De Neurobiologie van ADHD - RUhosting

De Neurobiologie van ADHD
ADHD: een dopaminerge of een
noradrenerge stoornis?
Dr.C.C. Kan, psychiater
UMC St Radboud Nijmegen

Waarom dopaminerge / noradrenerge hypothese?
• Psychofarmaca die heropname van dopamine en/of
noradrenaline remmen hebben positief effect op de
ADHD symptomen
• Methylfenidaat
• Dextro-amfetamine
• Atomoxetine
• TCA’s

VTA PFC
dopaminerg
noradrenerg
glutaminerg
Himelstein,-et al. Front-Biosci. 2000

PFC Striatum
LC PFC
Himelstein,-et al. Front-Biosci. 2000

Prefrontale Cortex (PFC)
• Impaired Response Inhibition (Barkley 1997)
• Inhibition of Impulsivity
• Inhibition of distractibility
• Executieve functies o.a.:
• Werkgeheugen
• Planning
• Concentratie

Prefrontale Cortex (PFC)
•PFC lesions “ADHD phenotype”
•Stoornissen in frontale functietesten
•Morfologische en functionele verschillen
bij neuroimaging

dopaminerg
noradrenerg
glutaminerg
Himelstein,-et al. Front-Biosci. 2000

Anterior cingulate during the counting Stroop
(Bush et al 1999)
n=8
frontostriato–insular–thalamic activity
n=8
Anterior cingulate cognitive division activates in the normal control group
but not in the ADHD group during the counting Stroop.

N200 to the Stop signal
Topographic maps of
the controls minus
ADHD ERP difference
wave (Plizka, 2000)
Maximal difference
Right frontal anterior

NA pathway of attention
(Arnsten, 1996)

The role of the Locus Coeruleus (LC)
• Regulation of Arousal
• Stimulation/inhibition of the PFC

Typical LC neuron recorded in a monkey during
performance of the discrimination task (vertical or
horizontal bar)
FAs = False Alarms
Aston-Jones,
1999

LC activity during visual discrimination task. (A, B): response
for targets; (C, D): response for distractors
(A, C): periods of good performance (phasic LC mode); and (B, D):
poor behavioral performance (FA rate typically > 7%; tonic LC mode).

U-shaped curve
(Aston-Jones, 1999)

LC PFC
Himelstein,-et al. Front-Biosci. 2000

Influence of NE on delayed-response performance

VTA PFC
dopaminerg
noradrenerg
glutaminerg
Himelstein,-et al. Front-Biosci. 2000

Influence of D1-receptor stimulation on spatial working-memory performance

Catecholamine
influences on
prefrontal cortex (PFC)
working-memory
functions
•PFC is taken
offline during stress!
LC VTA

Nucleus Accumbens (Nac): knooppunt tussen het mesolimbische
systeem en de inhiberende input vanuit PFC

Role of Striatum in neural circuitry w.r.t.:
• Motor control
• Executive functions
• Response inhibition
• Modulation of Reward

15-Year-Old Boy With ADHD and a Brain Lesion and His
Unaffected Monozygotic Twin (Castellanos, 2003)

Rol van het Striatum in neuraal netwerk:
• Hoogste Dopamine Activiteit
• Verlaagd of verhoogd in ADHD?

Activation during response inhibition on the stimulus-controlled task in a coronal slice located 12
mm anterior to the anterior commissure for an ADHD and a control child
fMRI
Opposite effect of
MPH in the head of
the caudate and
putamen
in the ADHD and
control child
Vaidya, Chandan J. et al. (1998) Proc. Natl. Acad. Sci. USA 95, 14494-14499
Copyright ©1998 by the National Academy of Sciences

Role of Striatum in neural circuitry:
• Highest DAT density (contrary to PFC)

Specific binding ([STR–BKG]/BKG) of [Tc–99m]TRODAT-1 to the DAT
is displayed before and after treatment with methylphenidate as
compared to normal controls (Krause, 2000)
SPECT

Representative SPECT scans for ADHD patients as compared to agematched
controls (Krause, 2000)
MPH lowers increased striatal DAT availability in ADHD adults !
A: Before MPH B: After MPH C: Controls

PET Distribution volume images of [ 11 C]raclopride at the
level of the striatum and at the level of the cerebellum
(Volkow, 2001)
striatum
MP reduced binding
of [ 11 C]raclopride in
the striatum where it
competes with
dopamine (DA) for
binding to DA D2
receptors
Sample: 11
healthy males

Grace, 2001: Interaction between PFC, hippocampus,
amygdala and striatum
VTA

8
7
1
3
2
6
4
5
•1 DA release
•2 postsynaptic DA
receptor stimulation
•3 reuptake by DAT
•4 DA escape from
synaptic cleft
•5 GLU from PFC
•6 Stimulation of
GLU heteroreceptor
•7 Stimulation of DA
autoreceptor
•8 tonic downmodulation
of DA
release

D
F
Model of MPH actions: (A) blockade of DAT (B) Accumulation of DA in
synaptic cleft (C) Stimulation postsynaptic D-receptors (D) Feedback
inhibition of DA neuron firing (E) escape of DA in extrasynaptic space (F)
increase of autoreceptor stimulation attenuating DA release
E

Neural ADHD Circuit
NA
Locus Coeruleus
Posterior Cortex
DA
Attention
Impulsivity &
Hyperactivity

Belangrijke Knooppunten in neurale ADHD circuit
• PFC; aandrijving en remming door NA en DA
• Aandrijving via 2 en D1 (matig), D2
• Remming (offline!) via 1 en D1 (sterk), D5
• Striatum; belangrijkste dopaminerge aangrijpingspunt
van MPH door overmaat aan DATs; door DA RI herstel
van tonische downmodulatie van dopamine aanmaak
• Bij laag stressniveau onvoldoende inhibitie in NAc via
dopamine autoreceptoren
• Bij hoog stressniveau onvoldoende inhibitie in NAc via
PFC (off-line!)
Krappere marge qua stressniveau waarbij wel
voldoende inhibitie optreedt

Hypothese:
• ADHD is een heterogene stoornis tgv
verschillende afwijkingen in het NA of DA
systeem waardoor de inhiberende invloed
van de PFC wordt geremd of onvoldoende
bijdraagt aan de frontostriatale respons
inhibitie