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