Pharmacological and genetic imaging of executive function deficits

Executive-function-deficits (EFD) are cognitive abnormalities of planning,
problem-solving, response-inhibition, and goal-directed behaviour. They result
in perseveration, obsessionality and repetitive-stereotypes, which are
prominent clinical characteristics in several neuropsychiatric disorders. EFD
are cognitive predictors for bad clinical outcome, but their aetiology and
neurobiology is unclear.
Neuroanatomically, EFD are monitored by the frontal lobes. Neurofunctionally,
frontal lobe EFD lead to *negative* symptoms and social-communicative
impairments, which are core clinical features of autism, schizophrenia, and
22q11 deletion syndrome (22q11DS). Neurochemically, EFD are thought to be
increased with reduced frontal lobe related dopaminergic neurotransmission.
Frontal lobe dopaminergic degradation is modulated by
catechol-O-methyltransferase (COMT), an enzyme located on chromosome 22q11.
People with 22q11DS, who are haploinsufficient for COMT, have a 50% chance of
having autism, and a 30% chance of developing schizophrenia-like-psychosis.
EFD are common to all three disorders, causing serious cognitive impairments
that result in functional disabilities for which no treatment is available.
The aim of this study is to reveal the underlying neurobiological substrates
and genetic markers of EFD.
We will investigate the influence of dopaminergic depletion and genetic
variation in COMT on EFD in 20 adults with autism, 20 with schizophrenia, 20
with 22q11DS and healthy controls, measuring frontal lobe executive and
resting-state brain function (RSB) (using functional magnetic-resonance-imaging
(fMRI)), before and during a pharmacological challenge (administering
alpha-methyl-p-tyrosine, AMPT). The underlying neuroanatomy of EFD and the
influence of COMT polymorphisms on brain metabolite concentrations,
white-matter-connectivity and morphometry will be assessed using
Magnetic-Resonance-Spectroscopy, Diffusion-Tensor and
high-resolution-structural imaging.
We hypothesize that (i) EFD are increased by dopaminergic depletion, showing a
common clinical aetiology across autistic spectrum disorders, schizophrenia and
22q11DS; and (ii) COMT polymorphisms have an influence on EFD, RSB (their brain
activation pattern during dopaminergic depletion), and the neuroanatomy of the
frontal lobes; revealing a neurogenetic profile of cognitive impairment.

With this study we want to identify the common aetiology and neurobiology of
EFD, by employing pharmacological and genetic imaging in three neuropsychiatric
disorders. We want to identify an underlying functional and structural model
for EFD, including possible dopaminergic genetic markers.
We will employ event related fMRI during executive function tasks designed to
measure motor- and interference-inhibition, and set-shifting. Event related
fMRI will be acquired, both, with- and without dopaminergic depletion.
Furthermore, frontal lobe metabolite concentration, white-matter connectivity
and morphometry will be measured to obtain neuroanatomical correlates of EFD.
Also, the relationship between dopaminergic markers and frontal lobe function,
metabolite concentration, connectivity and structure will be assessed using
information on Val/Met COMT polymorphism.

EFD and frontal lobe brain activity is assessed during three different tasks of
the MARS battery using event related fMRI. MARS is a fMRI adapted
neuropsychological battery designed to, amongst others, measure: (1)
motor-inhibition (GO/NO-GO-task); 2) cognitive interference-inhibition (spatial
STROOP-task); and 3) set-shifting (SWITCH-task). All tasks are presented with
standardized instructions and in random order to account for systematic errors
and fatigue. All three EF-tasks will be assessed twice: with-and without
introducing dopaminergic depletion. All subjects will undergo two MRI
measurements (part 1 and part 2) and one dopaminergic challenge (subjects will
be randomly selected for a cross-over design).
At their first appointment (part 1) at 9:00h (four hours before the first MRI
measurement) subjects will receive an oral administration of
a) reversible tyrosine hydroxylase inhibitor (AMPT) or
b) placebo tablets (cellulose, corn starch).
Thereafter, AMPT or placebo will be administered at 11:00h and 13:00h.
One hour after the last dose (at 14:00h) MRI scanning will start.

Blood will be taken at three time points (8:30h: baseline; 12:30h: during the
challenge, and 15:00h: after the MRI-measurement) for the assessment of
prolactine, and catecholaminergic metabolites (dopaminergic neurotransmission)
and AMPT levels. Blood taken at baseline will furthermore be used for the
assessment of dopaminergic genetic markers including COMT.
At part 2 of the cross-over design (implemented to assess the effect of AMPT on
EFD),
group a) will receive placebo and
b) AMPT.

temporary, acute dopamine depletion by giving alpha-metyrosine (AMPT)

Possible side effects are stifness (extrapyramidal symptoms), dysphoria,
transitory anxiety, tiredness, sedation and sleeping problems. In a previous
study of our research group with 24 comparable individuals, in reaction to the
proposed dose of AMPT only sleepiness was reported. There have not been any
reports of longer lasting side effects, which would also not be expected
farmacologically, because of the half life of 3.4- 3.7 hours. In addition,
there is a burden in time of 12 hours.