Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00808782 |
| Other study ID # |
277/07 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
December 14, 2008 |
| Last updated |
February 6, 2013 |
| Start date |
December 2008 |
| Est. completion date |
October 2012 |
Study information
| Verified date |
February 2013 |
| Source |
Bayside Health |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Australia: Department of Health and Ageing Therapeutic Goods AdministrationAustralia: Human Research Ethics Committee |
| Study type |
Interventional
|
Clinical Trial Summary
Theory of mind (ToM) refers to the ability to infer others mental states. It includes a
recognition that other individuals experience thoughts, feelings, intentions, and desires
that may be different to our own. ToM is often impaired among individuals with an autism
spectrum disorder (such as autism and Asperger's disorder), and may underlie aspects of
social dysfunction in this population. Indeed, it has been suggested that impaired ToM is
the core deficit of autism and Asperger's disorder.
Imaging studies suggest that the bilateral medial prefrontal cortex, the most important
brain region in ToM processing, is underactive in autism. The current study examines whether
repetitive transcranial magnetic stimulation (rTMS) to the bilateral medial prefrontal
cortex can modulate ToM ability among healthy adults, and improve ToM ability among adults
with autism or Asperger's disorder. With the prevalence of autism increasing, there is a
clear need to develop appropriate therapeutic interventions to improve social functioning.
This study involves a double-blind study using high-frequency rTMS in an attempt to improve
ToM among adults with either autism or Asperger's disorder. Theory of mind will be measured
using behavioural tasks that require the participant to infer what someone is thinking or
feeling by observing their behaviour. These tasks will administered both before and after
rTMS to determine whether any change in theory of mind has occurred.
Thirty adults with either autism (n = 15) or Asperger's disorder (n = 15) will initially
undergo functional and structural MRI to determine the site on the scalp that lies over the
medial prefrontal cortex (to which rTMS will be administered). They will then attend our lab
each consecutive weekday for a two-week period, during which they will 15 minutes
high-frequency (5 Hz) rTMS (either active or sham) to the medial prefrontal cortex. ToM and
clinical measures will be collected before the first session, soon after the last session,
and one month after the last session.
Based on prior imaging data, it is expected that high-frequency rTMS (compared with sham
rTMS) to the medial prefrontal cortex will improve ToM ability and reduce social dysfunction
among adults with autism or Asperger's disorder. Should these hypotheses be supported, it
will indicate the suitability of rTMS as a neurobiological intervention designed to improve
ToM and social function among individuals with autism and related disorders.
Description:
Autism and Asperger's disorder are life-long neurodevelopmental disorders that involve
significant social, communicative, and behavioural abnormalities. Social impairments are
arguably the most debilitating aspect of these disorders, and persist into adulthood,
creating difficulties in various domains including employment, education, and interpersonal
relationships. This impairment is also frequently associated with additional mental health
concerns, including depression and anxiety, with the former affecting as many as 40% of
individuals with autism (Stewart, Barnard, Pearson, Hasan, & O'Brien, 2006). It has been
suggested that the core deficit underlying social dysfunction in autism and Asperger's
disorder is impairment in "theory of mind" (ToM) (Baron- Cohen et al., 2005).
An important aspect of social cognition, ToM refers to the ability to use environmental cues
to infer others' mental states. It includes the recognition that other individuals
experience thoughts, feelings, intentions, and desires that may be different to our own. ToM
is crucial to social functioning, allowing us to predict others behaviour and gain an
appreciation of their perspective, thereby facilitating effective social interactions.
ToM has been assessed using an array of behavioural tasks. Such tasks typically illustrate a
social scenario, and the aim of the task is to identify various aspects of a character's
mental state. Increasingly, researchers distinguish between cognitive ToM, which encompasses
inferences of another individual's beliefs, knowledge or memory, and affective ToM, which is
concerned with predicting others' emotional states (Shamay-Tsoory & Aharon-Peretz, 2007).
Cognitive ToM measures include false-belief tasks, successful completion of which requires
an understanding that another individual can hold a mistaken belief (first-order
false-belief), and that are therefore different to their own belief, or that another
individual can hold a mistaken belief about the mental state of a third person (second-order
false-belief; Harrington, Siegert, & McClure, 2005). Another cognitive ToM task involves
inferring intention from a series of short animations that demonstrate interactions between
non-human objects (e.g., geometric shapes; Castelli, Frith, Happe, & Frith, 2002).
By contrast, affective ToM measures include the "eyes task" (Baron- Cohen, Wheelwright,
Hill, Raste, & Plumb, 2001), which requires the inference of another individual's emotional
experience through the presentation of their eyes only. The eyes task is considered a ToM
measure in that it involves the inference of another individual's mental state from
environmental stimuli, but unlike false-belief tasks there is a central affective component.
An additional ToM test that is thought to involve both cognitive and affective aspects of
ToM is the faux pas test (Stone, Baron- Cohen, & Knight, 1998), which assesses the ability
to recognize a faux pas within the context of a series of vignettes describing social
interaction. This ability requires an understanding of the mental state of two people: the
individual who unwittingly committed the faux pas (cognitive ToM), and the individual who
might be offended or insulted by the faux pas (affective ToM). Thus, ToM tasks are all
concerned with the inference of others mental states, but whereas cognitive ToM tasks
require inferences concerning others beliefs, affective ToM tasks require inferences
concerning others emotions.
The brain basis of ToM is increasingly well established; recent fMRI studies utilizing
cognitive ToM tasks indicate widespread frontotemporal activity. This includes the temporal
poles bilaterally and the right superior temporal sulcus (STS), which seem to reflect the
role of memory and visual perception respectively (Gallagher & Frith, 2003; Schultz &
Robins, 2005). It is the activation within the bilateral medial prefrontal cortex, however,
that is thought to reflect a unique contribution to ToM. Gallagher and Frith (Gallagher &
Frith, 2003) suggest that a distinct area within the medial prefrontal cortex, the bilateral
anterior paracingulate cortex (x = 8, y = 54, z = 1), is the crucial region for ToM ability.
While the medial prefrontal cortex is strongly implicated in cognitive ToM, neural networks
recruited during affective ToM are somewhat different (despite substantial overlap), and
involve the amygdala, orbitofrontal cortex, and ventromedial frontal lobes in addition to
temporal regions. A recent lesion study of ToM supports this neuroanatomical dissociation
between cognitive and affective ToM (Shamay-Tsoory & Aharon-Peretz, 2007).
There is substantial evidence for impaired ToM in autism and Asperger's disorder.
Individuals with these disorders consistently demonstrate delayed or impaired performance on
both cognitive and affective ToM tasks (Baron-Cohen, Jolliffe, Mortimore, & Roberstson,
1997; Baron-Cohen, Leslie, & Frith, 1985; Kaland, Smith, & Mortensen, 2007; Rogers, Dziobek,
Hassenstab, Wolf, & Convit, 2007). Indeed, it has been suggested that ToM impairment is the
core deficit of autism, and that it underlies the characteristic social and communicative
symptoms (Baron-Cohen et al., 1985; Tager-Flusberg, 2001). Imaging studies among individuals
with autism demonstrate reduced activity with the medial prefrontal cortex, particularly
during cognitive ToM tasks (e.g., Castelli et al., 2002).
Justification for project
Social dysfunction, including impaired ToM, is arguably the most debilitating aspect of
autism and associated disorders. There are currently few treatment options for targeting
these social deficits in autism and Asperger's disorder. An increasing prevalence of autism
spectrum disorders (Chakrabarti & Fombonne, 2005) ensures that the next decade will see an
unprecedented number of adult cases; it is therefore imperative that we now develop
effective therapeutic techniques to reduce the impact of core autistic symptoms. Functional
imaging data reviewed above suggests that the bilateral medial prefrontal cortex is a
promising site for neurobiological intervention in these groups to improve ToM (particularly
cognitive ToM) and broader social functioning.
We suggest that repetitive transcranial magnetic stimulation (rTMS) may be an effective
therapeutic technique to enhance medial prefrontal cortex activity and improve ToM in
individuals with autism, with anticipated benefits to social aspects of this disorder. rTMS
is a safe and non-invasive technique that involves the repeated administration of localized
magnetic pulses to a distinct cortical region. When applied at high-frequencies, rTMS
enhances cortical activity at the site of stimulation. This is particularly useful in a
clinical setting, where rTMS is administered to a cortical region that functional imaging
suggests is underactive in a particular psychiatric disorder (e.g., left dorsolateral
prefrontal cortex [DLPFC] in depression), an approach that is effective in alleviating core
symptoms of the disorder. Conversely, low-frequency rTMS decreases cortical activity at the
site of stimulation.
Hypothesis/research questions
It is hypothesized that two weeks of high-frequency rTMS to the medial prefrontal cortex,
which is expected to increase cortical activity within this region, will significantly
improve ToM performance (particularly cognitive ToM) among individuals with autism or
Asperger's disorder. Improvements in social function are expected to be seen one month after
the last treatment session.
Methodology including project design and sequence of procedures
This project will involve the administration of rTMS via a "deep TMS'" H-system coil
(Brainsway Inc., Jerusalem, Israel). This is administered by a modified TMS coil, but uses
our existing stimulator equipment (Magstim), which has been used in our previous rTMS
studies. This H-system coil will allow deeper penetration of the TMS pulse, which will
ensure that we accurately stimulate the part of the medial prefrontal cortex that is most
relevant to ToM. Safety and efficacy studies of deep TMS indicate equivalence with the
conventional TMS (figure-of-eight) coil (Levkovitz et al., in press; Zangen, Roth, Voller, &
Hallett, 2005).
This study is an rTMS trial to improve ToM and social function among adults with autism or
Asperger's disorder. Adults diagnosed with either autism or Asperger's disorder will be
randomized (via a computer generated number sequence) to either active rTMS or a sham
condition, under strict double-blind conditions. Based on prior imaging data, rTMS will be
administered to the bilateral medial prefrontal cortex. This study will involve deep TMS via
the use of the H-system coil.
Prior to the rTMS sessions participants will undergo high-resolution (3T) structural and
functional MRI. The fMRI component will again include cognitive and affective ToM measures.
Using reliable neuronavigational methods, each individual's brain scan will be used to
determine the site on the scalp that lies above the cortical region of interest (bilateral
medial prefrontal cortex), and which will therefore be targeted for rTMS.
Prior to the first rTMS session, the participant will complete a battery of neurobehavioural
tests that assess theory of mind (e.g., false-belief task, eyes test, faux pas test). In
order to gauge whether there is any impact on the broader realm of social functioning in
autism, participants will also be administered the "Autism Spectrum Quotient" (AQ;
Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001), a fifty item self-report
measure.
At the beginning of the first rTMS session, we will determine resting motor threshold (RMT)
by administering TMS to the left motor cortex, and recording (via EMG) the response from the
right thumb muscle. RMT is again defined as the lowest intensity at which 3 out of 5
consecutive TMS pulses results in an EMG response greater than 50 µV.
Using the deep TMS coil, participants will receive 15 minutes of either active or sham rTMS
(5 Hz) each consecutive weekday for a two-week period. During each session, there will be 10
seconds of 5Hz rTMS, followed by a 20 second rest. Thus, for each session there will be 30
10s trains of 5Hz rTMS administered.
After the final rTMS treatment, the three ToM measures and the AQ will be readministered.
These measures will then be administered one-month after the final rTMS treatment. The
researcher administering these measures will be blind to the participant's treatment (i.e.,
active or shame).
After the completion of the one-month follow-up, participants will be unblinded to their
study condition. Those who were allocated to the sham condition will be given the
opportunity to complete two weeks of active rTMS treatment.
Statistical analyses and sample size calculations
As the effect of rTMS on ToM has not been investigated, it is somewhat difficult to conduct
a power analysis. However, based on the sample size of previous rTMS studies that involves
modulation of a cognitive ability (e.g., Giovannelli et al., 2006; Kwan et al., 2007; Tunik,
Frey, & Grafton, 2005) or treatment for psychiatric disorders (e.g., Fitzgerald et al.,
2006; Horacek et al., 2007), we are confident that our sample size will be sufficient to
detect a significant result.
ANOVA will be used to investigate the effect of rTMS to the medial prefrontal cortex on ToM.
Outcome variables will not only include ToM measures, but also an autism-relevant rating
scale to determine social functioning and associated aspects. Thus, we will conduct repeated
measures ANOVA for each measure (pre, post, and one-month post rTMS), with group (active vs.
sham) included as the between-subjects variable.
