THE STATE OF AUTISM INTERVENTION SCIENCE: PROGRESS, TARGET

PSYCHOLOGICAL AND BIOLOGICAL MECHANISMS AND FUTURE PROSPECTS

Jonathan Green and Shruti Garg, University of Manchester

A recent systematic review (Kennedy et al JCPP this issue) gives a

methodologically rigorous summary of the key evidence for psychosocial

intervention research in autism. The purpose of this current research review is

complimentary. Firstly we provide analysis and commentary on what the

evidence such as reviewed by Kennedy et al represents for the current state of

autism intervention science as a whole, in terms of methodological

developments, implicit or explicit intervention targets and common factors in

treatment. We focus particularly on intervention and mechanism targets in order

to provide a clarifying and unifying thread with which to compare evidence

across different interventions, to establish precisely what overall progress has

been made, and what has been learned about autism as a developmental

condition from intervention research. We aim for this to point a systematic way

forward to new and refined mechanism targets in future.

Next we extend the focus on mechanism to bridge between intervention work

targeting psychosocial development and emerging work on complimentary

neural system targets. These two domains are usually considered separately; it is

the thesis of this review that considering them together now at a mechanism

level is timely. It points the way forward to a new phase of autism intervention

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science addressing potential synergies between psychological and biological

intervention strategies in this neurodevelopmental disorder.

PROGRESS IN PSYCHOSOCIAL INTERVENTION RESEARCH

Trial Methods

An immediately striking feature of the contemporaneous systematic review by

Kennedy et al is how few of the studies identified met basic Cochrane quality

criteria for absence of risk of bias (just 6 trials out of the 48 that met their

inclusion criteria, even though most had been conducted in the last few years).

Another is how chaotic the autism intervention field is internationally, with

those 48 trials testing no less than 34 different models of intervention, usually in

underpowered small N trials from single sites.

While there has been substantive progress in recent years, it remains striking

and paradoxical that the intervention science in such an important

developmental disorder continues to be so fragmented and methodologically

fragile. This cannot just be put down to lack of funding. The majority of

interventions tested have been behavioural or psychosocial, areas in which there

has been debate (historically but also currently) as to the appropriateness or

viability of conducting rigorous trials. Any doubts as to the value and importance

of Randomised Controlled Trials (RCT) methodology in this area however should

have been laid to rest. It turns out that they are not only feasible but can have

huge advantages in clarifying and adjusting for the many potential confounds

involved in properly testing complex interventions within an equally complex

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phenotype (Green & Dunn, 2008). It has been a genuine achievement for the field

(in parallel certainly with other areas of psychosocial treatment research) to

have demonstrated the value of RCT methods and, increasingly, the

implementation of CONSORT reporting standards; but the Kennedy et al review

shows how patchy this has been in practice. Vast sums of public and private

money are spent in health care systems across the world on interventions that

have no rigorous evidence base. For instance, probably the most ubiquitous

interventions globally (under the umbrella of Early Intensive Behavioural

Intervention (EIBI) or ABA) continue to be actively promoted on the basis of

single case designs alone, internationally considered to be low levels of evidence

in healthcare; a Cochrane review of EIBI (Reichow, Barton, Boyd, & Hume, 2012)

found only one historic, small and equivocal RCT and the situation has not

changed subsequently. Consequently such interventions do not feature at all in

the Kennedy et al review or in relevant guidance such as UK NICE (National

Institute for Health & Care Excellence, 2013). This is truly an extraordinary

situation given the high profile and importance of autism in public health, and its

economic and social costs. On just one metric, the lifespan economic burden of

autism has been estimated as up to $2.4 million in the US and £1.5 million in the

UK (Buescher, Cidav, Knapp, & Mandell, 2014; Knapp, Romeo, & Beecham, 2009),

higher than asthma or diabetes. The reader might imagine the reaction if

international clinical practice in these latter conditions was underpinned in this

way.

In a further paradox, the autism field actually has a significant advantage over

some other areas of psychosocial intervention research in having developed

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relatively valid, predictive and blind-codable measures of social interaction and

autism symptom outcomes; something that has often been elusive in other areas.

Lack of assessment blinding in self- or informant- reporting can seriously inflate

treatment effect estimates, especially in trials without participant blinding to

treatment, inevitably the norm in most psychosocial treatments (Sonuga-Barke

et al., 2013). In addition to incorporation of common blinded outcomes, a further

key next step in methodological development would be widespread

implementation of pre-recruitment trial registration and pre-specification of

analysis plans and primary outcomes, avoiding the post hoc selective reporting

of multiple measured outcomes that has often been the norm. At a stroke this

discipline, although arduous initially, would transform the validity and salience

of the trial reporting.

A third key step will be the explicit investigation of mechanism, which will allow

an iterative evolution towards more refined treatments (Green, 2015; Kraemer,

Wilson, Fairburn, & Agras, 2002). The first part of this review consequently

builds on Kennedy et al by focusing on the (explicit or implicit) mechanisms and

treatment targets within the variety of treatments tested to date – particularly in

those studies reviewed by Kennedy et al as having relatively low risk of bias. We

aim through this to provide a unifying view of the current research along with an

agenda for moving forward with new and refined mechanism targets. We point

the way forward to some of these new potential targets in brain science in the

second part of the review.

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Co-construction of outcome targets

A further achievement for autism intervention has been an emerging dialogue

with user groups, advocates and families towards co-constructing relevant

outcome variables and outcome targets after intervention. Autism has benefitted

from active debates and dialogue between these groups, which should be

creative for future progress. At the extreme some advocates object to any idea of

intervention at all as impacting negatively on ‘autism identity’, wanting instead a

focus on acceptance, social rights and associated mental health. These latter

objectives are certainly important but the review below addresses how

interventions, theoretically targeted at core early developmental processes in

autism, can impact positively on key autism features and adaptation, even in this

highly heritable neurodevelopmental disorder. This empirical evidence,

alongside early diagnosis, forms the ethical case for intervention; but the

outcomes selected do need to be of shared relevance. This is a theme we return

to at the end of the review.

TARGETS AND MECHANISMS IN PSYCHOSOCIAL AUTISM INTERVENTION

Parent-child dyadic interaction as a foundation for social development

The rationale for targeting early parent-child social interaction (PCI) in autism as

a social impairment disorder comes from decades of child development research

suggesting the foundational value of positive early dyadic social interaction for

later child social communication and adaptation (Landry, Smith, Swank, & Miller-

Loncar, 2000; Page, Wilhelm, Gamble, & Card, 2010; Tomasello, 2008). Alongside

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this, autism developmental science has identified variations from such normative

patterns in young children at risk of or diagnosed with the condition. Thus

increased parent directiveness (but not reduced responsiveness) is found in the

latter part of the first year in infant siblings at risk of autism (Harker, Ibanez,

Nguyen, Messinger, & Stone, 2016; Wan et al., 2013) along with reduced child

attentiveness to parent, affective signaling and coordinated dyadic

communication (Parlade & Iverson, 2015; Wan et al., 2013). Similar patterns are

seen in established autism as well as in other developmental disabilities

(Blacher, Baker, & Kaladjian, 2013; Doussard-Roosevelt, Joe, Bazhenova, &

Porges, 2003). We cannot of course assume that such patterns of PCI are

responsible for autism outcomes; it could be in theory that these different PCI

trajectories are incidental or even actually adaptive (Mottron, 2017).

Nevertheless a transactional account (Sameroff, 2009) of the early reciprocal

interplay between intrinsic developmental atypicalities in autism and the early

social environment suggests that evoked perturbations in interaction can indeed

serve to amplify social impairments and symptom impact over time; on this

basis, reversing these deficits and optimizing (‘normalizing’) social interaction

could in theory improve social functioning or reduce symptoms in autistic

children. This PCI target has the added theoretical advantage of being

‘naturalistic’ (i.e. working with the everyday developmental/family system of the

child) and potentially more easily generalizable than clinic-based interventions

directly with the child. It is however also based on the assumption that

intervening in the developmental system in this way will be ‘powerful’ enough

significantly to impact autism development, traditionally seen to be intrinsic and

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relatively environmentally stable. Whether this assumption holds is an empirical

question to which we will return.

Interventions designed to impact PCI have often used demonstration and

modeling by the therapist working directly with the child in the parent’s

presence, or mixed with didactic education. More recently, there has been a rise

in more exclusive work with the parent using direct coaching in real-time during

interaction, or use of video-feedback techniques. The precise ‘proximal’

intervention targets within PCI (that is, the immediate goal for change with

intervention) have varied from parental ‘responsiveness’ and ‘non-

directiveness’, parental ‘communicative synchrony’, to mutual ‘joint attention

and engagement’ and ‘affect sharing’ (see Figure 1). Each of these targets implies

a slightly different theoretical orientation and defined goals.

Figure 1 about here

Parental responsiveness and non-directiveness

The concept of parental responsiveness is often associated with early relational

research but terms are used subtly differently between groups. These aspects of

PCI are typically coded with global measures such as Maternal Behavior Rating

Scale (Mahoney, Powell, & Finger, 1986), Manchester Assessment of Caregiver

Infant interaction (MACI; (Wan, Brooks, Green, Abel, & Elmadih, 2016),

Emotional Availability Scale (EAS; Biringen et al 2005), but also with event-

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sampling; for instance, defined as the parent showing ‘follow-in engagement

with their child's actions, measured as the proportion of times the parent

responded to the child within 10 minutes parent child play’ (Kasari, Siller, et al.,

2014).

Two recent studies in the Kennedy review found treatment effects on parent

‘responsiveness’ in autism. A 12 week ‘Focused Playtime Intervention’ (FPI)

combined live modelling from therapist to parent with video-feedback and

psycho-education was tested in a pre-emptive study of 66 toddlers at high

autism-risk mean age 22 months (Kasari, Siller, et al., 2014). It found a positive

endpoint effect on level of parental responsiveness, but the effect was not

sustained at 3 months follow up nor associated with effect on child variables

(language scores, joint attention or child communication, diagnostic outcome). A

10-week Joint attention, Symbolic Play, Engagement and Regulation (JASPER)

intervention also produced proximal effect on responsiveness in an RCT of 86

toddlers with diagnosed ASD (22-36 months) against psycho-education, here

associated with improved child initiated joint engagement with parent (Kasari,

Gulsrud, Paparella, Hellemann, & Berry, 2015; Shire et al., 2017). By contrast a

parent-mediated version of the behavior-learning focused Early Start Denver

Model (ESDM) using therapist direct coaching and modeling for parents in 98

children in a 12 week wait-list controlled trial, found no effect on responsiveness

or other parent interaction or child outcome (Rogers et al., 2012). The

subsequent 3 site trial of ESDM on this cohort also reported no overall group

effect (Rogers et al., 2014), so prior parent-coaching did not appear to enhance

subsequent therapist-mediated treatment.

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Studies of interventions using other methods have found effects on non-

directiveness but not responsiveness. A 3 month 6 session video-feedback

intervention (VIPP-AUTI) tested against home-based nursing care in 78 children

with ASD aged 16-61 months (Poslawsky et al., 2015) found a treatment effect

on reduced parental ‘intrusiveness’ in dyadic interaction at endpoint but no

effect on parent sensitivity or structuring. Child effects on initiation of joint

attention (but not other aspects of behavior) were found at three-month follow

up, although not associated with the prior parent change. A separate 12-session

‘iBASIS-VIPP’ intervention was tested in a pre-emptive RCT for infants at familial

autism-risk against no intervention in 54 dyads, and found to have good effect at

15-month endpoint in reducing parent non-directiveness, but no effect on

responsiveness; there was associated improvement in child attentiveness to

parent (Green et al., 2015). Two year follow up of this trial (Green et al., 2017)

showed sustained improvement in parent non-directiveness 1 year after

treatment but evidence of fall-off thereafter, although improvement in child

communication initiation with parent and prodromal symptoms was sustained

(see below).

Parent communicative synchrony

The concept of synchrony is allied to ‘responsiveness’ but derived more from the

communication development literature, predicting communication and language

outcomes in autism (Siller & Sigman, 2002) and usually measured using event-

sampling rather than global rating. Subtle differences in the way this behavior is

conceptualized and measured again hamper comparison across treatments at a

detailed mechanism level. Thus one definition is of ‘parental verbal behaviour

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directed to the child’s focus of attention and actions’ (ie child-focused behaviors)

(Siller, Hutman, & Sigman, 2013), and another is of ‘parent communication

responses that acknowledge, confirm or reinforce the child’s focus, play, actions,

thoughts or intentions; in tune with what the child is thinking, saying or doing

rather than redirecting the child away from his play, thoughts or communication’

(Aldred, Green, Emsley, & McConachie, 2012).

Parental synchrony has been targeted particularly by the video-feedback

Preschool Autism Communication (PACT) treatment, which targets social

interaction and communication impairments, firstly by increasing parental

sensitivity to child communication and reducing mistimed responses using

video-feedback, and secondly by promoting a range of positive social

communication strategies. PACT was tested in an RCT of 152 children with core

autism (age 2-5 years), which found large endpoint effect in optimizing parental

synchrony across three geographically varied contexts in the UK (Green et al.,

2010; A. Pickles et al., 2016). The same effect was replicated in an RCT testing

adaptation of PACT to South Asia in 64 children aged 2-9 years (Rahman et al.,

2016). The FPI intervention as above, also partially video-aided, found small

gains in parental synchrony confined to dyads with more language-delayed

children (Siller et al., 2013).

Joint engagement and Joint attention

An alternative target for treatment is the quality of shared interaction rather

than the separate behaviour of each partner. Typically this will be measured as

‘duration’ counts of the phenomenon of interest from video-tape and like all

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these methods importantly can be coded blind to treatment allocation. ‘Joint

engagement’ as an outcome is a particular feature of the JASPER model and a

number of trials have shown reliable increases in joint engagement or joint

attention following relatively brief (usually 12 week) treatments. Typically the

caregivers are coached in the treatment model, encouraged to use strategies for

setting up the learning environment, modeling and prompting for joint attention,

expanding play, and using developmentally appropriate language. For instance,

Kasari et al. (2014) randomized 147 ‘low-resourced’ families of a child diagnosed

with ASD, aged 24-60 months, to either a caregiver-mediated intervention

(CMM) following the 12 week JASPER treatment and involving the child, or a

group caregiver-only education programme. Significant interaction between

treatment group and time during treatment was identified on the primary

outcome of Joint Engagement, with the caregiver-mediated group exhibiting a

significantly greater rate of improvement. Both groups also demonstrated

improvement in joint attention, but not in functional play. Chang et al (Chang,

Shire, Shih, Gelfand, & Kasari, 2016) randomly assigned 66 children with ASD

aged 36-60 months to a teacher-delivered JASPER intervention or wait-list

control. Endpoint intervention effects were reported for a number of the

multiple measured outcomes, including child-initiated joint engagement and

joint attention, receptive language, but not on others such as expressive language

or symbolic play. However, a qualification would have to be that this

interpretation did not adjust for the multiple testing. A third study (Landa,

Holman, O'Neill, & Stuart, 2011) randomly assigned 50 children, aged 21-33

months with a diagnosis of ASD, to parent education and parent education

supplemented with a group focusing on ‘Interpersonal Synchrony’ within a

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supplementary social curriculum. Intervention took place for two-and-a-half

hours a day, four days per week, for six months. A significant treatment effect

was found for socially engaged imitation, with a large increase (17% to 42%) in

imitated acts paired with eye contact in the Interpersonal Synchrony group

(Landa, Holman, O'Neill, & Stuart, 2011). A caveat is that these outcomes were

collected within the training environment and close to the trained targets of

intervention. No significant between-group differences were observed for

initiation of joint attention and shared positive affect, although gains were made.

Behavioural training methods

Behavioural learning methods use focused behaviour modification techniques to

influence behaviour change. In traditional behavioural interventions for autism

the targets are reduction in unwanted (often repetitive or assumed non-socially

functional) behaviours along with increase in identified social behaviours. In

more recent studies, the targets for behavioural change are more

developmentally informed; for instance in pivotal response therapy (PRT) the

targets are behaviours such as motivation for engagement and interaction

considered theoretically ‘pivotal’ for generating wider generalised change.

Broader ‘curriculum’ models such as Early Start Denver Model (ESDM) select a

broad range of developmentally relevant targets, from communication to play to

motor activity. What distinguishes these models however is that the methods

used to achieve therapeutic change towards such targets are still taken from

behavioural learning theory, largely using repetition and contingency

reinforcement for desired behaviours (Koegel, Singh, Koegel, Hollingsworth, &

Bradshaw, 2014). While use of contingencies is part of naturalistic parenting, its

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use in these models is much more exclusive and intensively focused.

Interventions of this kind are typically intensive and therapist-child delivered

over several years. The only trial of this type of intervention identified by

Kennedy et al as having acceptable low risk of bias was however of a relatively

low intensity (one session/week over 12 weeks) group PRT intervention,

focused on improving functional communication (Hardan et al., 2015). The

primary outcome was the frequency of functional child utterances in the dyad

coded during structured lab interaction in which parents were instructed to ‘try

getting the child to communicate as much as possible’. Parents were rated as

implementing PRT methods successfully; total child utterances increased in the

PRT group, with the effect driven by imitative and non-verbally prompted

utterances rather than spontaneous utterances; and verbal prompts had no

effect. The pattern of this result might be understood as an example of ‘training

to the test’; parental contingent reinforcement of child utterances, trained in the

therapy, produced local context-specific increase in the target child behaviour.

Evidence for generalisation is modest; independent global impression of social

communication from same tapes alongside parent interview reported

improvements as did parent-reported communication on Vineland, but there

was no effect in parent-reported language use, standard language measures or

parent-rated autism behaviours. A subsequent similar intervention model

combining PRT and ABA reported effects on dyadic joint engagement and shared

enjoyment but also no generalised effect (Brian, Smith, Zwaigenbaum, & Bryson,

2017).

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Summary - proximal dyadic targets

The evidence outlined above shows that caregiver dyadic behaviours with their

child (Figure 1A) are notably responsive to a number of different interventions

(just as they can be in non-autism contexts). This applies across the spectrum of

social class, ethnicity and education. Replicated effects from robust trials of

various interventions in autism show moderate to large effect sizes, particularly

to improve parental responsiveness sensitivity and synchrony, theoretically linked

in development to positive child social and communication outcomes. In relation

to intervention techniques, video feedback probably has the strongest evidence

for producing reliable parental change of this kind in both autism (Aldred, Green,

& Adams, 2004; Green et al., 2010; Kasari, Siller, et al., 2014; Poslawsky et al.,

2015; Rahman et al., 2016) and neurotypical groups (Juffer, Bakermans-

Kranenburg, & van IJzendoorn, 2008). Live coaching and modeling techniques

have shown effects to improve parental responsiveness in some studies (Carter

et al., 2011) but not in others (Carter et al., 2011; Rogers et al., 2012). Targets

involving reciprocal dyadic interaction between parent and child, such as joint

engagement and joint attention (Figure 1B) have also proved treatable in

replicated studies. There is less consistent evidence that the child’s dyadic social

interaction in turn can be improved (Figure 1C). Many studies demonstrating

increased parental responsiveness have not found that this transmitted well into

child effects; others have shown change in both parental responsiveness and

child initiated joint engagement joint attention (Shire et al., 2017). Focused

video-feedback for parents in the PACT and iBASIS trials and a mixed coaching,

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modeling and video work in JASPER are all associated with reciprocal effects on

spontaneous child communication in the treatment dyad.

Convergent evidence thus demonstrates that immediate PCI targets are

amenable to intervention. However such targets are highly proximal to the

intervention effort, and in many studies these outcomes are measured within or

in very similar contexts to the treatment setting, potentially confounding

independence and making possible a simple ‘training to the test’ result. It is

moreover a feature of autism development that the generalisation of acquired

skills across contexts is particularly difficult: it cannot be assumed that short-

term changes in dyadic interactions of this kind will translate well into more

generalized social gains for the child. In this sense the majority of autism

intervention science to date (and the vast majority of published papers) has not

really moved beyond what are in effect the equivalent of pre-clinical or early

phase studies looking at potential developmental mechanisms, on the (implicit

or explicit) assumption that these will go on to effect more generalized autism

development and functioning. Even if well done, we can hardly infer from such

evidence that a treatment is ‘effective for autism’: and the (frequent) claims to

this effect are inflated and unjustified.

Concurrent child outcomes beyond the dyad

By contrast, measuring child concurrent outcomes beyond the immediate dyadic

context (Figure 1D) represents a first stage of true generalisation for

interventions whose proximal focus is the dyad. It also represents the immediate

outcome for therapist-child interventions without parental involvement. An

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example of such concurrent child social outcome is the behavoural symptoms

that define autism disorder itself.

Autism symptoms

The symptoms of autism are most rigorously measured in standardized

researcher administered tests of social interaction, which are reliable and can be

blind-coded. Because these symptom measures capture the child’s social

communication with an unfamiliar adult in a context different to the parent-child

dyad or treatment setting, they do represent the generalisation of any treatment

gains across both context and interaction partner. The most validated of these

symptom measures is the Autism Diagnostic Observation Schedule (ADOS-2

(Lord et al., 2000), which can rate social communication (SC) and repetitive and

restrictive behavior (RRB) dimensions separately or together in a ‘Combined

Severity Scale’ (ADOS CSS). A related new symptom measure from the ADOS

originators is the Brief Observation of Social Communication Change

(Grzadzinski et al., 2016) designed to be more sensitive to total symptom change

in treatment trials. Parent-rated symptom measures such as the Social

Communication Questionnaire (Rutter, Bailey, & Lord, 2003) and the Social

Responsiveness Scale (Constantino, 2002) are commonly used but are less

rigorous because they are unblinded. The specificity of the SRS has also been

significantly challenged since it measures such broad range of behaviours

beyond core autism (Kaat & Farmer, 2017; Sturm, Kuhfeld, Kasari, & McCracken,

2017). Intervention trials highlighted by Kennedy et al. reporting concurrent

autism symptom outcomes have had mixed results. Dawson et al. 2010, showed

no effect on ADOS CSS scores after a 2 year Early Start Denver Model (ESDM)

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intervention and Fletcher-Watson (Fletcher-Watson et al., 2016) found no effect

on BOSCC symptoms with a computer-aided iPad intervention. No parent-rated

SRS effect was observed with PRT treatment (Hardan et al., 2015). On the other

hand, significant endpoint reduction in total symptom severity on the ADOS CSS

was found after the 1 year preschool PACT intervention (A Pickles et al., 2016)

where change in Social Communication symptoms alone had failed to reach

significance (Green et al., 2010). It has been harder to show effects on other

concurrent outcomes using objective measures. For instance, two year intensive

ESDM training tested against usual care in 48 children (Dawson et al., 2010) did

find significant improvements in researcher measured IQ (carried by

improvements in IQ components of receptive and expressive language), but not

other child measures. These IQ effects were not sustained at two year follow-up

(Estes et al., 2015).

Downstream developmental targets – symptoms and adaptation

There has been a relative lack of developmental follow-on studies after early

intervention (Figure 1E), although the situation is now beginning to change. The

results are somewhat encouraging but have been mixed. On relatively short-term

follow-up, Poslawsky et al (Poslawsky et al., 2015) found sustained treatment

effect on child initiation of joint attention at three months after the video

feedback VIPP-AUTI intervention, but not on other measures. Kasari et al. 2008

showed effect on objective language outcomes from the JASPER intervention

using the Reynell Developmental Language Scales (RDLS) at 12 month follow-up

but this was not replicated in a later study (Kaale, Fagerland, Martinsen, & Smith,

2014; Kasari, Paparella, Freeman, & Jahromi, 2008). Chang et al 2016 measured

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uncontrolled follow-up of the intervention group only, and reported mixed

findings. Kasari, Lawton et al showed maintenance of improvement in their CMM

group at 3 month follow-up, but no between-group effect. Other controlled

studies that showed between-group endpoint effects on either parent or child

dyadic social behaviours do not see them at short or medium term follow-up

(Baranek et al., 2015; Chang, Shire, Shih, Gelfand, & Kasari, 2016; Kasari, Lawton,

et al., 2014; Kasari, Siller, et al., 2014).

Four RCTs have however now reported longer-term (> 1 year) autism symptom

outcomes after pre-school intervention. Estes et al (Estes et al., 2015) measured

ADOS total score at a mean age of six years, two years after the end of a two-year

intensive developmental behavioural intervention (ESDM). While there had been

no symptom effect at trial endpoint, the 21 of the 24 children in the intervention

group followed-up showed greater total and RRB symptom reduction over the

follow-up period compared to 18 of 24 followed from the control group. Causal

treatment effect inference from these findings is limited by the lack of intention

to treat (ITT) analysis or adjustment for baseline pre-treatment variables. Kaale

et al (Kaale et al., 2014) reported no effect on non-blinded parent- or teacher-

rated autism symptoms (SCQ) 12 months after a 12-week teacher-mediated

JASPER intervention (n=33) compared to controls (n=27). Follow-up of the

original PACT trial, 6 years after treatment endpoint, assessed 121 of the original

152 trial participants with core autism at mean age 10·5 years. ITT analysis

showed reduction in autism symptom severity (ADOS CSS) at both treatment

endpoint (ES 0·64, 95% CI 0·07,1·20) and follow-up (ES 0·70, 95% CI -

0·05,1·47), resulting in a substantial averaged treatment effect on symptoms

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over the total period (ES 0·55, 95% CI 0·14, 0·91). Non-blind parent-rated autism

symptoms on SCQ (ES 0·40, 95% CI 0·05, 0·77) and repetitive behaviours on

RBQ (ES 0·87, 95% CI 0·47, 1·35) also showed comparable improvement at

follow up (A. Pickles et al., 2016). A similar video-feedback social communication

intervention for infants at-risk of autism, implemented between 9 and 14 months

of age and followed at one and then two years from end of treatment (Green et

al., 2015), showed interestingly parallel ITT results, with a significant effect of

intervention over the treatment and follow-up period for autism prodromal

symptoms (ES=0.32; 95% CI 0.04, 0.60; p=0.026), parental dyadic non-

directiveness/synchrony (ES=0.33; CI 0.04, 0.63; p=0.013), and child

attentiveness/communication initiation (ES=0.36; 95% CI 0.04, 0.68; p=0.015).

Mediation testing in psychosocial intervention

Only two studies in the extant autism literature have mounted a substantive test

of mechanism through a mediation test within an RCT. Gulsrud et al (Gulsrud,

Hellemann, Shire, & Kasari, 2016) used videotape analysis of the content of

therapeutic sessions in the JASPER intervention on key putative active

ingredients. There was a possible methods confound in that mediator and

primary outcome (joint engagement) were both coded (albeit independently) at

endpoint from the same video-material with no midpoint assessment, allowing

the possibility of "reverse causation" in the inference of effect. Nevertheless, the

analysis did identify a particular aspect of the therapy (parental ‘mirrored

pacing’) as mediating the joint engagement outcome; which is an important

result with generalizable value and points forward to potential further

refinements of the therapy procedure. Within the PACT trial, Pickles et al

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(Pickles et al., 2015), identified a latent midpoint mediator variable using

baseline, midpoint and endpoint repeated measures, a method of analysis that

also reduces the measurement error intrinsic to observational video coding.

Treatment effect on parent synchrony strongly mediated (90%) the change

found in child communication initiations with parent, supporting the treatment

theory. Both these mediation analyses are thus convergent in identifying similar

specific parental interaction behaviours (‘mirrored pacing’ and ‘communicative

synchrony’) that improve child engagement and communication in the dyadic

context. They stand as the clearest mechanism findings to date in autism

intervention science, and provide important and generalizable information about

what are the active components of the therapies in facilitating interaction and

child outcomes. Further, the Pickles et al analysis also showed that it was the

change in child dyadic communication initiations with parent (rather than the

parental synchrony) that mediated the subsequent change in child autism

symptoms with a researcher – thereby demonstrating a causal chain of

generalization of child-acquired skill from the PCI context into a researcher-child

interaction. More mechanism tests of this kind will be important going forward.

Summary of psychosocial mechanism targets

Autism particularly impacts social functioning in development. We have seen

above that a transactional account of social development and reciprocity in

autism, recruiting ideas from social-developmental research in neurotypical

populations, has led to a rationale for interventions targeting key aspects of

social development in autism. The evidence to date shows that a number of such

theoretically based and targeted interventions can indeed reliably improve

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various aspects of the local dyadic social communication of children with autism,

particularly with their caregivers (Figure 1A-C). There is less work on whether

such dyadic change can produce more generalised impact on concurrent within-

child outcomes (Figure 1D): there have been positive findings but the overall

evidence is mixed. There is even less work on the crucial issue of longer-term

developmental outcomes (Figure 1E), but some emerging evidence, especially

from the PACT trial, that this is possible over the medium to long term. With a

developmental disorder like autism, interventions must surely aspire to such

longer-term effects in order to be convincing as disorder-specific treatments.

Given the convergent evidence that short-term context-specific proximal change

is possible using a variety of intervention methods, further replication of this

established result on its own is redundant moving forward (although they are the

easiest and cheapest designs to carry out!). It is true that mechanism findings

from one trial (Pickles et al 2015) show a causal link between treatment change

on child dyadic interaction with caregiver and generalised symptom change

across context, and this is encouraging that these proximal changes may indeed

be meaningful in relation to symptoms and generalised adaptation. But such a

finding needs replication, and the field now needs larger and more ambitious

psychosocial trials that address mechanism, generalisation and the possibilities

of long-term developmental and adaptive change, as well as adaptive

interventions tailored to patient characteristics and individual response (for

instance using sequential multiple assignment randomised ‘SMART’ trials).

Accumulation of such trial evidence will refine approaches and further answer

an enduring question; what are the limits to clinically relevant effectiveness of

21

‘environmental’ interventions in a condition that is highly heritable and

developmentally persistent?

MOVING TO THE LEVEL OF NEURAL MECHANISM

The neurodevelopmental context of autism inevitably leads to a consideration of

expanded targets for treatment beyond the purely psychosocial into the assumed

neural system pathogenesis. No straightforward targets present themselves. The

known genetic background of autism shows great heterogeneity and no common

final pathways of effect within the neural system linked to the behaviour

phenotype have yet been established. At a descriptive level, the large number of

genetic variants associated with autism outcomes show convergence on

functional networks related to intracellular signaling (see below), neuronal

development and axon guidance, and chromatin modification and transcription

regulation (Pinto et al., 2014), but brain localization of effects is less established

and findings point to generalised functional aspects such as neural system

connectivity (O'Reilly, Lewis, & Elsabbagh, 2017). Further challenges arise in

linking such neuroscience findings to the autism cognitive and behavioural

phenotype. Prospective neuroscientific studies of the emergence of autism in the

prodrome have suggested some specific risk markers, but as the work has gone

on more and more aspects of early neurodevelopment are found to be atypical in

autism emergence (Johnson, Gliga, Jones, & Charman, 2015; Szatmari et al.,

22

2016), replicating perhaps a sense of the heterogeneity in other aspects of

autism science.

A promising strategy for limiting this heterogeneity has been to constrain the

primary genetic variance by studying monogenic disorders with a high autism

expression. As well as simplifying the biological system for study, this strategy

has the added advantage that knockout animal models can be bred for detailed

biological investigation. There is an inevitable question of whether these

‘syndromic models’ of ASD in humans actually represent the same phenotype as

the idiopathic condition; detailed phenotypic studies suggest they can do (Garg

et al., 2015), but this remains an important question. Some of these syndromic

models have indeed demonstrated the searched-for causal chain between

genetic variation, cell biology, neural system atypicality and phenotypic

behavior. Thus for instance in animal knock-out models of the monogenic

disorder neurofibromatosis 1 (NF1), pharmacological intervention or genetic

manipulation can downregulate the cell signaling abnormality directly related to

the genetic variation and show consequent effects on improved synaptic

function, synaptic protein expression, long-term potentiation and finally rescue

of the cognitive and behavioural phenotype (Li et al., 2005; Molosh et al., 2014).

Analogous results have been shown in other syndomic autism conditions such as

fragile X (FXS) and tuberous sclerosis complex (TSC). Such animal findings will

not necessarily translate into human study (see below) but they provide a proof

of principle that intervention in theoretically relevant neural system targets can

produce predictable and relevant improvements in relevant behavior outcomes.

This has led to an accelerating effort to study the effect of intervention on a

23

variety of these neural system targets relevant to autism, many but not all of

which involve work with monogenic syndromic autism. We thus now review the

various neural system mechanisms targeted in these studies, moving in turn

from the most ‘proximal’ in terms of synaptic function; to post-synaptic

molecular pathways; to more general brain-growth and neurotropic factors; and

finally to more generalized neural system function reflected in EEG and

connectivity measures (see Figure 2).

Figure 2 about here

A) Neurotransmitters/neuromodulatory system targets

(i) Glutamate

Glutamate is the main excitatory neurotransmitter in the brain, exerting its effect

through the activation of several receptor subtypes. Fast excitatory synaptic

transmission is mediated via ionotropic (AMPA, NMDA and kainite) receptors,

whilst modulatory action is exerted through metabotropic G-protein coupled

(mGluRs) receptors. The mGluRs play an important role in synaptic plasticity,

learning and memory and glutamate signaling is hypothesised to be relevant to

aetiology of chronic brain disorders such as schizophrenia and Alzheimers

dementia as well as ASD (Uzunova, Hollander, & Shepherd, 2014). FXS animal

model work suggests that exaggerated mGluR signaling induces enhanced

hippocampal long-term depression related to the behavioural phenotype (Bear,

24

Huber, & Warren, 2004). Fenobam, the first mGluR antagonist used in human

clinical trials, showed reduced anxiety, hyperarousal, and attention in FXS

patients in a small (n=12) single-dose, single-arm open label study (Berry-Kravis

et al., 2009), but no Phase II studies have been reported, probably due to CNS

adverse effects with Fenobam use (Freidmann, Davis, Ciccone, & Rubin, 1980).

Mavoglurant (AFQ056), a structurally novel noncompetitive mGluR5 inhibitor,

showed promise in FXS mouse models in rescuing the aberrant dendritic spine

morphology and concurrent improvements in the molecular and social

behavioural phenotype; however, results from human clinical trials have been

less encouraging. Two 12 week, multicentre phase 2b RCTs of Mavoglurant in

175 adults and 139 adolescents with FXS, showed no significant treatment

effects between mavoglurant and placebo on primary endpoints of FXS specific

Aberrant Behaviour Checklist (ABC) (Berry-Kravis et al., 2016). These results

suggest that manipulation of the mGluR signaling alone may be insufficient for

attenuating the FXS autism phenotype in humans.

Defects in NMDA receptors have been reported in FXS & Rett syndrome although

the mechanism is not clearly understood. Memantine, an NMDA receptor

antagonist approved for use in Alzheimers disease, improved attentional

processes and working memory in patients with Fragile X-associated

tremor/ataxia syndrome (Yang et al., 2016). In FXS, a small open label trial of

memantine in 6 subjects, mean age 18.3 years showed symptom improvement

on Clinical Global Impressions (CGI) but no effect on symptom specific rating

scales, which included ABC, SRS and ADHD rating scales (Erickson, Mullett, &

McDougle, 2009).

25

(ii) GABA

GABA is the main inhibitory neurotransmitter in the brain, exerting its effect

through the GABAA and GABAB postsynaptic receptors. Abnormal GABAergic

signaling has been demonstrated in a number of syndromic autism models such

as FXS and NF1. The leading hypothesis here is that abnormal GABA signaling

leads to an inhibition/excitation imbalance, including dysregulation in protein

synthesis. GABAergic signaling is now consequently an important therapeutic

target in ASD. In FXS, along with increase in glutaminergic signaling, there is

deficiency in GABA receptor expression and GABA mediated inhibition, which

has led to the development of therapies aimed to increase GABA mediated

inhibition. A double-blind RCT of GABAB agonist arbaclofen in 63 FXS patients

aged 6-40 years found significant treatment effects in social behaviours and

function (Berry-Kravis et al., 2012) but not on the primary endpoint measure of

the Aberrant Behaviour Checklist-irritability subscale. A recent double-blind

placebo controlled RCT of Arbaclofen of 125 adolescents/adults (age 12-50

years) and 172 children (age 5-11 years) found no significant treatment effect in

either group on the primary outcome measure of FXS specific ABC social

avaoidance sub-scale. However in the child study, significant effects were noted

on secondary outcome measures of ABC-irritability subscale and parenting

stress index, suggesting that younger patients may derive some benefit.

Acamprosate is a mGluR5 receptor antagonist, a GABAA receptor agonist, and has

complex actions on NMDA receptors depending on glutamate concentration

(Erickson, Early, et al., 2011). A small open label trial in 12 FXS children aged 6-

17 years suggested some improvements in social behaviours, inattention and

26

hyperactivity (Erickson, Mullett, & McDougle, 2010); larger studies using

Acamprosate in FXS are currently underway and results from trials of other

GABA agonists such as ganaxolone are awaited. More recently, there has been

interest in the diuretic Bumetanide, which enhances GABAergic inhibition. In a

multi-centre phase 2 RCT (n-=88, aged 2-18 years), Bumetanide use was

associated with significant improvement on parent and clinician rated autism

measures (Lemonnier et al., 2017); replication is awaited.

(iii) Dopamine

Dopamine plays a crucial role in synaptic plasticity, cognitive functioning and

neuropsychiatric pathologies. Interest in the role of Dopamine was stimulated by

the observation that Dopamine blockers (anti-psychotics) were effective in

treating co-morbidities associated with autism such as aggression, hyperactivity

and self-injury (Nakamura et al., 2010). Deficits in dopaminergic functioning

have been demonstrated in syndromic models such as FXS, NF1 and TSC. An

double-blind cross over trial of methylphenidate in 15 children with FXS

demonstrated that compared to placebo, two-thirds of patients responded well

with improvements in social skills, hyperactivity and attention (Hagerman,

Murphy, & Wittenberger, 1988). An open-label trial of 12 weeks of the partial

dopamine D2 agonist Aripiprazole in 12 subjects with FXS showed good

tolerance and significant improvement in irritability (Erickson, Stigler, et al.,

2011), though this is not a core autism symptom.

27

(iv) Serotonin

Serotonin (5-hydroxytrytamine, 5-HT) is a critical modulator of neuronal

interaction that supports diverse behaviours and physiological processes

including social behaviour, sleep, affective regulation, learning, memory and

synaptic plasticity. The serotonergic system was one of the first

neurotransmitter systems to be investigated in the pathophysiology of ASD.

Several studies have reported elevated levels of platelet serotonin in a third of

ASD samples (Cross et al., 2008); short-term dietary depletion of serotonin is

linked to increase repetitive behaviours and anxiety in ASD subjects (Veenstra-

Vanderweele et al., 2009); and mutations in serotonin transporter genes such as

SLC29A4 have been linked to ASD symptoms (Adamsen et al., 2014).

Neuroimaging studies using PET have shown significantly lower levels of

serotonin synthesis in ASD children compared to controls (Chandana et al.,

2005), particularly in medial frontal cortex, midbrain and temporal lobe areas

(Makkonen, Riikonen, Kokki, Airaksinen, & Kuikka, 2008). Treatment with

selective serotonin uptake inhibitors has been shown to have some effect in

ameliorating the repetitive/ obsessive behaviours in ASD; however, a Cochrane

review of nine RCTs found no overall evidence of positive effect of SSRIs on core

features (Williams, Brignell, Randall, Silove, & Hazell, 2013).

(v) Oxytocin

Oxytocin is widely distributed in the CNS and plays an important role in social

recognition, memory, attachment, as well as stereotyped behaviours. It mediates

the perinatal excitatory to inhibitory shift of GABA. A number of human studies

28

have examined the effect of oxytocin on social cognition, with mixed results. In a

double blind placebo-control within-subject design, application of intranasal

Oxytocin was associated with attenuated amygdala response to faces regardless

of valence (Domes et al., 2007). In a RCT of 15 adults with ASD, oxytocin was

associated with significant reduction in repetitive behaviours in comparison to

placebo (Hollander et al., 2003). However a number of studies have reported no

significant improvement of oxytocin treatment. Dadds et al evaluated oxytocin

intervention in a double blind RCT in 38 children (age 7-16 years) with ASD

administered during parent-child interaction training sessions over four

consecutive days and found no treatment effect on social interactional skills or

emotional recognition (Dadds et al., 2014). Similarly a double blind RCT of

Oxytocin nasal spray twice daily in 50 males with ASD (12-18 years) showed no

effects on caregiver rated SRS and CGI (Guastella et al., 2015). One hypothesis for

the differences between studies is that individual differences in endogenous

oxytocin levels may moderate treatment response. Addressing this issue, a

recent RCT of 32 children with ASD investigated the efficacy of four-week

intranasal oxytocin treatment measuring pre and post treatment blood oxytocin

levels. The study found treatment effects on SRS social abilities confined to those

with low baseline oxytocin levels (Parker et al., 2017).

B) Signaling pathways targets downstream of neurotransmitter receptors

(i) The MAPK/ERK pathway

Dysregulation of the intracellular Ras/MAPK (mitogen activated protein kinases)

signaling pathway is considered a major risk factor for ASD and prominent in

29

functional networks of autism-related genes (Pinto et al 2014). The RAS/MAPK

pathway is embedded in a network of other pathways including PI3K and mTOR

(see Figure 2). Mutations in a number of genes on the Ras pathways have been

shown to be associated with ASD (Garg et al., 2017; Garg et al., 2013). NF1 is

directly associated with Ras/MAPK pathway overactivity, causing downstream

increase in GABA and impairments in synaptic plasticity, making this pathway a

rational target for intervention. Statins downregulate the Ras pathway through

inhibiting farnesylisation and this rescues the social and behavioural phenotype

in knock-out animal models (Li et al 2005). Subsequent translational trials in

human NF1 have shown mixed results. Improvements in verbal and non-verbal

memory were reported within a 12-week phase 1 observational study of

lovastatin in 23 children aged 10-17 years (Acosta et al., 2011) and in a 14-week

RCT of lovastatin in 44 10-50 years olds (Bearden et al., 2016); an n=7 case

series from the former cohort showed evidence of treatment normalizing

pseudo-resting state functional connectivity in areas of the default mode

network (Chabernaud et al., 2012). Four days of high-dose (200 mg) lovastatin

improved synaptic plasticity and phasic alertness, as measured with trans-

cranial magnetic stimulation, in a case-controlled study of 11 adults with NF1

(Mainberger et al., 2013). Larger statin trials, however, have found little effect on

cognitive/behavioural outcomes. A 12-week double-blind, placebo controlled

RCT of simvastatin in 62 children with NF1 aged 8-16 found no group differences

on the Rey complex figure test (Krab et al., 2008); another RCT of simvastatin

(84 children aged 8-16 years) found no improvements in cognitive deficits or

parent-reported behavioural problems (van der Vaart et al., 2013); and a 16-

week RCT of lovastatin in 146 8-15 year olds with NF1 found no improvements

30

in paired associate learning (Payne et al., 2016). By contrast, a recent pilot data-

rich RCT (n=30) of simvastatin in young children with NF1–autism (4.5-10.5

years) studied for the first time the full hypothesized pathway from peripheral

MAPK activity, through multiparametric imaging of neural system function to

autism-related behaviours (Stivaros et al., 2018). Indications of relevant statin

effects towards normalizing function were found at all these levels, encouraging

the view that detailed mechanism studies of this kind may have potential to be

illuminating, but the study needs replication on larger samples. The MAPK/ERK

pathway is also implicated in FXS pathogenesis. A 16-week open label trial of

Lovastatin in children with FXS suggested significant endpoint improvements on

clinician rated measures (Caku, Pellerin, Bouvier, Riou, & Corbin, 2014).

However no placebo-controlled trials have so far been reported.

(ii) mTOR

Mammalian target of rapamycin (mTOR) is a key regulator in cellular processes

including cell growth, gene expression and synaptic function. Hyperactivity of

the mTOR pathway is associated with several syndromic autism models

including TSC, NF1, PTEN, and FXS. Dysregulated mTOR signaling leads to

abnormal development of fundamental processes such as axonal and dendritic

morphology, synapse formation and cell growth, which have been associated

with an ASD phenotype in animal models (Sato, 2016). Rapamycin is a specific

inhibitor of mTOR and in pre-clinical study has improved social behaviour in TSC

(Sato et al., 2012), PTEN-related disorders (Zhou et al., 2009) and 15q11-13

duplication (Oguro-Ando et al., 2015). In TSC, preliminary trials of mTOR

inhibitors Sirolimus improved executive function (Davies et al., 2011) and

31

Everolimus reduced seizure frequency and ASD related symptoms on quality of

life measures (Krueger et al., 2013). Based on these initial results, several more

TSC RCTs are currently underway testing mTOR pathway inhibitors for

neurocognitive and ASD related deficits.

C) Growth & Neurotrophic factor targets

Deletion/mutation of the SHANK3 gene in Phelan-McDermid syndrome (PMS;

also known as 22q13 deletion syndrome) results in reduced expression of

scaffolding proteins in the postsynaptic density of excitatory synapses, impairing

glutaminergic transmission and synaptic plasticity (Moessner et al., 2007). PMS

is associated with 0.5%-2.0% of all ASD cases. Similarly loss of function

mutations of the X-linked gene MECP2 in Rett syndrome affects the structure and

function of synapses at the microcircuit level critical for synaptic transmission

and plasticity (Guy, Hendrich, Holmes, Martin, & Bird, 2001). Recent studies

suggest that Insulin-like growth factor-1 (IGF-1) can have a beneficial effect on

synaptic development by promoting neuronal cell survival, synaptic maturation

and synaptic plasticity (Bozdagi, Tavassoli, & Buxbaum, 2013). A pilot placebo-

controlled double blind RCT using Insulin-like growth factor in 9 children with

PMS was associated with significant improvements in social impairments and

repetitive behaviours (Kolevzon et al., 2014). In Rett syndrome, an open label

phase 1 study of IGF-1 in n=12 girls with MECP2 showed good safety, tolerability

and improvements in behavioural abnormalities (Khwaja et al., 2014). Studies of

IGF-1 in FXS are also underway.

32

Other drugs such as Minocycline (a tetracycline derivative approved for

treatment of acne) have been shown to have neuroprotective effects and

upregulate neurotrophic and growth factors in the brain. In FXS animal models,

Minocycline has been shown to have an inhibitory effect on matrix

metalloproteinase 9 activity which is fundamental in modulating hippocampal

plasticity. A double blind placebo controlled cross-over trial of Minocycline in 55

FXS children aged 3.5-16 years over 12 weeks found significant treatment effect

on clinician rated Clinical Global Impression Scale (CGI) but not on any

behavioural measures (Leigh et al., 2013). Further, minocycline use was

associated with alteration of event-related potentials in an auditory oddball

paradigm in 12 subjects taken from the same trial (Schneider et al., 2013),

possibly suggesting reduced hypersensitivity to auditory stimulation.

D) Electrophysiological targets

At the more general level of neural system functioning and long-range

integration and connectivity, EEG and habituation responses to social stimuli

have been investigated as targets for ASD intervention. Linked to underlying

social processing and social attention, these can be some of the earliest apparent

atypicalities in infants at risk who go on to develop ASD (Johnson et al., 2015;

Szatmari et al., 2016). As an example of EEG as a target of this kind, Jones et al.

2017 reported on the EEG outcomes within an RCT of parent-delivered

psychosocial "promoting first relationships" intervention designed to facilitate

parent infant interaction and delivered between 9-11 months of infant age. Both

at twelve month and 18 month follow-up they reported increase in social

habituation to faces versus objects and greater increase in frontal EEG theta

33

power (Jones, Dawson, Kelly, Estes, & Jane Webb, 2017). The study was relatively

small with valid data available from 15 or less in the PFR group and 10 or less in

the control group over the range of assessments, but the findings provide proof

of principle and suggestive results that neurophysiological measures can be

impacted by relatively low intensity social communication focused intervention.

The results echo a previous study (Dawson et al., 2012), which studied EEG in

60% of the trial cases at endpoint only after two years intensive ESDM therapy.

Although the findings showed no intervention effect across a number of

parameters, there was reported increase EEG-theta to social stimuli with faces,

which correlated with a parent-reported social communication rating (although

not with autism symptoms, IQ, language or adaptive behavior).

Summary of neural mechanism targets

Studies of syndromic autism have provided a way of identifying causal links from

genes to specific molecular and biological pathways and alterations in

behavioural outcomes. An underlying hypothesis is that there may be a finite

number of common molecular pathways in autism that could act as intervention

targets and that treatments thus identified in the context of syndromic ASD could

then be applicable to broader idiopathic ASD; thus raising the possibility of a

precision medicine approach to autism based on the underlying pathophysiology

(Loth, Murphy, & Spooren, 2016). The work reviewed above reflects the active

international effort now in this area, which has already produced some

clarification of neural system pathways and encouraging therapeutic leads.

These include for instance mTOR inhibitors, statins, oxytocin and pleiotropic

growth factors. Despite this, no single treatment has so far been approved for a

34

Phase III trial and there are clearly conceptual as well as practical challenges.

Animal experiments cannot fully recapitulate the complexity of higher-order

cognitive processes in humans and translation by simple analogy is likely to be

overly simplistic. The targeted interventions are not specific for autism

symptoms but rather target an underlying pathway. Practical challenges include

patient selection, age of treatment onset, dose and duration of treatment, dose-

limiting side-effects and lack of CNS biomarkers (Berry-Kravis et al., 2016). Most

human intervention work has been in adolescents or adults and it may be that

targeting the developing brain in much younger samples may be crucial.

Outcome measurement in these studies – commonly the parent-rated Aberrant

Behaviour Checklist (ABC; Aman, 1994), or the clinician-rated Global

Improvement Scale (CGI; Leucht & Engel, 2006), Table 2 – have also been very

different to that in psychosocial research, unfortunately limiting comparability.

This is important because to be convincing, treatment studies in this area will

need to aspire to the same outcome standards as discussed above for

psychosocial research. The need for a common outcomes framework is further

discussed below.

SUMMARY

Our focus on target mechanisms for intervention across various pathways to

autism outcome aims to give an integrated vantage-point to consider the breadth

of current autism intervention research and the continuum of targets across

35

social and biological development. In that context, the targets of the psychosocial

approaches to intervention that we have reviewed can be seen as focusing on

endpoint pathways nearest in development to autism symptom outcomes. They

target child-environment social interaction and child behavior within

developmental processes. We have seen from many studies that targeted

psychosocial interventions of various kinds can positively improve over the

short-term the most immediate parent-child social communication in

development; but the review may have surprised in showing how limited at

present is the further evidence of generalized treatment effect. While we do not

need more studies to replicate these immediate effects on their own, there are

therefore pressing research questions as to how and whether such proximal

communication change can be generalized to improve child social functioning

beyond the dyad (generalisation across context and person) and sustained

longer-term within development (generalisation over time). Only with these

demonstrations can an intervention be truly persuasive as an autism treatment.

We have seen the recently emerging evidence that this is indeed possible, with

generalized symptom effects shown for several years following psychosocial

intervention. But more replication studies of this kind are needed. The evidence

on social communication intervention is now at a stage of maturity where we

should be looking to focus on the common mechanisms across therapies that

mediate treatment effect, and to combine evidenced effective treatment

mechanisms into new implementation approaches combining modular aspects of

intervention in clinically useful ways (Marchette & Weisz, 2017). A recent

example has been the integration of social communication intervention with

assisted communication (Kasari, Kaiser, et al., 2014). We do not yet know the

36

limits to developmental improvement that may be possible from psychosocial

intervention in this essentially neurodevelopmental disorder.

We have then reviewed a new generation of emerging pharmacological

treatments that are addressing underlying ‘upstream’ neural mechanism targets

associated with ASD. Most of these are pre-clinical or early phase trials; but we

have suggested above that many of the psychosocial trials described actually

have directly analogous status. (It is a sign of the different standards applied to

the two domains that, while no one would consider widespread promotion of

some of the biological treatments on this basis, the review suggests that some

psychosocial interventions with similar or lower levels of evidence are widely

implemented. Even if the downside risks associated with psychosocial

treatments are felt to be less, we still argue that this situation is highly

unsatisfactory and will hamper progress). One question for the future is whether

there may be synergy between psychosocial treatments of demonstrated effect

and emerging interventions targeting biological and neural system targets. No

substantive trial of such synergy has yet been published and this remains an

aspiration. How might such synergy work? We must imagine the developing

brain in transaction with the quality of its social experience. A great advantage of

reviewing biological and psychosocial treatments together is to provide such a

perspective. Understanding the complex transactional pathways to social

impairment and development in this way will work against a reductionism that

may follow from linear translational models from animal work. The process of

synergy might be simply additive on treatment outcome. However there might

be multiplicative effects through for instance: i) timely neural system

37

enhancement allowing enhanced response to psychosocial intervention, for

instance the hypotheses that oxytocin administration might help social learning

in therapy has been tested in pilot studies; ii) psychosocial intervention altering

neural system targets in a way that could be adjunctive to biological

intervention, or promoting sustained effects on development. Preliminary

evidence is provided above of psychosocial intervention impacting EEG markers

of social processing at least in the short term. Understanding the continuities and

transactions of mechanism between these psychosocial and biological targets

will help progress, clinical work and a coherent sense of the task.

Common methods of process and outcome measurement across biological and

psychosocial studies will be critical going forward - something that has not so far

happened; the two fields having different traditions of outcome measurement.

Some argue that autism symptom outcomes are the most appropriate outcome

metric since they define the disorder and can be measured blind, however,

methods of symptom measurement have unfortunately to date differed between

psychosocial and biological intervention domains; psychosocial trials using

ADOS which addresses autism behavioural symptoms with high external validity,

biological trials using ABC or CARS which have poor specificity for diagnostic

symptoms and less external validity. Others argue that more "real world"

adaptive assessments are appropriate, although there is a lack of blinded

assessments of this kind. There are no appropriate assessments as yet of child

and parent quality of life in autism, which could help look at wider outcome

38

(Jonsson et al., 2017; McConachie et al., 2015). Choice of assessment relates also

to an emerging debate on the appropriate ultimate aims for intervention in

autism; an interesting challenge that extends beyond the solely professional or

scientific arena. Applying the ‘4 P’s’ approach to autism intervention (Insel, 2007,

2014) will involve a Participatory approach whereby experts-by-experience of

autism should join with interventionists in thinking about the most beneficial

intervention outcomes; a Personalised approach that will be facilitated by quality

intervention science that investigates both mechanism and effect moderation; a

Predictive approach that follows intervention effects downstream and be shown

to change things that are theoretically important for developmental science – but

also for families and individuals; and Pre-emptive in the timeliness of such

intervention at a point in development where it may do most benefit. The fact

that this has added urgency now is a testament to the advances that have been

made in developing potentially effective interventions; a success that

necessitates wide dialogue between basic science, interventionists, ethicists,

families and the wider autism community, but can also have real promise for the

developmental outcomes of children with an autism development.

39

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