NEUROBIOLOGY OF ADHD

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

curatolo@uniroma2.it
Tel: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 nellADHD e neurotrasmettitori coinvolti

Funzioni Esecutive

Orientamento
Corteccia Parietale
Posteriore

Corteccia Prefrontale
NA & DA

Controllo della postura

(tono muscolare) e dei
movimenti (componente
involontaria dei
movimenti)
Regolazione della
motivazione e della
gratificazione,

NA

Striato

DA

Nucleus Accumbens

Locus
Coeruleus

Cervelletto
NA & 5HT

NA

Arousal
Allerta

Omeostasi (adattamento all'ambiente),

Regolazione della percezione del tempo,
Controllo e regolazione dell'equilibrio
e della coordinazione dei movimenti

P.Curatolo, C.Paloscia, E.DAgati, R.Moavero, A. Pasini. EJPN 2009

ADHD Neurochemistry - disturbed networks

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

Executive
Executive
functions
functions

Orientation
Orientation

Pulvinar nucleus of thalamus

Prefrontal cortex

Posteriorparietal
parietalcortex
cortex
Posterior

Anterior cingulate gyrus

Superior colliculus

Ventral tegmental area

Locus coeruleus

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

Anterior Attention System

Posterior Attention System

Arousal
Arousal
Adapted from Himelstein et al 2001

Anatomy of attentional network

Thalamus, Locus coeruleus, fronto-parietal cortex

Right temporal/parietal areas, right lower frontal area

Adapted from Raz, 2004

Anterior cingulate and lateral areas of the prefrontal cortex

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
Controls > ADHD P<0.003

ml

1100

1000

900

Control males
ADHD males
Control females
ADHD females
5

11

13

15

17

19

21

Age (years)
Castellanos et al 2002

AETIOLOGY

Caudate volume (ml)

Neuroanatomy caudate volume

11

10

Controls > ADHD, p<0.05

Interaction with age, p<0.05
Controls
ADHD

10

Age (years)

15

20

Castellanos et al 2002

Cerebellar volume (ml)

AETIOLOGY
Neuroanatomy cerebellar volume

135

125

115

Controls > ADHD, p<0.001;

Adjusted, p=0.003
5

10

15

Controls
ADHD
20

Age (years)

Castellanos et al 2002

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


Functional Neuroimaging in ADHD

 Reduced metabolism/ blood flow in
frontal lobe
parietal cortex
striatum
cerebellum
 Increased blood flow/ electrical activity in
sensorimotor cortex
 Activation of other neuronal networks

Structural connettivity deficits in ADHD

The core symptoms of ADHD might derived

from dysregulated modulation of cortical
plasticity in the developing brain

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

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

Development of attentional pathways

Arousal
Alertness
Focusing
Orienting
Shifting
Shared
Span

Time of first
evaluation

13

Superior colliculus
Ocular
Basal Ganglia
Ventral tegmental area movements
Saccades

Birth 1

months

18

15

60

Prefrontal cortex
EXECUTIVE functions

3-4

4-5
years

6-7

Development of attentional pathways

Structural factors,
genetics influences

Functional factors,
epigenetic-environmental influences

Time of first
evaluation

Birth 1

months

18

4-5

3-4
years

6-7

Genetic Factors in ADHD

Association of ADHD with known hereditary
diseases
Higher risk for the siblings
Frequent occurrence of milder phenotypes in
relatives

A.Lo Castro, E.DAgati, P. Curatolo. Brain Dev 2011

The genetic basis of ADHD

ADHD is highy familial and heritable
Replicated candidate genes are primarily linked
to 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 environmental
risk factors

Genetics of ADHD
M/F ratio = 4:1
High concordance rate in MZ twins (60-91%)
Hereditability = 76%
Causal and genetic heterogeneity

Curatolo P, Paloscia C, DAgati E, Moavero R, Pasini A, EJPN 2009

ADHD: Behavioural genetics

Family studies
High prevalence of ADHD and other mental
disorders in the relatives of patients
Adoption study
Higher prevalence of ADHD in biological
parents than in adoptive parents
Twin study
Concordance for ADHD symptoms: MZ > DZ
Heritability: 0.75 (mean)

ESTIMATED HERITABILITY IN ADHD

Faraone et al., 2005

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 dficit de lattention/hyperactivit. D. Purper-Ouakil et al. Medecine Science 2010

Genes associated with ADHD

Neurobiologie du trouble dficit de lattention/hyperactivit. D. Purper-Ouakil et al. Medecine Science 2010

ADHD is a genetically
heterogeneous, polygenic
disorder due to the additive and
epistatic effect of many different
genes, each with a small effect,
and a modest environmental
component

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.DAgati, P.Curatolo, Brain Dev. 2011

ENVIRONMENTAL RISK FACTORS

ALTERED GENES EXPRESSION

ABNORMALITIES IN NEURONAL MIGRATION AND IN PRECURSOR CELL LINES
ALTERED SYNAPTIC DEVELOPMENT AND PLASTICITY

DEFICITS IN BRAIN FUNCTIONS

ATTENTION

Lo Castro et al. 2011

MOTIVATION

MOTOR CONTROL

ADHD SYMPTOMS

EXECUTIVE FUNCTIONS

EARLY GENE-ENVIRONMENT
INTERACTION IN ADHD
Genes control behavior
Environment can change gene expression
Functional polymorphysms
Protective factors

could act as
Risk factors

The environmental basis of ADHD

Prenatal exposure to adverse fetal environments
and negative perinatal experiences increases
the 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 an
important role in developmental complications
(ODD)

Causal and clinical heterogeneity in ADHD

G1

G2

G3

E1

DYSFUCTIO
1

DYSFUCTIO
2

ADHD PHEOTYPE 1

ADHD PHEOTYPE 2

E2

E3

DYSFUCTIO
3

ADHD PHEOTYPE 3

ADHD: Gene-Environment
Interaction