Solid Grounds

Of Pioneers

The General Movement Assessment (GMA) has

contributed to shedding light on the early

features of developmental and genetic

disorders with a mean age of diagnosis at

or beyond toddler age, such as Rett

syndrome and autism spectrum disorder.

Whilst global GMA has proven to be most

valuable for clinical purposes, more fine-

grained and/or technologically supported

in depth analyses of general movements will

provide pre-diagnostic markers to predict

development in infant populations at risk

for subclinical or adverse neurological

outcome. Based on the pioneering work of

Prechtl and his team and the establishment

of the GMA over the last 20 years, we have

arrived at a point where we need to look

beyond the capacity of GMs in predicting

cerebral palsy and define in a broader

sense their predictive value in describing

the ‘disintegrity’ of neural functions in

early infancy.

Marschik PB, Einspieler C. Of pioneers and

advancements related to general movement assessment.

Eur J Paediatr Neurol. 2018; 22(4): 584-585.

2 2018 in Review

Research

Zika Virus

We performed the General Movement

Assessment (GMA) at 9 to 20 weeks’ postterm

age and associated the findings with the

neurodevelopmental outcomes at 12 months of

age in infants prenatally

exposed to acute maternal

illness with rash during the

Zika virus (ZIKV) outbreak in

Brazil. In this observational

cohort study, 111 infants prenatally

exposed to acute maternal illness with rash

were recruited at medical institutions in

Rio de Janeiro and Belo Horizonte, while

333 age-matched infants without any

exposure to maternal illness originated

from iDN’s database GUARDIAN(58% male for

both groups).

Eighty-two percent (46 of 56) of ZIKV-

exposed infants without congenital

microcephaly were normal at age 12 months.

Forty-four of 46 infants were correctly

identified by GMA at 3 months, with a

negative predictive value of 94%(95%CI,

85%-97%). Seven of 10 ZIKV-exposed children

without microcephaly with adverse

neurodevelopmental outcomes were identi-

fied by GMA. The GMA positive predictive

value was 78% (95%CI, 46%-94%), sensitivity

was 70% (95%CI, 35%-93%), specificity was

96% (95%CI, 85%-99%), and accuracy was 91%

(95%CI, 80%-97%). All 35 children with

microcephaly had bilateral spastic

cerebral palsy; none of them had normal

movements. The Motor Optimality Score

differentiated outcomes: the median Motor

Optimality Score was 23 (interquartile

range [IQR], 21-26) in children with normal

development, 12 (IQR, 8-19) in children

with adverse outcomes, and 5 (IQR, 5-6) in

children with microcephaly, a significant

difference (P = .001).

Although a large proportion of ZIKV-exposed

infants without microcephaly develop

normally, many do not. The GMA should be

incorporated into routine infant

assessments to enable early entry into

targeted treatment programs.

Einspieler C, Utsch F, Brasil P, Panvequio Aizawa CY,

Peyton C, Hydee Hasue R, Françoso Genovesi F,

Damasceno L, Moreira ME, Adachi K, Marschik PB,

Nielsen-Saines K, GM Zika Working Group. Association

of infants exposed to prenatal Zika virus infection

with their clinical, neurologic, and developmental

status evaluated via the General Movement Assessment

Tool. JAMA Netw Open. 2019; 2(1): e187235-e187235.

Lopes Moreira ME, Nielsen-Saines K, Brasil P, Kerin

T, Damasceno L, Pone M, Carvalho LMA, Pone SM,

Vasconcelos, Z, Ribeiro IP, Zin AA, Tsui I, Adachi K,

Gaw SL, Halai UA, Salles TS, Da Cunha DC, Bonaldo MC,

Raja Gabaglia C, Guida L, Malacarne J, Costa RP, Gomes

SC, Reis AB, Soares FVM, Hasue RH, Aizawa CYP,

Genovesi FF, Aibe M, Einspieler C, Marschik PB,

Pereira JP, Portari EA, Janzen C, Cherry JD.

Neurodevelopment in infants exposed to Zika virus in

utero. N Engl J Med. 2018; 379(24): 2377-2379.

Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a

neurodevelopmental condition of hetero-

geneous etiology. While it is widely

recognized that genetic and environmental

factors and their interactions contribute

to autism phenotypes, their precise causal

mechanisms remain poorly understood. This

article reviews our current understanding

of environmental risk factors of ASD and

their presumed adverse physiological

mechanisms. It comprehensively maps the

significance of parental age, teratogenic

compounds, perinatal risks, medication,

smoking and alcohol use, nutrition,

vaccination, toxic exposures, as well as

the role of extreme psychosocial factors.

Further, we consider the role of potential

protective factors such as folate and fatty

acid intake.

Evidence indicates an increased offspring

vulnerability to ASD through advanced

maternal and paternal age, valproate

intake, toxic chemical exposure, maternal

diabetes, enhanced steroidogenic activity,

immune activation, and possibly altered

zinc–copper cycles and treatment with

selective serotonin reuptake inhibitors.

Epidemiological studies demonstrate no

evidence for vaccination posing an autism

risk. It is concluded that future research

needs to consider categorical autism,

broader autism phenotypes, as well as

autistic traits, and examine more

homogenous autism variants by subgroup

stratification.

Our understanding of autism etiology could

be advanced by research aimed at

disentangling the causal and non-causal

3 2018 in Review

environmental effects, both founding and

moderating, and gene–environment interplay

using twin studies, longitudinal and

experimental designs. The specificity of

many environmental risks for ASD remains

unknown and control of multiple confounders

has been limited. Further understanding of

the critical windows of neurodevelopmental

vulnerability and investigating the fit of

multiple hit and cumulative risk models are

likely promising approaches in enhancing

the understanding of role of environmental

factors in the etiology of ASD.

Bölte S, Girdler S, Marschik PB. The contribution of

environmental exposure to the etiology of autism

spectrum disorder. Cell Mol Life Sci. 2018.

Rett Syndrome

Typically, early (pre-diagnostic) develop-

ment in individuals later diagnosed with

Rett syndrome (RTT) has been investigated

retrospectively using parent reports,

medical records and analysis of home

videos. In recent years, prospective

research designs have been increasingly

applied to the investigation of early

development in individuals with late

phenotypical onset disorders, for example,

autism spectrum disorder.

In this study, data collected by the Danish

National Birth Cohort lent itself to

prospective exploration of the early

development of RTT, in particular early

motor-, speech-language, and socio-

communicative behaviours, mood, and sleep.

Despite limitations, this quasi pro-

spective methodology proved promising. In

order to add substantially to the body of

knowledge, however, specific questions

relating to peculiarities in early

development could usefully be added to

future cohort studies. As this involves

considerable work, it may be more realistic

to consider a set of indicators which point

to a number of developmental disorders

rather than to one.

Marschik PB, Lemcke S, Einspieler C, Zhang D, Bölte

S, Townend GS, Lauritsen MB. Early development in Rett

syndrome - The benefits and difficulties of a birth

cohort approach. Dev Neurorehabil. 2018; 21(1):68-72.

Early speech-language development of

individuals with Rett syndrome (RTT) has

been repeatedly characterised by a co-

occurrence of apparently typical and

atypical vocalisations.

The aim of our study was to describe

specific features of this intermittent

character of typical versus atypical early

RTT-associated vocalisations by combining

auditory Gestalt perception and acoustic

vocalisation analysis.

Therefore, we extracted N=363 (pre-)

linguistic vocalisations from home video

recordings of an infant later diagnosed

with RTT. In a listening experiment, all

vocalisations were assessed for

(a)typicality by five experts on early

human development. Listeners’ auditory

concepts of (a)typicality were

investigated in context of a comprehensive

set of acoustic time-, spectral- and/or

energy-related higher-order features

extracted from the vocalisations.

More than half of the vocalisations were

rated as ‘atypical’ by at least one

listener. Atypicality was mainly related to

the auditory attribute ‘timbre’, and to

prosodic, spectral, and voice quality

features in the acoustic domain.

Knowledge gained in our study shall

contribute to the generation of an

objective model of early vocalisation

atypicality. Such a model might be used for

increasing caregivers’ and healthcare

professionals’ sensitivity to identify

atypical vocalisation patterns, or even for

a probabilistic approach to automatically

detect RTT based on early vocalisations.

Pokorny FB, Bartl-Pokorny KD, Einspieler C, Zhang D,

Vollmann R, Bölte S, Gugatschka M, Schuller BW,

Marschik PB. Typical vs. atypical: Combining auditory

Gestalt perception and acoustic analysis of early

vocalisations in Rett syndrome. Res Dev Disabil. 2018;

82(6):109-119.

4 2018 in Review

Fragile X Syndrome

While researchers and clinicians have

gained significant insights into the post-

diagnostic development of fragile X

syndrome (FXS), there is a dearth of

empirical knowledge with regard to the

prodromal development of FXS in general and

the emergence of stereotypic behaviour in

particular. This led us to extend our

previous work on early parental concerns by

retrospective video analyses aimed to

characterize developmental traits of FXS in

the first two years of life. Specifically,

with a benchmark procedure analysing home

videos, we investigated the onset and

characteristics of hand stereotypies in 13

infants later diagnosed with FXS. In

parallel, parents were asked whether and

when they had first recognized hand

stereotypies. Our video analyses revealed

a very early onset (i.e., by 6 months of

age) and the intraindividual persistency of

specific forms of hand stereotypies in the

early development of FXS. There was little

correspondence between the benchmark video

analyses and parental reports, calling into

question the reliability of the assessment

of developmental data based on parental

recall.

Zhang D, Poustka L, Marschik PB, Einspieler C. The

onset of hand stereotypies in fragile X syndrome. Dev

Med Child Neurol. 2018; 60(10): 1060-1061.

Cross-Syndrome Comparison

Responding to one’s own name (RtN) has been

reported as atypical in children with

developmental disorders, yet comparative

studies on RtN across syndromes are rare.

In this work we aim to (a) overview the

literature on RtN in different

developmental disorders during the first 24

months of life, and (b) report comparative

data on RtN across syndromes.

In a first part, a literature search,

focusing on RtN in children during the

first 24 months of life with developmental

disorders, identified 23 relevant studies.

In a second part, RtN was assessed

utilizing retrospective video analysis for

infants later diagnosed with autism

spectrum disorder (ASD), Rett syndrome

(RTT), or fragile X syndrome (FXS), and

typically developing (TD) peers.

Given a variety of methodologies and

instruments applied to assess RtN, 21/23

studies identified RtN as atypical in

infants with a developmental disorder. We

observed four different developmental

trajectories of RtN in ASD, RTT, the

preserved speech variant (PSV) of RTT, and

FXS from 9 to 24 months of age. Between-

group differences became more distinctive

with age.

In conclusion, RtN may be a potential

parameter of interest in a comprehensive

early detection model characterising age-

specific neurofunctional biomarkers

associated with specific disorders, and

contribute to early identification.

Zhang D, Roche L, Bartl-Pokorny KD, Krieber M, McLay

L, Bölte S, Poustka L, Sigafoos J, Gugatschka M,

Einspieler C, Marschik PB. Response to name and its

value for the early detection of developmental

disorders: Insights from autism spectrum disorder,

Rett syndrome, and fragile X syndrome. A perspectives

paper. Res Dev Disabil. 2018; 82(6):95-108.

Crying

The INTERSPEECH 2018 Computational

Paralinguistics Challenge addressed four

different problems for the first time in a

research competition under well-defined

conditions. In the Crying Sub-Challenge,

three types of infant vocalisations had to

be told apart. Challenge baseline feature

extraction and classifiers included data-

learnt feature representations by end-to-

end learning, the

‘usual’ ComParE and

BoAW features, and deep

unsupervised represen-

tation learning using

the AUDEEP toolkit for

the first time in the

challenge series.

5 2018 in Review

Schuller BW, Steidl S, Batliner A, Marschik PB,

Baumeister H, Dong F, Hantke S, Pokorny FB, Rathner

E-M, Bartl-Pokorny KD, Einspieler C, Zhang D, Baird

A, Amiriparian S, Qian K, Ren Z, Schmitt M, Tzirakis

P, Zafeiriou S. The INTERSPEECH 2018 Computational

Paralinguistics Challenge: Atypical & self-assessed

affect, crying & heart beats. Proceedings of the 19th

Annual Conference of the International Speech

Communication Association (Interspeech 2018). 2018:

122-126.

General Movement Assessment

Infants who have graduated from a neonatal

intensive care unit require close follow-

up because they have a greater chance of

experiencing later motor and cognitive

difficulties; however, these difficulties

are often challenging to identify at an

early age. The General Movement Assessment

is a low-cost and highly reliable tool that

can indicate abnormal neurological

development in young high-risk infants, but

it has not yet been widely implemented in

the United States. In this review, we

discuss the literature about the use of the

General Movement Assessment in high-risk

infants and how to implement the tool in a

clinical setting.

Peyton C, Einspieler C. General movements: A

behavioral biomarker of later motor and cognitive

dysfunction in NICU graduates. Pediatr Ann. 2018;

47(4): e159-e164.

Miscellaneous

Insights

iDN lab demontration @ the ‘Lange Nacht

der Forschung’.

Coding

An intense year of annotating infant

vocalisations: A beyond crying approach.

Championship

iDN proudly presents the winner of

the First Divison of Phoniatrics

Minigolf Championship 😉, Gunter Vogrinec.

Training

Christa Einspieler's Brain Days: iDN

lecture on early brain development.

Think Tank

Initiating a series: The First Göttingen

Symposium on Late Detected Developmental

Disorders (LD3) - Challenging the Asympto-

matic Early Development Assumption.

BRAINtegrity Lab 2.0

Building the new iDN lab in Göttingen.

6 2018 in Review

Staying Tuned

Credits

Acknowledgements

The iDN family 2018 (in alphabetical

order): Katrin D. Bartl-Pokorny, Mathias

Egger, Christa Einspieler, Sandra

Einspieler, Marlies Feiner, Dunia Garrido,

Magdalena Krieber-Tomantschger, Laura

Langmann, Christina Leitinger, Peter B.

Marschik, Florian B. Pokorny, Iris Krieber-

Tomantschger, Adriana Villarroel, Diego

Villarroel, Gunter Vogrinec, Dajie Zhang,

Clara Zitta, and Claudia Zitta.

Development: for some it’s too slow, for

others too fast, while still others believe

that the timing and pace are just fine.

When it comes to our development, opinions

are equally divided. The past year was –

undisputedly – an intense period of

development. We’ve seen some radical

changes; we’ve literally learned to stand

and walk on 2 x 2 legs in terms of

scientific insight into central-pattern-

generated neurofunctions. Observing a

child as it makes its first steps is a

milestone that parents will always

remember. Hopefully watching iDN taking its

first double steps and picking up pace

leaves its parents with the same sense of

delight.

We from the iDN core-team are extremely

grateful for your support, guidance,

loyalty, and faith in our approach and

work. As for our friends and cooperation

partners, universities and colleagues:

This annual review is to say thank you! It

is also an invitation to look beyond the

toddlerhood of iDN Graz-Göttingen.

Warm regards,

Peter B. Marschik

iDN - interdisciplinary Developmental Neuroscience

Division of Phoniatrics

Medical University of Graz

Auenbruggerplatz 26, 8036 Graz, Austria

Department of Child and Adolescent Psychiatry

and Psychotherapy,

University Medical Center Göttingen

von-Sieboldt-Straße 5, 37075 Göttingen, Germany

peter.marschik@medunigraz.at www.idn-research.org idn-research idn_research © February 2019 iDN

vectorworldmap.com; map reprinted by permission of Graphics Factory CC 2009

iDN’s scientific missions in 2018 to 32 destinations in 17 different countries on 5 continents (in alphabetical order):

Ankara (Turkey), Bengaluru (India), Berlin (Germany), Bonn (Germany), Buenos Aires (Argentina), Cologne (Germany), Göttingen

(Germany), Essen (Germany), Frankfurt (Germany), Kolkata (India), London (UK), Madrid (Spain), Mexico City (Mexico), Montreal

(Canada), Mumbai (India), Munich (Germany), New Delhi (India), Nuremberg (Germany), Oita (Japan), Pisa (Italy), Port Elizabeth

(South Africa), Portland (Maine, USA), Pretoria (South Africa), Rotterdam (Netherlands), Salzburg (Austria), Sao Paulo (Brazil),

Shanghai (China), Tübingen (Germany), Varanasi (India), Vienna (Austria), Winterthur (Switzerland), Zhangjiagang (China).