Short- and long-term effects of oxytocin on empathy in autistic male adults.

Problem Definition

So far, no treatment has been reported to alleviate one of the core problems
characterising the Autism Spectrum Disorders (ASD), that is a strongly impaired
capacity or even complete lack of feeling affective empathy. As, however, many
studies of healthy individuals have shown that the neuropeptide oxytocin , when
administered with nasal spray, enhances empathy-driven prosocial behaviour such
as social attachment, affiliative behaviour and trust, it is warranted to
investigate oxytocin effects on empathy experience in the above-mentioned
disorders.

Affective empathy, brain systems and the role of oxytocin

A crucial facilitator of attachment and affiliative behaviour is the affective
component of empathy, which is closely related to the concept of *emotional
contagion* meaning the tendency to feel similar emotions when observing another
person*s emotion. Recent studies have identified brain systems that are
involved in the experience of affective empathy. When observing or
communicating with an attached person the dopaminergic reward system including
the orbitofrontal cortex and midbrain-striatal structures, such as the nucleus
accumbens is activated. These pathways related to pro-social motivation and
reward processing contain high levels of oxytocin receptors (OXTR), while
furthermore oxytocin has been shown to facilitate dopamine release in
particularly the nucleus accumbens.
Other important systems involved in attending to and the recognition of
emotionally salient stimuli are the cortisol-controlled HPA axis and the
amygdala. Both have been found to be dampened by oxytocin in their response to
fearful and threatening stimuli. This has led to the hypothesis that OT may
increase trust and prosocial behaviour by its anxiolytic effects in potentially
frightening social situations, thereby promoting approach behaviour. Yet, there
are studies that did not report any decreased anxiety or increased calmness
following oxytocin treatment while trust did improve. This suggests a rather
direct effect of oxytocin on affiliative behaviour by stimulating the
previously mentioned reward system.

Autistic Spectrum Disorders

Impairment in affiliative behaviour, empathy and compassion are core features
of the Autism Spectrum Disorders (ASD). Individuals with an ASD (Diagnostic
Statistic Manual of mental disorders, DSM-IV: American Psychiatric Association,
1994) are characterised by an impaired ability in interacting and communicating
with others as well as by repetitive behaviours and restricted interests. Their
social impairments have been explained by deficits in both affective empathy
and higher order cognitive empathetic abilities, such as a poor Theory of Mind
(ToM), i.e. poor ability to understand the mental state (thoughts, feelings,
wishes, beliefs) of others.

Measures of empathy

Questionnaires
The most frequently used method for assessing empathy in adolescents and adults
are self-report questionnaires, where participants are requested to indicate
their agreement with empathy-related statements or to select the most suitable
interpretation of a social situation that is described in a vignette. Although
indispensable for screening, phenotyping and the selection of subgroups,
self-reports may have some limitations ranging from the comprehensibility of
the items to response biases resulting from impression management like faking.
Moreover, self-reports basically reflect the outcome of deliberate, conscious
processing while the perception of one*s own feelings and the feelings of
others may be quite spontaneous, effortless and unconscious cognitions with
relevant cues of empathy most frequently being communicated nonverbally.
Finally, as these questionnaires are generally assessing trait-related
qualities they are not suitable for measuring short-term treatment effects.

Electrocortical brain and autonomic cardiac responses to emotional stimuli
A more direct measure for investigating the non-deliberate aspects of emotion
processing that underlie affective empathy, is the measurement of
electrocoritcal brain responses to emotionally confronting pictures These are
measured by EEG event-related potentials (ERPs).A well-established and widely
used source of visual images that elicit affective responses is the
International Affective Picture System (IAPS). It consists of 942 colour
photographs and includes gender and age dependent normative ratings of the
images on three dimensions that are related to emotion processing. These
ratings have been well-validated by other rating procedures as well as by
psychophysiological (e.g. ERP) and functional magnetic resonance imaging (fMRI)
measures.
Due to its wide range of thematic contents, the IAPS allows for comparing
responses to pictures portraying humans in different positive and negative or
emotionally neutral contexts with responses to inanimate pictures with and
without an emotional loading. These comparisons have been done in numerous
studies investigating EEG ERPs.
Many ERP studies have demonstrated a specific component related to affect
processing. This is a parietally measured long lasting late positivity, called
the LPP. This component has been shown to be greater in response to emotionally
loaded (especially negative) pictures when humans are depicted as compared to
emotionally loaded pictures without humans or emotionally neutral pictures with
humans. This *empathy* effect moreover appeared to be greater in women than in
men.
Next to electrocortical responses, many studies have reported autonomic
responses as measured by, e.g., electrodermal and cardiac activity to be very
sensitive to the valence of the IAPS pictures, while these responses moreover
appeared to discriminate high functioning autistic from healthy adults. We will
investigate cardiac responses at the level of event-related changes in
inter-beat interval times as greater cardiac decelerations have been found to
occur in response to especially aversive stimuli.

Our study aims at investigating whether male adults with ASD differ from
healthy male adults in their neurophysiological responses to positive and
negative empathy-evoking pictures when taking oxytocin intranasally once.

To this end we will compare two groups of twenty-six normally intelligent 18-to
30-year-old males in their ERP and cardiac evoked responses to empathy-evoking
pictures from the IAPS in a condition of nasally administered oxytocin intake
and a placebo condition. Participants will be a group of healthy adults and a
group being diagnosed and systematically phenotyped as having respectively ASD.

We will further investigate whether pre-treatment (self-)reported personality
traits and psychpathololgy may predict potential changes in neurophysiological
empathy responses due to oxytocin treatment and how these changes relate to
pre- and post treatment blood serum oxytocin levels. We will finally explore
whether these effects are related to variants of the oxytocin receptor (OXTR)
gene.

For the measurement of the oxytocin effects on experiencing empathy, we
plan to carry out a double-blind placebo-controlled crossover study with
oxytocin (24 IU) and placebo being nasally administered to all participants
with an interval of one week. Each participant will perform the IAPS picture
task twice, once taking oxytocin and once taking the placebo. The one week
washout is considered to be long enough given the very short half-life of
oxytocin being only 3 to 15 min. The sequence of starting with oxytocin or
placebo will be randomly balanced across the participants within each group.

Within the experimental trial, oxytocin (24 IU) and the placebo shall be
administered to all participants. Nasal spray will be prepared for taking 3
puffs per nostril, each with 4 IU, the placebo (PL) being identical containing
all ingredients except the active compound. The time in between oxytocin and
placebo administration will be about one week. In agreement with the
pharmacokinetic qualities described for nonapeptides (see section 6.5. of the
main protocol), the spray will be taken 20 minutes before performance of the
experimental task where participants are confronted with the empathy-evoking
pictures.

Given the only rarely observed and tolerable side effects of nasally
administered oxytocin, these being a headache, nausea or skin rashes, the risks
of this study for our participants may be considered negligible and the burden
only minimal with the forearm venipunctures for blood sampling (4 times 10 ml)
probably being the most demanding events.

To conduct the study on the ASD patient group is considered justified as there
is not yet any therapeutical intervention for their core problems, while the
present study could contribute to finding novel options for medical treatment.