NEUROBIOLOGY OF ADHD
Paolo Curatolo, MD
Dept- Pediatric Neurosciences
“Tor Vergata” University, Rome, Italy
[email protected]
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 nell’ADHD 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.D’Agati, 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
7
9
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
9
5
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
7’
13’
Superior colliculus
Ocular
Basal Ganglia
Ventral tegmental area movements
Saccades
Birth 1
2
3
4
months
5
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
2
3
4
5
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.D’Agati, 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, D’Agati 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 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 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.D’Agati, 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