Effects of methylphenidate on resting state connectivity in healthy controls and in adults with Attention Deficit Hyperactivity Disorder.

One of the most controversial recent developments in psychiatry is the increase
in the number ADHD diagnoses (Frances 2010). The driving force behind this is
the possibility to improve cognitive performance in children with ADHD with
pharmacological interventions (Zhang et al. 2011). The effects of
pharmacotherapy in adults with ADHD are less well documented, although most
studies show a similar trend (Advokat 2010; Faraone and Glatt 2010).
Psychostimulants are the most effective pharmacological treatment for ADHD and,
among these, methylphenidate is the most commonly applied substance (Faraone
and Buitelaar 2010).
The broad use of psychostimulants, especially in subjects with sub-threshold
symptoms and in cases of uncertain diagnosis, is controversial (Mayes et al.
2008; Thakur et al. 2010). Concerns have been raised about the yet unknown
effects of long term stimulant use on the developing brain (Greely et al.
2008). Furthermore, psychostimulants may, to some extent, enhance general
performance by increasing sustained attention and postponing fatigue. This may
be in a way that is not disease-specific. The effects of psychostimulants on
performance in healthy adults are equivocal. It is still unclear if cognitive
improvement only occurs when there is a baseline deficit, or if it reflects the
general effect of psychostimulants (Advokat 2010). It is of pivotal importance
to provide a better understanding of how psychostimulants, such as
methylphenidate, act on the neuronal mechanisms of the brain, potentially
enhancing cognitive performance. In addition, it is important to know if
similar effects can be found in both persons with and without ADHD. This
information would illuminate if the common use of methylphenidate for patients
with a borderline diagnosis of ADHD should be encouraged or rather discouraged.
In the past years, neuroscientists have started to study the brain as a system
of interacting brain regions. These network studies have started to explore the
neuronal interactions between brain regions by combining functional MRI and
structural Diffusion Imaging with network theory. This novel approach of
applying graph analysis to MRI revealed that brain-wide functional
communication is not random, but organized according to a highly efficient
small-world organization. This is a network topology characterized by a high
level of local neighbourhood clustering, leading to efficient local information
processing, and several long distance connections that ensure a high level of
global communication efficiency across the network and integration of
information between the different regions of the brain (Bullmore and Sporns
2009; Latora and Marchiori 2001; Stam and Reijneveld 2007; Watts and Strogatz
1998). This kind of topology appears crucial for healthy cognitive functioning,
as more efficiently functionally connected brains are associated with a higher
level of intellectual performance (Li et al. 2009; van den Heuvel et al. 2009).
Graph analysis could thus be used to measure the effects of methylphenidate on
resting state functional connectivity and relating that to cognitive
performance. We propose to explore functional brain communication as a new
platform to test the neuropharmacological mechanism of action of
methylphenidate in the healthy and diseased brain. To our knowledge, three
other studies investigated the effect of methylphenidate with functional MRI. A
pilot study by Sheridan et al. (2010) found that stimulants altered lateral
prefrontal cortex functional connectivity. However, this study had a sample of
only 5 participants with ADHD. Another study investigated the effect of
methylphenidate on functional connectivity in 13 children with ADHD during a
vigilant attention task. They found that methylphenidate increased
frontoparietal, frontostriatal, and frontocerebellar connectivity, compared to
placebo (Rubia et al. 2009). A more recent study investigated the effect of
stimulants on regional functional connectivity during a working memory task in
18 children with ADHD, and found increased connectivity of fronto-parietal
brain areas compared to placebo (Wong and Stevens 2012) The medication used in
this study differed per individual, as they received their regular medication
(methylphenidate or dextroamphetamine/amphetamine) and dosage. Results may
differ when every participant receives the same type of stimulant and the same
dosage.
All three studies examined effects of stimulants on functional connectivity in
children or adolescents. To our knowledge, no studies have investigated this
effect in adults. These studies also measured functional connectivity during an
attention or working memory task. However, measuring functional connectivity
during resting state is optimal for finding more global organization patterns
in the brain (van den Heuvel et al. 2009).
Furthermore, effects of methylphenidate on functional connectivity in healthy
controls were not investigated in any of these studies. The question thus
remains if this mechanism of action is specific for a diagnosis of ADHD or
whether the use of these stimulants may also improve functional brain
communication, and therewith brain efficiency, of healthy controls.

Primary Objective:
The primary objective in the current trial is to use graph theory to examine
how the organization of the functional brain network may be altered by the
administration of methylphenidate. The main question we intend to answer in
this study, is whether, and if so to what extent, methylphenidate affects the
organization of brain networks.

Secondary Objectives:
- To examine how a reorganization of brain networks as described in the primary
objective is related to improvements in cognitive performance.
- To examine if any of the effects on brain connectivity differ between
participants with ADHD versus healthy controls.
- To examine if certain network structures of the brain, such as cortical
thickness and white matter volume, are related to susceptibility to medication
efficacy.
- To examine if the structural qualities are related to cognitive performance.

In the proposed study, we intend to measure the effects of methylphenidate on
cognitive performance and on resting state connectivity in a double blind
randomized placebo controlled design. A placebo-controlled design was chosen in
order to differentiate between clinical effects of methylphenidate and effects
caused by other factors associated with experimental treatment, such as induced
expectations in participants.
40 healthy adult men and 40 men with a diagnosis of ADHD will be included. The
two groups will be matched for age, handedness and education to minimize
differences between groups that may confound study results. Subjects will
participate in a cross-over design to remove between-subjects variability. For
each participant an MRI scan will take place twice, approximately two weeks
apart (no more than 4 weeks apart), to assess resting state functional
connectivity. For each subject this will happen once after ingestion of a
placebo capsule/tablet and once after a single oral dose of an identical
capsule/tablet with methylphenidate, in a randomized order. Following this,
subjects will engage in cognitive tests. Cognitive assessment includes 5 tests
tapping into the domains of, attention, sustained attention, working memory,
distractibility and executive functioning. Different sets of stimuli in the
cognitive tests of the first and the second occasion will be used, in order to
avoid learning effects. Blood samples for drug level measurement will be drawn
before the fMRI scan, before the cognitive testing, and after the cognitive
testing. All measurements will be done at the University Medical Center in
Utrecht.

After a thorough screening before inclusion, two visits are planned. These
visits are identical to each other for the major part; the participant will be
administered a tablet. After an hour, a blood sample is taken to measure the
blood level of methylphfenidate. Afterwards, the subject undergoes an fMRI scan
that takes approximately 45 minutes. After the scan, the participant gets a
short break. Following this, subjects will engage in cognitive tests. This
takes approximately an hour. Finally, a last blood sample will be taken to
measure the blood level of methylphenidate.
The one difference between these two visits is the contents of the tablet: in
randomised order, the participant receives a methylphenidate tablet once, and
once a placebo tablet with an inactive substance.

The major concern with the use of methylphenidate is occurrence of serious
cardiovascular events due to possible increase of heart rate and blood
pressure. However, a large study among young and middle-aged adults showed that
current or new use of ADHD medication such as methylphenidate was not
associated with an increased risk of serious cardiovascular events (Habel et
al.). As subjects in the current study will only ingest a dose of 0,5 mg/kg
methylphenidate once and are thoroughly screened before inclusion in the study,
chances of any serious side effects are greatly diminished and health risk is
minimal. Furthermore, blood samples will be drawn by experienced research
physicians so health risk attributable to this procedure is minimal as well.
The MRI scan procedure is painless and safe, there are no known health risks.
The cognitive testing will take 30 minutes on each occasion and requires
sustained attention from the participants.

There are no direct benefits for the participants of this study. However, the
results of this study may be of value for society. The study could help unravel
if cognitive effects of methylphenidate should only be expected in cases of
ADHD or if a positive response can also be found in persons without ADHD.
Furthermore, it can help answer the question of how this drug affects the brain
to improve cognition. If we can illuminate how methylphenidate affects the
brain to improve cognition, we may have better arguments to emphasize or
discourage the common use of methylphenidate for an extended population with
borderline diagnosis of ADHD. With the results of this study, better
recommendations can be made for people with ADHD related symptoms on optimal
drug use.
In addition, discovering the route by which methylphenidate influences
cognitive performance may help in the development of new cognitive enhancers.
Such new cognitive enhancers may not only prove useful for the treatment of
ADHD, but may, potentially, also lead to new possibilities of improving
negative symptoms of schizophrenia that are related to a lack of concentration
and lack of energy, or postpone the clinical symptoms of dementia such as
executive functioning deficits. As the project involves minimal risk to
participants, and as the potential benefits in terms of knowledge gained are
quite large, the benefits clearly outweigh the risks.