Cognitive rigidity and risperidone in children with autism spectrum disorders

Behavioral rigidity is an important restricting factor in the development of
adaptive social functioning. However, it is also a characteristic of early
childhood; very young children, beginning in the first year of life, increasing
around three years of age and typically declining after age four, display
ritualistic and rigid behaviors in daily life, such as ordering and arranging
objects in circumscribed ways or insisting on specific bedtime rituals.
Although in typical development this behavioral rigidity gradually declines, it
remains a significant and exaggerated characteristic in individuals with autism
spectrum disorders (ASD).
Both in human and animal research, dopaminergically innervated interactions in
the fronto-striatal brain network have been implicated in rigid and stereotypic
behavior, with a prominent role for the anterior cingulate cortex (ACC).
Indeed, there is recent evidence for a relation between clinical measures of
behavioral rigidity in ASD and the fronto-striatal system. E.g. it was shown
that impairments in fronto-striatal white matter tracts are present in
individuals with ASD which relate to their clinical rigidity (Thakkar et al.,
2008). Also, a recent study showed a relation between clinically defined
rigidity in ASD, formal measures of rigid and stereotypic behavior, i.e. set
shifting abilities in neuropsychological tests, and ACC functioning (Shafritz
et al., 2008).
Functioning of the fronto-striatal network can be studied in humans by
measuring the event-related brain response to errors, the so-called
error-related negativity (ERN). The origin of ERN activity has been repeatedly
localized within the ACC (Dehaene et al., 1994). It is thought that ERN
activity reflects self monitoring, a prerequisite to flexible and adaptive
behavior, and it is therefore conceptually related to behavioral rigidity. We
have shown atypical ERN activity in children with ASD (Vlamings et al., 2008).
There is evidence that the fronto-striatal system shows a protracted
development in healthy children, as indicated by changes in childhood in ACC
functioning, but it is not known whether rigid and stereotypic behavior in
individuals with ASD is qualitatively different from that seen in typically
developing children, and how this relates to the abnormal development of the
fronto-striatal system.
Developmental changes in ERN activity indicate an increase in ACC activity and
therefore maturity of the DA innervated connections (Segalowitz et al., 2009).
The putative role of dopamine in behavioral rigidity is further suggested by
the fact that in clinical practice, the atypical antipsychotic risperidone is
often used to treat individuals with ASD, as it ameliorates the rigid and
repetitive behavior associated with this disorder. Its mode of action, however,
is not clear. We hypothesize that risperidone enhances activity of the
ACC-dopamine midbrain network, as reflected in the ERN, and that this is
directly related to clinically relevant measures of rigidity. In this study we
want to find evidence for this hypothesis.

The global aim of the proposal is to expand our knowledge on the functioning of
the fronto-striatal system and the relation to behavioral rigidity, and how
these are affected by dopaminergic modulation. The specific aim is to study the
effects of risperidone on fronto-striatal functioning in individuals with ASD,
and the effects on behavioral rigidity. We hypothesize that risperidone
enhances activity of the fronto-striatal network, as reflected in the ERN, and
that this is directly related to improvement on clinical measures of behavioral
rigidity.

Participants will conduct a go/nogo task twice, the second one month after the
first administration. They will conduct the task just before medication is
started and one month after. During the task we will measure event-related
brain potentials (ERPs) that will be analyzed with respect to latency and
amplitude of the ERN, as well as to source localization. In addition, we will
quantify rigidity in daily life. This will be done with diagnostic information
obtained from the ADI-R.
A go/nogo task will be used (Durston et al., 2002). In this task the children
will be asked to press a button in response to visually presented stimuli (go
trials), but to avoid responding to rare non-targets (nogo trials). They will
perform 5 blocks, each containing 108 stimulus presentations, with 75% go
trials, resulting in a total of 135 nogo trials. Additionally, we vary the
number of go trials preceding a nogo trial, with 1, 3, or 5 preceding go
trials. Each type of nogo trial therefore contains 45 stimulus presentations.
To make the study better suitable for use with children, stimuli will be taken
from the Pokemon cartoon series. Stimulus duration is 500 ms and the intertrial
interval will vary randomly between 500 - 1500 ms, during which a central
fixation stimulus is presented on screen. The children are asked to push a
designated button every time a go trial occurs, but to withhold from responding
as soon as the character 'Meowth' appears on screen.
Many studies using a go/nogo paradigm have found ACC activity following an
erronous nogo-response, which makes this task ideally suited for our study
(e.g. Hester et al., 2004).
EEGs will be recorded at a sample rate of 2048 Hz from 64 locations using
standard Ag/AgCl pin-type active electrodes (BIOSEMI, Amsterdam, the
Netherlands) mounted in an elastic cap, referenced to two additional electrodes
(Common Mode Sense, and Driven Right Leg) during recording. The children are
seated in a comfortable chair in front of a computer screen in an electrically
shielded room. After a standardized instruction the children perform a short
practice block consisting of 24 trials. After application of the electrodes the
children perform the 5 experimental blocks (each lasting less than 3 min).

The EEG itself does not elicit any risk of complications. The burden for the
participant is minimal as it only requires administration of two EEGs during
planned visits to the clinic. Travel expenses will be reimbursed, and all
participants will receive a 10 euro cheque after each visit to the UMC Utrecht.
The benefits are twofold. First, the study will provide clinicians with
neurobiological markers for behavioral rigidity related to ASD. Although
repetitive behaviors are included in all major diagnostic criteria for ASD and
can be reliably diagnosed in children, it is unclear, as yet, whether this
relates to the abnormal development of ACC functioning and maturation of the
dopaminergic neuronal connections between ACC and the limbic system. Second,
the study is expected to provide clinicians with more knowledge about
underlying mechanisms leading to successful treatment of rigid and stereotypic
behavior. The daily clinical practice clearly requires such knowledge, as it is
unknown beforehand who will respond positively to risperidone treatment and who
will not.