Structural and functional connectivity in relation to cognitive and social functioning of children with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen*s disease, is
a genetic disorder affecting about 1 in 3000 people. Physical manifestations of
NF1 include café-au-lait spots, skin fold freckling, optic nerve glioma,
osseous (bone) abnormalities, iris Lisch nodules, and cutaneous and plexiform
neurofibromas. The most common complications however are cognitive and social
impairments. Recent studies indicate that, despite the fact that some more
basic skills such as motor speed appear to be affected as well, the most
evident deficits are present in the area of cognitive control. As social
functioning requires increasing levels of cognitive control with increasing
age, it is important to determine whether cognitive control and its associated
networks of brain regions underlie social functioning in general and social
impairment in NF1 in particular. The transition into adolescence is
characterized by increasing and changing demands in social functioning. This
period is also an important developmental stage for cognitive control.
Therefore, this represents the best possible stage to investigate development
of cognitive control and social functioning and its neural correlates. There is
reason to believe that a suboptimal development of networks of brain regions
may underlie cognitive control- and social problems in NF1. NF1 leads to a
decreased production of the protein neurofibromin, which acts as a tumor
suppressor and is associated with processes that are of general importance to
cortical development, such as synaptogenesis and neuronal differentiation.
Different abnormalities in the brains of NF1-patients have been demonstrated,
including T2-hyperintensities, macrocephaly, and abnormal gray to white matter
ratios (driven by small gray matter- and large white matter volumes), but these
have not (yet) been convincingly related to social and cognitive function in
this population. Further investigations are required, but these should be
supplemented with studies into the relation between the quality of
communication between different brain regions on the one hand and the quality
of cognitive control and social functioning on the other. Cognitive and social
problems are often cited by NF1-patients themselves as having the greatest
impact in daily life. In order to be able to understand and treat these
problems better it is necessary to reveal the underlying pathological
mechanisms. For example, whereas behavioral interventions might aim at the
organization of different cognitive abilities rather than separate cognitive
abilities, medicine-based treatment might want to focus on transmitters that
are specifically important for communication between brain regions such as
glutamate and GABA.

Our general objective is to find out whether impaired communication within
networks of specific brain regions underlies the cognitive control- and social
problems of individuals with NF1. It is very important to examine these
relations in children who are in the transition towards adolescence, as this is
a developmental stage characterized by complex and changing social demands as
well as one where cognitive control abilities undergo a rapid development.
Moreover, it has been shown that children with NF1 differ strongly from
normally-developing children of the same age with respect to social functioning
and cognitive control abilities. We have further operationalized our general
objective with the following specific hypotheses:

Hypothesis 1: Children with NF1 will perform more poorly than age- and
IQ-matched controls on the N-back task and the Facial Affect Recognition task
(both administered in the scanner, see section 6.3).
Hypothesis 2: Children with NF1 will have more social problems than age- and
IQ-matched controls. For questionnaires measuring social skills, see section
6.3.
Hypothesis 3: Children with NF1 will show less activation of individual brain
regions associated with performance of the N-back- and Facial Affect
Recognition tasks (see Figure 2) than age- and IQ-matched controls. However,
based on previous studies, it is expected that reduced activation in these
brain regions can only explain a marginal proportion of the variance in
performance differences with controls.
Hypothesis 4: Children with NF1 will have reduced gray matter and increased
white matter volumes throughout the brain compared to healthy controls, but
again it is expected that this will explain a marginal proportion of the
variance in performance differences with controls.
Hypothesis 5: Children with NF1 will show less functional connectivity between
brain regions of interest for the N-back task and the Facial Affect Recognition
task (see Figure 2) and this will be related to performance deficits.
Hypothesis 6: Both tasks have different levels of complexity, presumably
related to the required levels of connectivity and possibly related to
additional connectivity (e.g. with other brain regions). It is hypothesized
that NF1-patients will particularly demonstrate connectivity-related
performance deficits in more complex task parts.
Hypothesis 7: Hypotheses #6 and #7 propose that reduced functional connectivity
will become particularly evident when specific networks of brain regions should
be actively communicating because of task demands. Hypothesis #8 proposes that
such networks should already show increased connectivity at rest, as the brain
regions they are composed of often work together in everyday life. It
postulates that among NF1-patients such connections will be less developed than
in healthy controls, leading to reduced connectivity at rest.
Hypothesis 8: With respect to structural connectivity, it is expected that
decreased white matter integrity in NF1-patients will explain a substantial
proportion of the variance in their cognitive and social difficulties.
Hypothesis 9: It is expected that associations between structural connectivity
abnormalities and social and cognitive outcomes will be mediated by functional
connectivity abnormalities.

Observational study, case-control study. See also the answer to question E4.

The requested time investment is a total of 1.5 hours (1 visit), of which 45
minutes will be spent in the scanner, for the NF1-patients. Control data will
be provided by the aforementioned parallel study (NL25924.058.08). With respect
to the MRI session, other studies from the LIBC in which children participate
in MRI research give us confidence that children will have no problems with
this study. Participants will be also thoroughly screened (using standard
procedures) before scanning. Even though the MRI scans will not be
diagnostically screened for abnormalities, we will ask the neuroradiologists,
who always screen the scans made at the LIBC, to be alert to the fact that
abnormalities in brain matter of individuals with NF1 are more likely than in
most other people. We will convene a meeting where the neuroradiologists will
be briefed about often-occurring abnormalities in the brains of individuals
with NF1, such as optic nerve glioma. The procedure in case of unexpected
findings will be explained (in person and in writing) to parents of
participants. Specifically, it will be explained that such findings will be
communicated to their General Practitioners, who will discuss them further with
the participants and their families.