. Evalua2on of candidate genes approach

One strength of 5HTT gene as a candidate gene for ASD suscep2bility is that it is supported by research evidence from psychoac2ve drugs studies. 5HTT can be targeted by serotonin specific reuptake inhibitors (SSRIs), which has been proved effec2ve in reducing repe22ve behaviour in au2sm . The fact that SSRIs are effec2ve in ASD cases implies that au2sm involves serotonin 32

system dysfunc2on, which is controlled by 5HTT gene muta2on as explained in Sec2on 3.1.2. Moreover, above-men2oned finding is derived from a double-blind study, meaning that both par2cipants and prac22oner, who issued either SSRI or placebo, were unaware of their involvement in the procedure. This increases internal validity of such inves2ga2ons in that pa2ents are unaware of condi2on alloca2on (i.e. whether they are taking SSRI or placebo), decreasing the risk of demand characteris2cs.

Persico, A.M. et al. ‘Reelin gene alleles and haplotypes as a factor predisposing to au2s2c disorder’ Molecular 28

Psychiatry, 2001, vol. 6, p. 150-159.

Heils, A. et al. ‘The human serotonin transporter gene polymorphism-basic research and clinical implica2on’ 29

Journal of Neural Transmission, 1997, vol. 69, p. 1005-1014.

Cook Jr., E.H et al.’ Platelet serotonin studies in hyperserotonemic rela2ves of children with au2s2c disorder’ Life 30

Sciences, 1993, vol. 52, p. 2005-2015.

Chugani, D.C. et al. ‘Altered serotonin synthesis in the dentatothalamocor2cal pathway in au2s2c boys”, Annals of 31

Neurology, 1997, vol.42, p. 666-669.

Hollander, E. et al. ‘Targeted treatments for symptom domains in child and adolescent au2sm’ Lancet, 2003, vol. 32

362, p. 732-734. � 13

A strength of REELIN as a candidate gene for au2sm is that suppor2ng evidence has high internal validity. Researchers oSen employ case-control method when studying associa2on between a candidate gene and ASD. Case-control method includes matching healthy subjects to individuals diagnosed with ASD prior to performing required experimental procedures. It ensures that only associa2on between REELIN polymorphism and au2sm is studied, decreasing the risk of confounding variables that might distort research outcomes.

However, the effect of GGC repeat men2oned in Sec2on 3.1.1. is evidently small. Only 20% of ASD sample in Persico et al. study possessed long repeats, indica2ng that REELIN polymorphism is significant at only a small percentage of au2sm cases. That said, REELIN variant cannot be considered the only feature than makes one gene2cally suscep2ble to ASD development.

In addi2on, iden2fica2on of candidate genes for ASD offers liJle prac2cal values for psychiatry. ASD is considered to be polygenic, meaning it is associated with varia2ons in mul2ple genes. At least 20 candidate genes associated with increased risk of au2sm development have been iden2fied cross-culturally. Iden2fica2on of candidate genes is viewed as an opportunity for pre-natal screening. However, in case of ASD this method is currently not likely to lead to interven2on and elimina2on of these genes in a foetus. Moreover, this might raise ethical issues such as foetal termina2on viewed as unacceptable by the vast majority of people. Thus, iden2fica2on of candidate genes may not be frui}ul in terms of early diagnosis and successful interven2on.

3.3. Family and twin studies of ASD

Research into ASD ae2ology involves determining the extent to which different family members (e.g. twins, siblings, etc.) share the same phenotypic characteris2c. This extent is opera2onalised using a measure called concordance rate – the probability that a pair of individuals will possess a certain characteris2c, given that one of the pair has the characteris2c. In the majority of cases, pairs of monozygo2c (iden2cal) and dizygo2c (non-iden2cal) twins are studied in order to calculate concordance rates. A higher concordance rate in monozygo2c (MZ) twins than in dizygo2c (DZ) twins is considered prima facie evidence for gene2c component since MZ twins develop from one zygote.

Concordance rates obtained in various inves2ga2ons reflect the paradigm shiS regarding categorical and spectral views of ASD. Folstein and RuJer studied 21 twin pairs and found that 33

MZ twins were only 36% concordant, meaning that in just over a third pairs both twins shared the diagnosis. In DZ twin pairs, concordance rate was 0% - DZ were disconcordant for au2sm, with only one twin having the diagnosis. However, when studying broader au2sm phenotype

Folstein, S. and RuJer, M. ‘Gene2c influences and infan2le au2sm’ Nature, 1977, vol. 265, p. 726-728.33

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(BAP), in 44 sets of twins, the MZ concordance was found to be 92%, whereas DZ concordance was 10% . 34

3.4. Evalua2on of family and twin studies of ASD

Employment of twins as a sample for determining gene2c ae2ology of ASD poses a ques2on of generalisability to the popula2on as a whole. It is known that twins, in general, are born 3-4 weeks earlier than an average singleton. This acts as a confounding factor that varies systema2cally with the subject examined. Thus, there is a risk that concordance rates calculated in numerous twin studies are limited in their usefulness, telling liJle about gene2c cons2tuent of ASD in general popula2on.

It is important to consider the measurement tools used to assess the phenotype of individuals when drawing conclusions from twin studies. Reliability of the assessment method is reflected in the extent to which any research finding is internally valid (i.e. unreliable method cannot lead to valid conclusions being made). Gene2cists employ a range of different measurements including the Au2sm Quo2ent (AQ), which is a self-report technique. Although ques2onnaires are a convenient way of data collec2on, they can have considerable repercussions for internal validity of data since respondents provide researchers with subjec2ve answers that might not be reflec2ve of their actual experience.

One strength of twin studies as a method of inves2ga2ng ASD is that they are carried out longitudinally (i.e. the same individuals are followed up at different periods of their development). Cross-sec2onal design would be an alterna2ve that is less 2me consuming as different twins represent different age groups. However, this increases a risk of par2cipant variables distor2ng the results. When twins are compared against themselves, it is more likely that researchers will come to valid conclusions, providing proper direc2ons for future research.

4. Environmental risk factors for ASD development

It has been shown in Sec2on 3.3 that on average concordance rates between monozygo2c twins are 60-92% compared with 0-10% for dizygo2c twins. Incomplete concordance in monozygo2c twins indicates the importance of the environment in contribu2ng to ASD development . It 35

might be, thus, possible that gene2c polymorphisms and effect of environment comprise ae2ology of au2sm. In the past decade, pregnancy-related factors have been the focus of epidemiological research into ASD risk factors.

Bailey, A. et al. ‘Au2sm as a strongly gene2c disorder: evidence from a Bri2sh twin study’ Psychological Medicine, 34

1995, vol. 25, p. 63-77.

Gardner, H. et al. ‘Prenatal risk factors for au2sm: comprehensive meta-analysis’ The Bri#sh Journal of Psychiatry, 35

2009, vol. 195, p. 7-14. � 15

4.1. Increased parental age

Current research shows that increased parental age of concep2on is associated with increased risk of au2sm. Associa2on between maternal age and au2sm might be explained by an increased risk of chromosomal abnormali2es in aged ova . Although maternal age is related to obstetrical 36

difficul2es, it is not known whether any of these increase individual’s risk of ASD development. Regarding paternal age, Reichenberg suggested that elevated incidents of au2sm might be linked to spontaneous muta2ons in spermatagonia . 37

4.2. Gesta2onal bleeding

Another environmental risk factor supported by numerous research studies is gesta2onal bleeding. Maternal bleeding is one of perinatal complica2ons associated with foetal hypoxia - a condi2on where foetus is deprived of an adequate oxygen supply. Prolonged labour followed by Caesarean delivery are one of the several factors that are believed to be related to foetal hypoxia, and thus playing a role of risk factors for ASD development. Hypoxia is also linked to hyperdopaminergia (increased ac2vity of dopamine in one’s brain), which is one of the neural features of ASD . However, evidence for these assump2ons is of inconsistent nature, meaning 38

causality between au2sm and above-men2oned factors cannot be established.

4.3. Evalua2on of environmental factors

One issue that seriously weakens the validity of environmental explana2ons is that proposed associa2ons are correla2onal in their nature. Correla2on involves studying a rela2onship between two co-variables, which is represented by product moment correla2on coefficient obtained aSer employment of a suitable inferen2al test. Correla2onal analysis does not allow causal links to be drawn as there is a risk of intervening variable affec2ng both co-variables that are being studied. Thus, further inves2ga2ons are necessary to establish causality between environmental effects and development of au2sm.

Methodological limita2ons of research into environmental factors involve assessment method used to obtain data concerning pre-natal experiences. In a vast majority of inves2ga2ons into pregnancy-related factors, informa2on is collected through retrospec2ve recall of exposures to poten2al risk factors. There is a probability that parents do not men2on important incidences or follow situa2onal clues of the experiment (i.e. demand characteris2cs), either way providing

Kolevson, A. et al. ‘Prenatal and perinatal risk factors for au2sm: a review and integra2on of findings’ Archives of 36

Pediatrics and Adolescent Medicine, 2007, vol. 161, p. 326-333.

Reichenberg, A. et al. ‘Advancing paternal age and au2sm’ Archives of General Psychiatry, 2006, vol. 63, p. 37

1026-1032.

Previc F.H. ‘Prenatal influences on brain dopamine and their relevance to the rising incidence of au2sm’ Medical 38

Hypotheses, 2007, vol. 68, p. 46-60. � 16

researchers with untruthful responses. This might significantly decrease the internal validity of data and conclusions made from it, leading to unjust assump2ons regarding ASD ae2ology.

5. Discussion

ASer outlining three of the poten2al explana2ons of ASD onset and development, it is possible to note that there is no theory that would only have strengths behind it. For explana2ons that are biological in their origin, strengths and limita2ons are balanced, leaving one to judge their validity and applicability.

Research studies that offer suppor2ng evidence for both mirror neurone theory and gene2c explana2ons of au2sm employ empirical methodology. This includes using reliable measurement tools to assess dependent variables, aJemp2ng to replicate results of baseline inves2ga2ons and controlling for variables that can lead to invalid conclusions. Paying aJen2on to adequate manipula2on and control of variables is crucial in order to ascertain that detected change in dependent variable is a result of independent variable manipula2on. This, in turn, increases internal validity of such research, meaning that its conclusion can be reliably applied to explain ae2ology of au2sm.

As well as that, studies into neurobiology and gene2cs of au2sm oSen employ case-control method as means of studying individuals with broader au2sm phenotype. This involves matching each study subject with ASD diagnosis to individual who does not possess ASD as closely as possible, considering age, gender and other characteris2cs that could act as par2cipant variables, exer2ng deteriora2ng pressure on study’s outcome.

Moreover, biological explana2ons of au2sm could contribute to development of interven2on that can help diagnosed individuals lead produc2ve lives. If ASD is largely biological in its origin, than understanding the mechanism behind diagnos2c criteria of this condi2on is likely to aid development of treatment such as drug therapy (e.g. psychoac2ve drugs). If serotonin transporter men2oned in Sec2on 3.1.2. is one of the main features that cause cogni2ve symptoms in ASD, then medica2on that aids reabsorp2on of serotonin into pre-synap2c neurone can be developed, decreasing levels of serotonin in the brain.

However, the evidence behind biological explana2ons outlined in this report is obtained from inves2ga2ons performed on small sample sizes. This is an important issue because small sample is unlikely to represent diversity of general ASD popula2on. Findings derived from studying unrepresenta2ve sample cannot be applied across various setngs, meaning they lack external validity (i.e. generalisability). In order to establish valid causal mechanisms behind au2sm, large-scale studies are necessary to be carried out.

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Regarding environmental cons2tuents of ASD, studies offering support for the nurture side of the debate suffer from being specula2ve. Employing correla2on as a mean of studying pre-natal exposures, researchers mistakenly suggest that discovered factor is in causal rela2onship with au2sm. There is a large probability that both environmental factors and ASD are affected by other variables. That said, conclusions from inves2ga2ons concerning environmental factors should be treated with cau2on when it comes to determining ae2ology of such complex neurodevelopmental disorder.

It is evident from above sec2ons that none of the explana2ons discussed can provide a full account for all diagnos2c criteria of ASD. Thus, it can be concluded that au2sm is a heterogeneous mental health condi2on, implying it has several origins contribu2ng to its onset and expression. Nevertheless, future research will have to determine the extent to which each of the three cons2tuents discussed in this project contributes to development of ASD.

6. Bibliography

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