From behaviour to genes…and back again

Dr Dougal Julian Hare

School of Psychological Sciences

University of Manchester

Psychology is a science (don’t laugh, it really is supposed to be a science)

Basis of science is classification With a classification system, can determine both membership

and relationships: Is Xn a member of class X ? What is the relationship of Xn to X¹ or to Y¹ ?

With an adequate classificatory system, can begin to examine mechanisms i.e. move to explanation: Why does Xn have features a,b & c ?

Scientific explanations can be holistic and reductionist Reductionist explanations can be parsimonious and satisfy

Occam’s razor

Science aims to produce predictive general laws and models Failure to predict is important as breakdowns in models and

laws leads to new developments and in some case paradigms (Kuhn 1962)

Therefore, should we focus on when cognition and development goes wrong ?

Two fields in clinical psychology are concerned with evident neurocognitive dysfunction: Acquired brain injury (inc. progressive disorders) Intellectual disabilities

In the case of neuropsychology, almost all advances in knowledge and theory have come from the study of acquired brain injury, both structural and functional.

Most ABI is idiopathic People with ABI can be compared to non-ABI population Some examples of genetic aetiology in both seizure disorders

such as juvenile myoclonic epilepsy (Iqbal et al 2009) and progressive disorders such as Parkinson’s and Huntington’s

Very different with regard to disordered developmental processes and development of psychological knowledge

Very distinct split between intellectually disabled [mental retardation/mental handicap/learning disabled] and non-intellectually disabled populations with developmental disorders

Emphasis in research on non-ID populations e.g. autism

Major problem with psychiatric theorising is failure to develop either valid descriptive [diagnostic] or reliable predictive [prognostic] models (Bentall 2004)

Clinical psychology as a whole has been successful in developing idiosyncratic predictive models having moved away from psychiatric diagnostic systems

Clinical psychology and intellectual disabilities

Clinical psychology practice and research with people with ID has developed in a unique manner due to: Different classificatory system based on g / IQ [IQ testing] Explicit emphasis on observable behaviour based on

Skinnerian operant conditioning Obsolete technologies that are used primarily with people with

ID…

In clinical practice, this has worked – up to point: Crude identification of ID Function of behaviour and immediate contingencies

identifiable for and intervention effective ~ 75% of cases (Symons & Thompson 1997).

As both g/IQ and behaviourism are base level explanations (i.e. no lower level explanation is possible/permitted), focus has been on higher-level supra-individual explanation

In effect, psychological research and practice with regard to people with ID has been driven by 1930s technology (IQ testing and operant conditioning) rather than current science.

Most non-behaviourist psychological research in ID has necessarily focussed on systemic and social level explanation – social constructionism

Led to social level interventions (normalisation, person-centred planning) and also theories of social aetiology of ID being dominant

WHO impairment-disability-handicap model

Impairment - physiological disorder or injury

Disability - inability to execute some class of movements, or pick up sensory information of some sort, or perform some cognitive function, that typical unimpaired humans are able to execute or pick up or perform

Handicap - an inability to accomplish something one might want to do, that most others around one are able to accomplish

In effect, psychology has focused on describing Disability and ameliorating Handicap

Ironically, the obsolete term ‘mental handicap’ is possibly more descriptive of how psychologists view people with ID…[NB I’m being ironic here]

The focus of psychological research has thus been essentially reactive, aiming to reduce the handicapping effects of disability

Not very interested in the nature and aetiology of ID ?

The one exception to this has been autism Recognition in the 1960s that autism was an organic and

probably highly inheritable disorder Autism is not reducible to or explicable in terms of low g/IQ Autism always regarded as not just a discrete syndrome but as

qualitatively different

Moreover, this sense of difference manifested not just in terms of presentation but also in terms of their needs for education, support and care

Led to ground-breaking research of the 1980s (Baron-Cohen, Leslie, Frith etc) into the psychological and neuropsychological basis of autism i.e. moving beyond merely describing the behavioural manifestations of the disorder.

Initial notion that people with autism have specific needs best met by specific service provision proved to be correct (e.g. Bennett, Wood & Hare 2004)

Autism as a discrete disorder

Research into mentalisation and subsequent work on executive dysfunction, innate emotional recognition, episodic memory etc in autism carried out, disseminated and utilised outside of ‘mainstream’ ID

Autism research has explicitly worked on identifying the links between the biological, psychological & behavioural domains

Developed framework for more recent work into other syndromes and their behavioural phenotypes.

Some clinical psychologists, (applied behaviour analysts ?) do not ‘believe’ in autism –which begs the response of what is not being believed in ?

Case of autism illustrates another issue with using g/IQ to define a research or clinical population - the curious case of Asperger syndrome.

Can be contrasted with the other forms of developmental disorder such as Klinefelter’s syndrome, Turners syndrome and the other readily identifiable conditions with mean IQ ≥ 70

Recognised as having specific difficulties resulting from developmental disorder that are not the result of impaired general intelligence.

Categorical models of ID

Effectively started by John Langdon Down (1866) with descriptions of Downs, Prader Willi and West Syndromes

Wrote first ID textbook (1876) advocating a psycho-educational approach to ID

Correctly identified that there exist real entities, in the form of distinct intellectual and developmental disorders:

Several hundred forms of IDD now identified: 40-50% known genotype 40-45% known ante- or peri-natal damage 10-15% unknown aetiology

Downs syndrome as a discrete disorder

Phenotype of Downs syndrome identified in 1866 Genotype of Downs syndrome identified in 1959 Most common form of discrete ID (40% of ID population) Physical features of DS make it hard to ignore (not that some

ID services haven’t tried…)

DS as ‘prototype’ form of intellectual disability ?

Modern genetic technology has identified new syndromes (e.g. X linked syndromes Muir, 2010) as well as accounting for known disorders: Prader-Willi syndrome - micro-deletion on chromosome

15q11-q13 was determined by a new high-resolution banding; fluorescent in situ hybridisation (FISH)

related aetiology of Prader-Willi and Angelman syndromes - genomic imprinting, (Muir, 2000) where one inherited gene from either parent in a gene pair is repressed or inactive through an epigenetic mechanism.

Percentage of cases of ID of unknown aetiology is steadily reducing

Recent work on de novo mutations (Vissers et al., 2010), where neither parent possesses or transmits the mutation, has identified that these now account for many cases of mild -moderate IDD, previously regarded as environmentally caused (Ellison et al., 2013; Veltman & Brunner, 2012)

Science of behavioural phenotyping has developed alongside advances in genetic technology (Oliver & Hagerman, 2007)

Genotype Genetic constitution of an individual; the particular set of

genes carried. Inherited influences that facilitate development of particular

traits Phenotype

Manifest structure, function or behaviour

Behavioural phenotypes

Concept of behavioural phenotype initially used by Nyhan (1972) in description of stereotypic hand wringing in people with Lesch-Nyhan syndrome

Broadened to describe distinctive physical, behavioural and cognitive profiles of genetic syndromes (O'Brien, Barnard, Pearson & Rippon, 2002).

Probabilistic definition of BP - behaviour reliably occurring in most cases of a syndrome and/or genotype can be considered part of the phenotype (Dykens 1995)

Can conceptualise the specificity of the aetiology-behavioural phenotype linkage as: No specificity i.e. no link between outcome and disorder Partial specificity i.e. specific outcome(s) may result from

several disorders (e.g. repetitive behaviour is associated with several disorders)

Total specificity i.e. unique outcome for given disorder Substantive empirical support (Basile, Villa, Selicorni &

Molteni; Levy & Ebstein, 2009; Lewis et al., 2006; Sinnema et al., 2011; Varela, Kok, Otto & Koiffmann, 2004).

Behavioural phenotypes can be regarded as information-giving devices that explain: why a given syndrome has occurred, how it will affect development a proportion of the variance in problematic behaviours.

Tunnicliffe & Oliver (2011) note that phenotypic behaviour can be subject to change via operant reinforcement by environmental and internal contingencies

Early intervention with known BPs, including provision of information to services regarding the phenotype, improves quality of life and challenges deterministic views of diagnoses.

Understanding BPs facilitates the development of tailored interventions (Courtenay et al 2009): self-injurious behaviour in various syndromes (Oliver &

Richards, 2010;Arron et al 2011) early-onset dementia in people with Down syndrome

(Kozma, 2008) impact on carer well-being (Adams 2013)

People with IDDs and their families have welcomed genetic and BP research in ID (Costain et al 2012; Trottier et al 2013).

Participating in genetic research gives opportunities to determine a diagnosis and/or to obtain understanding of an existing diagnosis (Statham et al. 2010)

Parent support groups are a key driving force in behavioural phenotyping research (Harris 2010)

Genetic diagnoses result in greater understanding and control by providing prognosis and facilitating access to services and care (Costain et al 2012).

Classification by aetiology and psychological research

Understanding the genetics & aetiology of ID permits a fine-grain classification of the previously homogenous ID population (i.e. IQ≤70)

Behavioural phenotyping facilitates a rational programme of research based on this classification

Down syndrome is the most common chromosomal cause of ID

Fragile X is most common inheritable cause of ID

Chromosomal aetiologies of ID

Other important forms of ID/DD with known genetic aetiology include: Velocardiofacial (VCFS)[c22q-del] Rubinstein-Taybi [c16p 13.3 ?] Prader-Willi (PWS) / Angelman (AS)[both c15 q11-13 del.

– paternal/maternal] Williams (WS) [c7 continuous gene deletion] Smith-Magenis (SMS) [c17p11.2] cri-du-chat (CDC) [5p del]

(1) Possibility of identifying specific behaviours uniquely associated with specific behavioural phenotypes: Prader-Willi [hyperphagia] Lesch-Nyan [extreme SIB] Smith-Magenis [bodily self-hugging & insertion of objects

into bodily orifices] Rett [stereotyped hand movements] Cri-du-chat [“cat cry” in infancy & distinctive

vocalisation/screaming] Williams [very poor visuo-spatial skills]

(2) Quantifiable proportion of the variance in a person’s behaviour : Hyper-sociability [‘attention seeking’] in WS and SMGS Abnormal sleep in San Filippo syndrome Self-injurious behaviours in Lesch-Nyan and Retts

(3) Prognosis: Early on-set dementia in DS Early mortality in RS and SFS Psychosis in VCFS

Syndromic variation in topologies of SIB (Arron et al 2011):

Syndrome-specific topology:FgX – self-bitingPWS – scratchingLowe syndrome – eye poking [90% visual impairment]

Multiple topologies:CDC – self-pulling, rubbing or scratchingCdLS – self-hitting and pullingSMS- multiple topologies

Inter-syndrome variations in challenging behaviour

Correlates of SIB (Arron et al 2011): Low ability (CdLS)Repetitive behaviour, over-activity & impulsivity (CdLS, FX/ LS/ PWS)Over-activity & impulsivity (SMS)

Correlates of physical aggression:Over-activity &impulsivity (AS/CDC/CdLS/FX/PWS/LS/SMS)

Inter-syndrome variations in challenging behaviour

Genes to behaviour to families

Genes-enzymes-neural architecture-cognitive- emotional functioning-behaviour- social & familial

Pathways already mapped for Prader Willi Syndrome and Fragile X Syndrome

Recent work from the Manchester ClinPsyD programme on Muccoplysaccharidosis type III [Sanfilippo syndrome]

MPS III/Sanfilippo Syndrome

Rare genetic disorder causing progressive mental and physical degeneration, resulting in premature death usually in 2nd or 3rd decade of life

1 in 89,000 live births in the UK Lysosomal storage disorder - deficiency in one of four

enzymes involved in the break down of the glycosaminoglycan heparan sulphate

Based on the enzyme deficiency, four main subtypes found - MPS III A - D

Progressive degeneration in MPS III

Currently no cure but disease-modifying therapies under development [ Genestein trial utilising stem cell transplantation ongoing utilising research to be described]

Clinical input mainly supportive care to manage child symptoms – no psychological support for children or parents

Rarity of disorder and normal initial development - families may have 2-3 children with MPS III prior to diagnosis

Evidence base

Extreme heterogeneity, even among siblings (Valstar et al 2008) makes prognosis difficult

UK-wide survey of life-limiting diseases (Malcolm et al 2011) highlighted MPS III as priority area for research

Specific difficulties of behavioural problems,financial and emotional impact of progressive decline and social isolation of families

Methodological limitations in previous research Limited research on MPS III behavioural phenotype

(Ulcar et al 2010; Malcolm et al 2012)

Sleep & circadian functioning [Mahon et al 2014; Mumford et al submitted]

Sleep problems prevalent associated with MPS III (Fraser et al 2005): Settling difficulties, nocturnal waking, disruptive/dangerous

behaviours during the night, and early morning waking. Most studies use questionnaire Mariotti et al. (2003) – PSG and reported reduced night-

time sleep/ increased daytime sleep compared to age- and sex-matched controls.

Hendriksz et al. (2012) - aggressive behaviour, hyperactivity, and severe sleep disorders due to abnormal circadian rhythm ?

Method

Eight children with MPS III A/B (5 males & 3 females, age range 2-15 years) and eight age-matched typically developing children (4 males, 4 females, age range 3 – 15 years)

All participants wore a Respironics AW2/Cambridge Neurotechnology AW4 for 7-10 days to collect data on circadian rhythm activity and sleep.

Melatonin prescriptions were ceased two weeks prior to data collection.

Saliva samples were collected at three time points at the start and end of data collection to permit analysis of endogenous melatonin levels.

Parents completed a one-off sleep questionnaire (Children’s Sleep Habits Rating Scale) and a daily diary detailing times the child went to bed and got up, lights on/off times, as well as any night-time events such as seizures.

Sleep parameter MPS III n = 8 Controls n = 8 p U

Mean SD Mean SD

Time in bed (min) 559.6 75.4 544.9 53.7 0.23 44.0

Night-time sleep (min) 447.2 111.5 479.0 32.9 1.0 32.0

Daytime sleep (min) 13.8 19.2 1.7 4.9 0.046* 48.5

Sleep onset latency (min) 53.2 55.6 14.2 5.1 0.01** 56.0

Sleep efficiency (%) 68.7 17.7 80.8 8.0 1.4 17.5

WASO (min) 112.5 58.9 75.1 51.1 0.279 43.0

Actigraphic summary data for MPS III and Control groups

WASO = wake after sleep onset; * p < .05, ** p < .01

Sleep - Questionnaire data Data from the Children’s Sleep Habits Rating Scale revealed that parents

of children with MPS III saw their child displaying more sleep problems compared to controls in the areas of : bedtime resistance sleep onset delay sleep duration sleep anxiety night waking night behaviours parasomnias sleep disordered breathing daytime sleepiness

Melatonin analyses

88.5% data useable and reliable (SDs < 20% of mean) [1 outlier removed] No significant effects of day of collection (first day vs. last day) (p > 0.05) Sig. diff. in melatonin level in control group time points (Time 1: 6-8h,

Time 2: 10h-12h, Time 3: 22-24h) on the first [p = 0.002] and last day [p = 0.006] and between Time 2 & Time 3 (p = 0.016) and Time 1 &Time 3 (p = 0.031) on both days

No reliable differences across time points for the MPS III group on the first day χ² (2) = 0.50, p = 0.931, or last day χ² (2) = 2.80, p = 0.367.

Visual inspection suggested that the MPS III group had higher melatonin concentrations at 6-8h and lower levels at 22-24h, compared to controls

NB Exogenous melatonin stopped two weeks prior to actigraphy

No reliable differences across time were found in the MPS III group, demonstrating abnormal circadian rhythm of melatonin concentration - melatonin levels lower at night / higher early morning in children with MPS III, compared to controls

Disruption in the melatonin CR in MPS III (cf Guerrero et al., 2006) could account for sleep disturbances: Lower levels of melatonin at night = difficulties falling asleep Higher levels of melatonin in the morning = increase in daytime napping.

Some MPS III were on hypnotic medications (choral hydrate, zopiclone) -without these sleep may have been reduced and disrupted to a greater degree.

Hypnotic drugs have little/no effect on sleep disorders with an irregular sleep/wake cycle (Guilleminault et al1993) and all parents described sleep medication as having little or no benefit

Oldest child prescribed hypnotic drugs had poorest sleep of the entire group.

Empirical basis for melatonin prescription Advice on behavioural modification to be provided to

caregivers with focus on bedtime resistance, sleep onset difficulties, sleep anxiety, night time waking, disruptive/dangerous behaviours at night, daytime sleep and tiredness.

Objective assessment using actigraphy and melatonin assays both recommended and practical

Future research to focus on efficacy and side-effects of sleep interventions in MPS III.

Behavioural phenotype [Cross et al submitted]

2-9 yrs: Gross motor skills differentiate MPS III and ID groups. Hyperactivity, orality, body movements, interactions with

objects and inattention 10-15 yrs:

Impaired daily living skills, communication, coping skills and understanding & expression.

level of disability increases / challenging behaviour decreases with age in in the MPS III group

Family functioning [Grant et al 2013]

Parents of children with MPS III had significantly lower rates of future-orientated and goal-directed resilience factors than

parents of children with ID (Grant et al 2013)

Future directions

A small set of behaviours & functions (Repetitive & restricted behaviour, executive control, language, social communication, attachment) are dysfunctional in various combinations in many ID syndromes: Reflects a taxonomy of genetic disorders ? Possibility of a taxonomy of behavioural phenotypes ? Basic genetically-encoded “tool kit” for developmental

‘bootstrapping ?

dougal.hare@manchester.ac.uk

School of Psychological SciencesZochonis BuildingBrunswick St.Manchester M13 9PL