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NEUROBIOLOGY OF ADHDNEUROBIOLOGY OF ADHD
Paolo Curatolo, MD Dept- Pediatric Neurosciences“Tor Vergata” University, Rome, Italy
[email protected]: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
DYSFU�CTIO�
1
DYSFU�CTIO�
2
DYSFU�CTIO�
2
DYSFU�CTIO�
3
DYSFU�CTIO�
3
ADHD PHE�OTYPE 1 ADHD PHE�OTYPE 2 ADHD PHE�OTYPE 3
ADHD: Gene-Environment
Interaction