Congreso ORITEL http://www.congresooritel.org

1. Asuncion
November, 2015
Neurodevelopmental disorders and
cognitive training
Hans Forssberg, MD, PhD
Neuropaediatrics, Karolinska Institutet
Chairman IAACD

2. NEURODEVELOPMENTAL
DISORDERS
PREVALENCE
ADHD 5-7 %
Autism Spectrum Disorders 1 % (autism 0.1-0.2)
Dyslexia 3 %
Language Disorders (SLI) 3-5 %
Mental Retardation (MR) 1 %
Cerebral Palsy (CP) 0.2 %
Dev. Coordination Disorder (DCD) 3-5 %
Tourettes syndrome 1 %

3. Comorbidity ??
ADHD DCD
Asperger
Autism
Tourette
Dyslexia
Language imp
Learning imp
CD
ODD
or a brain disturbance
with several facets?

4. ADHD – a symptom based diagnosis
Behavioural descriptors
Hans Forssberg

5. Complex disorders -
influencing early development
of brain circuits
 Heritability 70-80 %
Twin-, family-, adoption studies
 Genes with large effect
None (few)
 Genes with small effect (odds ratio < 1.5)
 Environmental risk factors
Obstetrical complications, preterm birth, maternal
smoking, stress, microbiome etc

6. Biederman & Faraone 2005

7. ADHD –
cognitive dysfunctions
 Executive functions
 State regulation
 Temporal information processing and motor
control
Hans Forssberg
JT Nigg Biol Psychiat 2005

8. Executive functions
 Core functions
Cognitive flexibility
Self control (inhibition)
Working memory
 Complex EF
Problem solving
Reasoning
Planning
Hans Forssberg

9. Hans Forssberg

10. Working memory
• The ability to keep information ”on-line”
for a brief period of time
• Limited storage capacity
• ”Storage” dependent on sustained
prefrontal neuronal activity

11. Number repetition 8 … 5 … 2 ”8 … 5 … 2”
Stimuli Response
Block repetition
Mathematics 73 – 7 + 2 =
Problem solving (IQ)
(Ravens matrices)
Working memory functions

12. Everyday usage
• Remembering plans
– What to do next
– What I am looking for
• Remembering instructions
• Mental calculation
• Reading comprehension
• Problem solving (gF)

13. 2
baseline
Working memory

14. Anatomy of WM
Klingberg et al. (2002)
Klingberg et al. 2002

15. Computerized Training of Working Memory
• 40 min training / day
• 5 days/week, 5 weeks
• Adaptive algorithm
• Internet based feedback
Training curve
N = 430
60
65
70
75
80
85
90
95
100
105
0 5 10 15 20 25 30
Day of training
WMcapacityindex

16. Results
• 80% subjects with ADHD improved
– working memory
– attention
– general IQ
– reduced symptoms
Klingberg et al 2002
Klingberg et al 2005
Jaeggi et al 2007
Dahlin et al 2008 0
1
2
3
4
5
6
7
8
0 5 10 15 20
Day
Level

17. AP
0
1
2
3
4
5
6
7
8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Day of training
LevelonWMspan
0.2
0.25
0.3
0.35
0.4
0.45
Reactiontime(s)
Level
RT
Plasticity of Working Memory
Olesen et al. Nature Neuorsci 2004

18. DOPAMINE deficit hypothesis
 Psychostimulants
60-80 % responders
Increase WM capacity
 Molecular genetics
e.g., DAT, D4, COMT
 Knock-out mouse
DAT, D1-D4
Hans Forssberg

19. Methylphenidate improves
visuo-spatial working memory
• Primates
– Arnsten, J Psychopharmacology 1997
• Healthy humans
– Elliot et al, Psychopharmacology 1997
– Mehta et al, J Neuroscience 2000
• ADHD subjects
– Tannock et al, JACAP 1995
– Kempton et al, Psychol Med 1999

20. Dopamine D1 receptors
effect of 5 weeks WM-training
 13 healthy males 20-28 year olds
 25 days of working memory training
 PET before and after training
D1 receptors: [11C]SCH 23390
 fMRI and Cognitive tests before and
after training
Hans Forssberg McNab et al 2009, Science

21. Cognitive tests
(Cogmed Cognitive
Medical Systems)
Spanboard backwards
NumbersHideAd Bygga Ord
CAT
Spanboard forward
Raven’s Advanced
Progressive Matrices
1, 3, 2, 1, 4, 6, .....
4 5 3 5 10
Paced Auditory Serial Addition Test:
T = 2.6,
p<0.05
T = 4.3,
p<0.01
T = 3.8,
p<0.01
T = 2.4,
p<0.001
T = 8.1,
p<0.001
T = 3.0,
p<0.05
T = 1.7,
p=0.111
Mean Score
T = 11.1, p<0.001
Group Means
3
3,5
4
4,5
5
5,5
6
6,5
7
7,5
8
0 5 10 15 20 25
Day
MeanAvMax3Level

22. Functional ROIs BOLD
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
before after
BOLD: t=-3.047, p=0.012
BOLD
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
before after
BOLD: t= -3.851, p=0.003
BOLD
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
before after
BOLD: t=-3.765, p=0.004
BOLD
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
before after
BOLD:
t=-2.875,
p=0.017
BOLD
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
before after
BOLD:
t=-0.873,
p=0.403
Cluster 1, right frontal
Cluster 1, right posterior
Cluster 1, left posterior
Cluster 2, left frontal Cluster 3, right frontal

23. Functional ROIs D1_BP cluster 1 right frontal
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
before after
BP: t=0.300, p=0.770
D1 BP
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
before after
BP: t=0.559, p=0.586
D1 BP
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
before after
BP: t=0.685, p=0.507
D1 BP
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
before after
BP:
t=1.182,
p=0.260
D1 BP
0
0,1
0,2
0,3
0,4
0,5
0,6
before after
BP:
t=-1.036,
p=0.321
BOLD
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
before after
BOLD: t=-3.047, p=0.012
BOLD
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
before after
BOLD: t= -3.851, p=0.003
BOLD
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
before after
BOLD: t=-3.765, p=0.004
BOLD
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
before after
BOLD:
t=-2.875,
p=0.017
BOLD
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
before after
BOLD:
t=-0.873,
p=0.403
Cluster 1, right frontal
Cluster 1, right posterior
Cluster 1, left posterior
Cluster 2, left frontal Cluster 3, right frontal

24. Prefrontal cortical DA D1 agonists/antagonists
affect WM performance and neuronal firing
Williams & Goldman Rakic 1995, Sawaguchi 2001, Wang et al 2004,
Vijayraghan et al 2007
Hans Forssberg

26. Also:
Olesen et al. 2004
Increases in
brain activity
in frontal and
parietal regions
associated with
working memory
Changes in cortical D1 Binding Potential
Right posterior
Right dorsal frontal
Right ventral frontal
Left frontal
Left posterior
R L R L
Right posterior
R L R
Right dorsal frontal
L
R L
Right ventral frontal
R L R
Left frontal
L
R L R
Left posterior
L
LR
Regions associated with Working Memory
McNab et al. Science, 2009.

27. fMRI imaging
Altered brain
activity
Olesen et al. 2004
ADHD
Behavioural symptoms
Impaired cognitive functions
Altered dopamine signalling
Cognitive training
Reduced clinical
symptoms
Klingberg et al. 2005
?
Improved cognitive performance
Klingberg et al. 2002, 2005; Olesen et al. 2004; Jaeggi et al.
2008; Dahlin et al. 2008; McNab et al. 2009.
Training curve
N = 430
60
65
70
75
80
85
90
95
100
105
0 5 10 15 20 25 30
Day of training
WMcapacityindex
PET imaging
Molecular changes
in dopamine system
McNab et al 2009

28. Collaborators
 PET
Lars Farde
Christer Halldin
Aurelija Jucaite
Joakim Tedroff
Susanna Walters
Andrea Varonne
Paulina Bystritsky
 Working memory & fMRI
Torkel Klingberg
Fiona McNab
 Clinician
Elisabeth Fernell
Hans Forssberg