Study on Working Memory in Adolescents with Autism in the Netherlands
(amendment regarding an extension using fMRI)

Approved neuropsychological study:
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopment syndrome in
category of pervasive developmental disorders. The aetiology of ASD is still
unknown, and in spite of many studies the main cognitive theories of ASD -
Theory of Mind deficit hypotheses, Weak Central Coherence account, and the
Executive dysfunction theory - fail to explain the broad spectrum of symptoms
found in ASD.
In the Netherlands a growing number of high average intelligent (HAVO/VWO)
adolescents with autism is in the need for special secondary education due to
their social, executive function (EF) and specific learning problems. Although
these adolescents experience many problems in their everyday life, it is very
difficult to objectify these problems in clinical or laboratory settings due to
the compensation strategies these adolescents apply in these structured
settings. This makes the need for finding new ways to objectify their problems
and to link these problems with their behavioural difficulties outside the
laboratory especially high.
Although there have been many studies that looked at working memory (WM) as a
core domain of EF in adolescents with high functioning autism (HFA), the
results remain inconclusive. In these studies it is assumed that WM only
processes abstract information, and only two studies made a direct link between
behaviour outside the laboratory and EF and/or WM. However, in our view a
proper functioning WM is not only important for cognitive processes as
language, memory etc. (i.e. *cold* cognitive information), but is also
essential for successfully navigating in the social world (i.e. *hot* cognitive
information).

AMENDMENT:

Also functional MRI studies strongly support a WM deficiency underlying the
broad spectrum of problems high functioning adolescents with ASD have. However,
structural imaging studies point to a more global connectivity problem in the
autistic brain. Abnormal growth patterns do indicate a ground for the WM
problems found in adolescents with ASD, but unfortunately, there are to our
knowledge no studies that combine behavioral, functional and structural imaging
data from the same cohort of subjects, so no direct conclusions can be made
over the clinical implications of these findings.

In light of these earlier findings, our hypothesis is that WM plays a more
central role in remembering, uploading and selecting social cues from the
environment, hence in processing both *cold* and *hot* cognitive information.
WM capacity problems therefore may play a leading role in the multiple symptoms
(both *cold* and *hot* cognitive) displayed by intelligent adolescents with
HFA.

Primary objectives: 1) Study EF in general and WM capacity specifically in
intelligent adolescents with HFA on a neuronal and cognitive level, as well for
abstract information as for social relevant information, using
neuropsychological assessments and MRI techniques , 2) find in this group of
adolescents a link between their WM capacity, functional WM network, micro
structural changes and their daily behaviour (questionnaires), and 3) propose a
new way of objectifying the problems of this specific group of adolescents and
4) to make an attempt to translate these results to the social (school)
settings where these adolescents experience their problems.

Primary Objective(s):
• Do high average intelligent (HAVO/VWO) adolescents with HFA have more EF
problems on a behavioural and/or cognitive level than matched normal developing
adolescents?
• Do high average intelligent adolescents with HFA have more WM capacity
problems than matched normal developing adolescents?
• Do the social and specific learning problems found in high average
intelligent adolescents with HFA find their origin in WM capacity problems?
• Is there a relationship between the behavioural problems and the strength
that is put on WM in adolescents with HFA and if so, is there a difference
between processing social relevant and abstract information?
• Are functional WM network properties different between high functioning
adolescents with ASD and normal controls? And if so, can this be related to
micro structural changes in the brain and/or with the problems these
adolescents have in everyday life?

Secondary Objective(s):
• If these high average intelligent adolescents with HFA show WM capacity
problems, are there new and better ways of objectifying their problems?
• Attempts will be made to translate the result of this study to the social
(school) settings where these adolescents experience their problems.

This study will be a case-control study. The study will be performed at
Epilepsy Centre Kempenhaeghe, Heeze, special secundairy education school de
Berkenschutse Heeze and Radboud University Nijmegen.

Adolescent, parent / caregiver, and teacher / mentor will be asked to complete
two questionnaires at home or at school. The neuropsychological assessment in
the HFA group will last approximately 4 hours. The neuropsychological
assessment in the normal control group will last approximately three hours. For
this, one appointment will be made. The neuropsychological assessment is
non-invasive and hardly stressful. Therefore, the risks of participating in
this study is minimal. All tests and tasks are in a quiz or game fashion and
will be offered on a computer or as a pen-paper task. The adolescent may work
in his / her own work pace, and if desired, additional breaks will be inserted.
Minors aged 12 years and older will participate in this study. Following the
WHO guidelines, we stress that the 'not unless' principle applies to this study
and that based on this principle approval for this study should be granted.

During adolescence, major changes take place in the neural systems that sub
serve higher cognitive functions as EF. A normal development of these neural
systems and EF is necessary to become an independent adult. Until now, the
relation between the neural changes, the cognitive problems and the behavioural
problems of adolescents with HFA is unknown, but the implications of this
deviant development are huge: As these children grow from early adolescents
into young-adults, more expectations of independence and social competence from
their environment arise, expectations that they often fail to meet. This makes
the need to get more insights in the neurocognitive system behind the HFA
problems of these adolescents, to try and find a new way to objectify their
problems and to find new ways to counteract these problems especially high. One
possible way to counteract these problems in the future could be in the form of
a WM training. Because the impact of training is bigger in an immature brain as
opposed to a mature brain, this training could best be given during
adolescence, when the development of WM is in full progress. This combination
of factors makes it essential to study the problems found in individuals with
HFA during adolescence. Because there are differences in WM strategies,
capacity and neuronal networks in adolescence and adulthood, it is not possible
to do this research with adult participants.
It is this combination of factors (neurodevelopmental changes, cognitive
developmental factors, and behavioural and environmental factors) that make it
essential to study the EF problems and social problems found in individuals
with HFA during adolescence. This all with the goal to get more insights in the
neurocognitive system behind the HFA problems of these adolescents, and to try
and find a new way to objectify their problems and find new ways to counteract
these problems.
Because all effects found in this study will be relative effects (not absolute
effects) a comparison with a matched normal development group is required to be
able to understand and interpret the results.

AMENDMENT

If the adolescent and his parent(s)/caregiver(s) wish to participate in the MRI
assessment of the SWAAN study, a date for a MRI scanning session and the ADI-R
will be scheduled. During this session (of 1 hour) a parent/caregiver will be
present. The MRI-techniques and neuropsychological assessment that are applied
in this study are non-invasive and scarcely stressful. Therefore, the risks of
participating in the study are minimal. The adolescent can work in his/her work
pace, and if desired additional breaks will be taken. This study involves
minors of and above the age of 12 years. Following the WHO guidelines, we argue
that the *not unless* principle should grant permission for this study.