NEUROBIOLOGY OF ADHDNEUROBIOLOGY OF ADHD

Paolo Curatolo, MD Dept- Pediatric Neurosciences“Tor Vergata” University, Rome, Italy

curatolo@uniroma2.itTel:06-41400165

•Former understanding of ADHD as “behavior disorder”

• Emerging understanding of the biological basis from

molecular genetics and functional neuroimaging

ADHD

Subtypes:

ADHD-Inattentive

ADHD-Hyperactive

ADHD-Combined

TIME

Aree cerebrali implicate nell’ADHD e neurotrasmettitori coinvolti

Corteccia Prefrontale

NA & DA

Nucleus Accumbens

Striato

Corteccia Parietale

Posteriore

NA

NA & 5HT

Cervelletto

DA

Funzioni Esecutive Orientamento

Locus

Coeruleus

NA

•Omeostasi (adattamento all'ambiente),

•Regolazione della percezione del tempo,

•Controllo e regolazione dell'equilibrio

e della coordinazione dei movimenti

• Controllo della postura (tono muscolare) e dei movimenti (componente involontaria dei movimenti)

• Regolazione della motivazione e della gratificazione,

• Arousal

• Allerta

P.Curatolo, C.Paloscia, E.D’Agati, R.Moavero, A. Pasini. EJPN 2009

ADHD Neurochemistry - disturbed networksADHD Neurochemistry - disturbed networks

Adapted from Himelstein et al 2001

Anterior Attention System

Posterior Attention System

OrientationOrientation

ArousalArousal

Executivefunctions

Executivefunctions

Dopamine selectively controls inputs to anterior attention system via D1 receptor inhibition of excitatory NMDA inputs

Posterior parietal cortex

Ventral tegmental area

Prefrontal cortex

Anterior cingulate gyrus

Noradrenaline enhances the signal-to-noise ratio of target cells by inhibiting basal neuronal firingLocus coeruleus

Superior colliculus

Pulvinar nucleus of thalamus

Posterior parietal cortex

Anatomy of attentional network

Thalamus, Locus coeruleus, fronto-parietal cortex

Right temporal/parietal areas, right lower frontal area

Anterior cingulate and lateral areas of the prefrontal cortexAdapted from Raz, 2004

Neuroanatomy of ADHD

•Smaller brain (∼4%): right frontal lobe (∼8%)

•Smaller basal ganglia (∼6%) � normalisation (∼18 yrs)

•Smaller cerebellum (12%) � more pronounced (∼18 yrs)

•Volumetric differences

– manifest early (∼6 years)

– correlate with ADHD severity

– are irrespective of medication status

– are irrespective of comorbidities

AETIOLOGY

Neuroanatomy – total brain volume

AETIOLOGY

Neuroanatomy – total brain volume

Castellanos et al 2002

Age (years)

900

1000

1100

5 7 9 11 13 15 17 19 21

ml

Control malesADHD malesControl femalesADHD females

Controls > ADHD P<0.003

AETIOLOGY

Neuroanatomy – caudate volume

AETIOLOGY

Neuroanatomy – caudate volume

Castellanos et al 2002

Controls > ADHD, p<0.05

Interaction with age, p<0.05

9

10

11

5 10 15 20Age (years)

Caudate

volu

me (m

l)

Controls

ADHD

AETIOLOGY

Neuroanatomy – cerebellar volume

AETIOLOGY

Neuroanatomy – cerebellar volume

Castellanos et al 2002

115

125

135

5 10 15 20Age (years)

Cerebellarvolume (ml)

Controls

ADHD Controls > ADHD, p<0.001; Adjusted, p=0.003

Neuroanatomy of ADHD:

Atypical development and disorders

• Atypical development

– Maturational lag

– Deviant developmental trajectory (mean-1.5-2 SD)

• Developmental disorders

– Known or partly known etiology

– Acquired impairments

– Syndromes

MRI parcellation methods

� Regional specific anatomic abnormalities in

cortical components of attention system

� Different anatomical abnormalities would

probably produce phenotypic variants of ADHD

� Correlation of brain volume with ratings of ADHD

severity

� Reduced metabolism/ blood flow in

• frontal lobe

• parietal cortex

• striatum

• cerebellum

� Increased blood flow/ electrical activity in

• sensorimotor cortex

� Activation of other neuronal networks

Functional Neuroimaging in ADHD

Structural connettivity deficits in ADHD

The core symptoms of ADHD might derived

from dysregulated modulation of cortical

plasticity in the developing brain

FUNCTIONAL connectivity deficits

might lead to ADHD SYMPTOMS,

possibly by altering interaction

between frontostriatal attentional

networks and a DMN active during

non-goal oriented processes

STRUCTURAL connectivity deficits

might be viewed as a nonspecific

markers of a history of dysregulated

plasticity arising secondary to a

common etiologic mechanism :

•Alterated synaptic pruning

•Genetic factors

•Enviromental risk factors

Liston et al. 2011

Development of attentional pathways

Birth 1 2 3 4 5 18 3-4 4-5 6-7

yearsmonths

Time of first

evaluation

• Arousal

• Alertness

• Focusing

• Orienting

• Shifting

• Shared

• Span

Prefrontal cortex

EXECUTIVE functions

Ocular

movements

Saccades

Superior colliculusBasal Ganglia

Ventral tegmental area

13’ 15’ 60’7’

Development of attentional pathways

Birth 1 2 3 4 5 18 3-4 4-5 6-7

yearsmonths

Time of first

evaluation

Structural factors,

genetics influences

Functional factors,

epigenetic-environmental influences

GeneticGenetic FactorsFactors in ADHDin ADHD

• Association of ADHD with known hereditary

diseases

• Higher risk for the siblings

• Frequent occurrence of milder phenotypes in

relatives

A.Lo Castro, E.D’Agati, P. Curatolo. Brain Dev 2011

The genetic basis of ADHD

• ADHD is highy familial and heritable

• Replicated candidate genes are primarily linkedto the dopamine sistem (DRD4,DAT1)

• Effects of individuals genes are small

• ADHD is geneticaly heterogeneous and has a complex genetic architecture

• Interplay of multiple genetic and environmentalrisk factors

GeneticsGenetics of ADHDof ADHD

• M/F ratio = 4:1

• High concordance rate in MZ twins (60-91%)

• Hereditability = 76%

• Causal and genetic heterogeneity

Curatolo P, Paloscia C, D’Agati E, Moavero R, Pasini A, EJPN 2009

ADHD: Behavioural genetics

• Concordance for ADHD symptoms: MZ > DZ

• Heritability: 0.75 (mean)

Twin study

• Higher prevalence of ADHD in biological

parents than in adoptive parents

Adoption study

• High prevalence of ADHD and other mental

disorders in the relatives of patients

Family studies

Faraone et al., 2005

ESTIMATED HERITABILITY IN ADHDESTIMATED HERITABILITY IN ADHD

GENES CONTRIBUTES TO ADHD

• 14 published twin studies (h: 60-91%)

• 5 adoption studies consistent with genetic

etiology

• Genetic risk factors contribute to:

� continuity of ADHD symptoms over time

� link between ADHD and social behavior

Genes associated with ADHD

Neurobiologie du trouble déficit de l’attention/hyperactivité. D. Purper-Ouakil et al. Medecine Science 2010

Genes associated with ADHD

Neurobiologie du trouble déficit de l’attention/hyperactivité. D. Purper-Ouakil et al. Medecine Science 2010

ADHD ADHD isis a a geneticallygenetically

heterogeneousheterogeneous, , polygenicpolygenic

disorderdisorder due due toto the additive and the additive and

epistaticepistatic effecteffect of of manymany differentdifferent

genesgenes, , eacheach withwith a a smallsmall effecteffect, ,

and a and a modestmodest environmentalenvironmental

componentcomponent

ADHD in Neurogenetics Syndromes

Marked prevalence of ADHD reported in the

complex behavioral phenotypes associated with

neurogenetic syndromes:

-Tuberous Sclerosis

-Fragile X Syndrome

-NF1, VCFS, WS, Sexual aneuplodies

A. Lo Castro, E.D’Agati, P.Curatolo, Brain Dev. 2011

• ALTERED GENES EXPRESSION

• ABNORMALITIES IN NEURONAL MIGRATION AND IN PRECURSOR CELL LINES

• ALTERED SYNAPTIC DEVELOPMENT AND PLASTICITY

ENVIRONMENTAL RISK FACTORS

DEFICITS IN BRAIN FUNCTIONS

EXECUTIVE FUNCTIONSATTENTION MOTIVATION MOTOR CONTROL

ADHD SYMPTOMSLo Castro et al. 2011

EARLY GENE-ENVIRONMENT

INTERACTION IN ADHD

•Genes control behavior

•Environment can change gene expression

•Functional polymorphysms

could act as

Protective factors

Risk factors

The environmental basis of ADHD

• Prenatal exposure to adverse fetal environmentsand negative perinatal experiences increasesthe risk of ADHD by a significant degree

• Moderate effect of maternal smoking and alchool exposure during pregnancy

• Postnatal diet may be more important than once thought

• Social environment within the family may play animportant role in developmental complications(ODD)

Causal and clinical heterogeneity in ADHD

G1G1 G2G2 G3G3 E1E1 E2E2 E3E3

DYSFU�CTIO�

1

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2

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3

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3

ADHD PHE�OTYPE 1 ADHD PHE�OTYPE 2 ADHD PHE�OTYPE 3

ADHD: Gene-Environment

Interaction