Mapping dopaminergic function using pharmacologic Magnetic Resonance Imaging (phMRI)

Rationale: Little is known about the pathophysiology of neuropsychiatric
diseases in which dopamine (DA) plays an important role in children and
adolescents, as positron emission tomography (PET) and single photon emission
computed tomography (SPECT) research studies are hardly allowed in the
pediatric population because of radiation exposure. Recent work suggests that
DA function can also be evaluated non-invasively using magnetic resonance
imaging (MRI) by measuring hemodynamic changes following an amphetamine
challenge, called pharmacological MRI (phMRI). There are three ways of
assessing pharmacological-induced changes in hemodynamic responses with MRI:
using BOLD (blood oxygenation-level dependent) contrast, perfusion weighted
imaging (PWI) and arterial spin labelling (ASL). However, the reliability of
these techniques in assessing DA function have not yet been assessed and
directly compared to each other. Therefore, this study will assess the
reliability of BOLD-, PWI and ASL based phMRI by assessing cerebral DA function
when compared to dopamine transporter (123I-FP-CIT) SPECT in 10 healthy male
volunteers, and identifies the best phMRI technique in doing so. Ultimately, it
is expected that DA phMRI will open a new horizon in the diagnosis and
treatment of children suffering from neuropsychiatric disorders, such as
attention deficit hyperactivity disorder (ADHD).

-to assess the reliability of phMRI (BOLD-, PWI and ASL based phMRI) in
assessing cerebral DA function when compared to dopamine transporter (DAT)
SPECT.
-to assess which MRI technique (BOLD-, PWI or ASL) is best in assessing
cerebral DA function when compared to DAT SPECT.

BOLD-, PWI and ASL DA-phMRI studies will be conducted and compared to a DAT
SPECT scan as reference (gold standard). A DAT SPECT scan will be conducted.
With an interval of 2-3 weeks, the BOLD and ASL DA-phMRI studies can be studied
in one scan session following a low dose challenge with amphetamine. In a
second MRI study with gadolinium (PWI based phMRI), again a low dose
amphetamine challenge will be given.

No serious side effects are foreseen. MRI itself is a non-invasive imaging
modality. In this study, a low dose amphetamine challenge (0.3 mg/kg i.v.) will
be administered during the two MRI studies, along with a contrast agent during
the PWI MRI study. There is no risk associated with participation. Gadobutrol
(Gadovist) is routinely administered for contrast enhanced MRI studies at the
departments of Radiology worldwide, also in healthy human volunteers.
Furthermore, low dose amphetamine (0.3 mg/kg) is nowadays frequently
administered in PET and SPECT studies, to study amphetamine induced dopamine
release. The pharmacy of the AMC will provuide the d-amphetamine, conform GMP
annex 13 criteria. No serious side effects of the low dose d-ampehtamine are
foreseen. It has been shown that while some subjects experience large increases
in happiness, restlessness and energy, other subjects experience almost no
subjective effects following 0.3 mg/kg, and that the quality and intensity of
the subjective responses to low dose amphetamine were similar during a second
exposure (Abi-Dargham 2003). The radiation exposure of the SPECT scan is
classified as category II, and routinely conducted at the AMC also in healthy
human volunteers. Moreover, [123I]FP-CIT is a registated radioligand, which is
produced routinely using GMP-criteria.