Download - Trastornos cognitivos - Dr. Hans Forssberg
AsuncionNovember, 2015
Neurodevelopmental disorders and cognitive training
Hans Forssberg, MD, PhDNeuropaediatrics, Karolinska InstitutetChairman IAACD
NEURODEVELOPMENTALDISORDERS
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 %
Comorbidity ??
ADHD DCD
AspergerAutism
TouretteDyslexiaLanguage impLearning impCDODD
or a brain disturbance with several facets?
Hans Forssberg
ADHD – a symptom based diagnosis Behavioural descriptors
Complex disorders -influencing early developmentof brain circuits
Heritability 70-80 %Twin-, family-, adoption studies
Genes with large effectNone (few)
Genes with small effect (odds ratio < 1.5) Environmental risk factors
Obstetrical complications, preterm birth, maternal smoking, stress, microbiome etc
Biederman & Faraone 2005
Hans Forssberg
ADHD –cognitive dysfunctions
Executive functions State regulation Temporal information processing and motor
control
JT Nigg Biol Psychiat 2005
Executive functions
Core functionsCognitive flexibilitySelf control (inhibition)Working memory
Complex EFProblem solvingReasoningPlanning
Hans Forssberg
Hans Forssberg
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
Number repetition 8 … 5 … 2 ”8 … 5 … 2”
Stimuli Response
Block repetition
Mathematics 73 – 7 + 2 =
Problem solving (IQ) (Ravens matrices)
Working memory functions
Everyday usage• Remembering plans
– What to do next– What I am looking for
• Remembering instructions• Mental calculation• Reading comprehension• Problem solving (gF)
time2
baseline
Working memory
Anatomy of WM
Klingberg et al. (2002)Klingberg et al. 2002
Computerized Training of Working Memory
• 40 min training / day• 5 days/week, 5 weeks• Adaptive algorithm• Internet based feedback
Training curveN = 430
60
65
70
75
80
85
90
95
100
105
0 5 10 15 20 25 30
Day of training
WM
cap
acity
inde
x
Results
• 80% subjects with ADHD improved– working memory– attention– general IQ– reduced symptoms
Klingberg et al 2002Klingberg et al 2005Jaeggi et al 2007Dahlin et al 2008 0
1
2
3
4
5
6
7
8
0 5 10 15 20
Day
Leve
l
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
Leve
l on
WM
spa
n
0.2
0.25
0.3
0.35
0.4
0.45
Reac
tion
time
(s)
Level
RT
Plasticity of Working Memory
Olesen et al. Nature Neuorsci 2004
DOPAMINE deficit hypothesis
Psychostimulants60-80 % respondersIncrease WM capacity
Molecular geneticse.g., DAT, D4, COMT
Knock-out mouseDAT, D1-D4
Hans Forssberg
Methylphenidate improvesvisuo-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
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
Cognitive tests(Cogmed Cognitive Medical Systems)
Spanboard backwards
NumbersHideAd Bygga Ord
CATSpanboard 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
Mea
n Av
Max
3Lev
el
Functional ROIsBOLD
-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
Functional ROIsD1_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
Hans Forssberg
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
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.
fMRI imaging
Altered brain activity
Olesen et al. 2004
ADHDBehavioural symptoms
Impaired cognitive functions
Altered dopamine signalling
Cognitive trainingReduced clinical symptoms
Klingberg et al. 2005
?
Improved cognitive performanceKlingberg et al. 2002, 2005; Olesen et al. 2004; Jaeggi et al. 2008; Dahlin et al. 2008; McNab et al. 2009.
Training curveN = 430
60
65
70
75
80
85
90
95
100
105
0 5 10 15 20 25 30
Day of training
WM
cap
acity
inde
x
PET imaging
Molecular changes in dopamine systemMcNab et al 2009
Hans Forssberg
Collaborators
PETLars FardeChrister HalldinAurelija JucaiteJoakim TedroffSusanna WaltersAndrea VaronnePaulina Bystritsky
Working memory & fMRITorkel KlingbergFiona McNab
ClinicianElisabeth Fernell