De Neurobiologie van ADHD

Transcriptie

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

2 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

3

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

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

6

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

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

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

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

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

12 NA pathway of attention (Arnsten, 1996)

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

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

15 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).

16 U-shaped curve (Aston-Jones, 1999)

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

18

19 Influence of NE on delayed-response performance

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

21

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

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

24

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

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

27 15-Year-Old Boy With ADHD and a Brain Lesion and His Unaffected Monozygotic Twin (Castellanos, 2003)

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

29 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, Copyright 1998 by the National Academy of Sciences

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

31 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

32 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

33 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

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

35 1 DA release postsynaptic DA receptor stimulation 3 reuptake by DAT DA escape from synaptic cleft 5 GLU from PFC Stimulation of GLU heteroreceptor 7 Stimulation of DA autoreceptor 8 tonic downmodulation of DA release

36 E F D 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

37

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

39 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

40 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