brain developm adhd2
DESCRIPTION
A presentation based on this widely cited paper> http://uais.lzu.edu.cn/uploads/soft/20111230/BraindevelopmentandADHD.pdfTRANSCRIPT
Brain development and ADHD
Author : Amy L. Krain, F. Xavier Castellanos
Clinical Psychology Review 26 (2006) 433–444
ADHD characteristcs• excessive inattention,• hyperactivity, • impulsivity,either alone or in combinationNeuropsychological findings suggest
that these behaviors result from underlying deficits in
• response inhibition• delay aversion• executive functioning presumed to be linked to dysfunction of
frontal–striatal–cerebellar circuits
MRI Technique• examine anatomic differences in these regions between ADHD and
control children• quantifying differences in total cerebral volume(TCV)• specific areas of interest have been prefrontal regions, basal
ganglia, the corpus callosum, and cerebellum• Differences in gray and white matter have also been examined
Goal of this research is to determine the underlying neurophysiology of ADHDand how specific phenotypes may be related to alterations in brain structure
Hypothesized pschychological deficits
• Dysfunction of frontal/striatal cerebellar circuits
Neural circuits
Prefrontal Cortex Basal Ganglia
Cerebellum• MOTOR COORDINATION centre
• Closely linked to NONMOTOR region of CEREBRAL CORTEX
• EXECUTIVE FUNCTION/Cognitive Planning
Module Response Inhibition
Anatomic MRI -Principle technology to study Pediatric Brain
Advantage1.Spacial resolution
2.No ionizing radiation
Disadvantage1.Cost of MRI scan (small sample size)-> less statistical power-
2.Cost increases by loss of scans due to excessive motion (hyperactivity of children)
3.ADHD characteristics vary with age, sex, clinical setting->heterogenous dataset+small sample size->Difficulty in comparison
4.Stimulant medication->children already with medication, no medication , previously medicated.
Current methodsHand-tracing of individual region of interest
•Decrease reliability
•Optimize validity
Fully-automated method
•Maximize test-retest reliability
•Best for large well/defined brain region
Semi-automated method
•Combined the two
Focus on Lateralization of language , indices and asymmetry
•Asymmetry measure , less reliable that volumetric measure
•Reliability inverses with degree of similarity between left and right side
Normal Brain Developement• 90% of young adult’s brain volume attained by age 5
• Total Cerebral volume (TCV)->Max. early adolescence
• Experimental data: 1mm/yr in PFC
Gender difference prominent
Cross-sectional analysisAge related decrease-thalamus, lenticular neucleusIncrease>lentricular size, after controlling TCV
Sex difference in development pattern
• Experiment-104 children(age 4-18)• Decrease in CAUDATE and PUTAMEN in boys only
Cerebram
Cerebellum Boy > Girl (7-10%)
Cortical Gray Matter Boy > Girl (10%) Even if TCV controlled
Subcortical Region
Putamen
Globus Pallidus
Boy > Girl
White matter development• Cross Sectional And Longitudinal Study• Increase In White Matter>pediatric Age Range• Increase In Myelination>more In Males• Maturational Increase > Frontal,parietal,occipital
Lobes
Experiment-111 children(age 4-17)
age related change in Neural Tracts
Increase in WHITE Matter
Internal Capsule
Posterior portion of LEFT ARCUATE FASCICULAS
Specific pattern in WHITE
Matter development
CORPUS CALLOSUM
Anterior cross/sectional area increases first followed by Posterior growth through late adolescence
FRONTAL
PARIETAL
OCCIPITAL
LEFT ARCUATE FASCICULAS
Gray matter developmentMore heterogeneous overall growth through CEREBRUM
13% increase in Gray MATTER age 6-9
5 % decrease in Gray Matter Per decade
Gray Matter peak 12 yr Frontal, Parietal lobes
Decrease in Gray Matter Post adolescence
Right Dorsolateral Frontal
Bilateral Occipito-Parietal
Anterior and Posterior inferior Temporal Cortices
Increase in CORTICAL THICKNESS
Restricted to classical language areas
Left Anterior, Posterior Perisylvial region
Max. Gray Matter earlier for girls
Brain maturation Age dependent
Temporal lobe Gray Matter Nonlinear development course Max at 16
Oxipital lobe Gray Matter Increase continuously till 20
Anterior and Posterior Cingulate
Basal Ganglia
High Parietal region
Variable in older children
Consistent with specific Gray Matter volume reduction
Individually adaptive, remodeling
Symmetry in normal development
Cerebral hemisphere
Prefrontal Cortex
Right > Left
Left >Right Lateral Ventricle
CSF volume
Right>LeftLeft>Right
Caudate Nucleus
Lenticular Nucleus
Putamen• Left sided• Right sided• Laterality
Neuroanatomical correlation in ADHDADHD brain <Healthy brain *childhood/adoloscence
Distributed Circuit ADHD syndrome
• Frontal Brain Region• Basal Ganglia• Cerebellar Hemesphere• Sub-region of Cerebellar
Vermis
In boys
Distribution of White and Gray matter alters in ADHD
Decreased global volume- experimental study
ADHD anatomy Overall reduction in total brain volume
ADHD 152, Control 139Study /1 Analysis with fully automated system
ADHD brain < Control brain 3.2%
Frontal,Parietal,Temporal,Occipital affected
Volume reduction not relates to medication/stimuli 49 medication naïve104 stimuli
Study /2 30 ADHD boys 4% reduction INTRA-CRANIAL VOLUME
3.4% reduction Cerebral, Cerebellar Volume
Frontal Cortex 12 ADHD boys,12 Control boys 48% reduction Cerebral Volume
Pre-Frontal Cortex Significantly smaller in ADHD boys Effects are more specific in Frontal region No difference in Parietal,Temporal,Occipital region
Asymmetry study
ADHD boys and bothers Diff in symmetry of Pre-Frontal region
Decreased in left/Occipital Gray and White matter volume
Right > Left symmetry in PFC Asymmetry is reduced in ADHD children
Significant Decrease in right-prefrontal regionLower reliability
PFC sub-region Right-Dorsolateral Prefrontal volume Smaller in 23 ADHD
8 adult ADHD never medicated Smaller left/orbital frontal cortical gray and white matter
Decrease in right-sided volumes are not significant
CORTICAL Surface of children with ADHD
Analyze distance between center of Brain and CORTICAL surface
Brain surface for ADHD reduced upto 4mm
Bilaterality in lateral anterior temporal corticesInferior portion of dorsolateral PFC
Pseudo-anatomical arrangement of the motor, associative and limbic pathways. (A) motor circuit. Neurons from the sensorimotor cortex project to the posterolateral putamen (put). From the putamen there are two main projections topographically organized onto the posterolateral region of the target nuclei: (i) the direct circuit to the gpi and (ii) the indirect circuit connecting the posterior putamen to the globus pallidus pars externa (gpe), the STN and the gpi. The gpi is the primary output nucleus of the basal ganglia to the cortex via the ventrolateral thalamus. (B) associative circuit. This circuit originates in the dorsolateral prefrontal and lateral orbitofrontal cortices, which project to the caudate nucleus (cn) and anteromedial portion of the putamen. From the striatum (cn + put) it projects to the dorsomedial region of the gpi and anteromedial parts of the gpe and STN to converge onto the gpi and back to the cortex via the ventral anterior nuclei of the thalamus. (C) limbic circuit. This loop starts in the hippocampus, amygdala and paralimbic and limbic cortices and projects to the ventral striatum (ventral portion of the caudate and putamen, including nacc). The ventral striatum projects to the limbic portion of the gpe and medioventral STN and ventral gpi and to the cortex via the mediodorsal nucleus of the thalamus
Reduced brain size
Right Parietal cortex of ADHD
Difficulty to integrate, as methods and subjects are different
Cortical surface is closer to centre of ADHD brain(less local growth)
BASAL Ganglia
Prefrontal cortex
Caudate nucleusPutamen
Volumetric and Asymmetry difference between ADHD and Control *not consistent
http://kin450-neurophysiology.wikispaces.com/Basal+Ganglia+II
Total Caudate volume
Study,fully automated measurement
Age<16 - ADHD with decreased volume
Age=16 – normal control consistent with ADHD, did not demonstrate large decrease from maximal values
Transient abnormalities
Diminish in motoric symptoms in ADHD , increase in age
Study 1-Functional Imaging
Putamen-Primary and Supplementary motor area
Decreased blood flow in Putamen (objectively hyperactive)
Motor Symptom of ADHD > Ambiguous result
CaudatePutamen
Significantly smaller in ADHD boys, with o without Tourette Syndrome
Globus Pallidus
Effect of head trauma , damage to Basal Ganglia-> Secondary development of ADHD
Complete elimination of basal ganglia
Case 1-traumatic amniocentesis at 17 weeks of gestation
Lesions of Right Putamen
Posterior Ventral Putamen
Higher in SADHD
Higher in ADHD
Case 2-99 children(age4 -19)
Closed head injury Chance of SADHD
basal ganglia-3.2% Thalamus-3.6%
Cerebellum coordination of motor movements
non-motor functions such as timing andattentional shifting through connections with frontal regionsTotal
Volume
smaller cerebellar hemispheric volumes (by up to 6%) sustainedthroughout adolescence
Total Volume and Area
Cerebellar Vermis and lobes
remain significant even afteradjusting for TCV
Vermal volume
smaller in ADHD children than controls, even after controlling for total cerebral volume and vocabulary scores
decreased size in ADHD subjects, as compared to controls
failed to find decreases in other cerebellar lobules
Posterior inferior lobe of the cerebellum (lobules VIII–X)
MRI
Gray and White matterStudy > gray–white matter segmentation in ADHD populations
Reductions in both gray and white matter have been reported for the right PFC
•Mostofsky et al.(2002) -> significant white matter reduction confined to the left PFC, gray matter reduced in both hemispheres but more so in the right.
•Overmeyer and his colleagues (2001) reduced gray matter primarily inright side in the posterior cingulate gyrus, superior frontal gyrus, and putamen, and bilaterally in the globus pallidus inchildren diagnosed with hyperkinetic disorder, when compared to normal controls.•Reductions in white matter were predominantly in the left hemisphere
Sowelland colleagues (2003)found •gray matter density to be increased by 15–30% in the posterior temporal lobes and inferior parietal lobes bilaterally in ADHD subjects. •Evidence of a significant increase in gray-matter density in the right occipital lobe of the ADHD children. •White matter volumes were significantly reduced in the ADHD group
corpus callosum Smaller in ADHD
•subregions such as the genu and splenium are smaller
•Smaller rostrum and rostral bodies
NO diagnostic differences in overall corpus callosum area or its subdivisions
Structural findings in girls with ADHD 50 girls with ADHD and 50 female controls
•total cerebral volumes to be smaller in girls with ADHD than controls,
•differences were no longer significant after controlling for vocabulary subscale score
adjustment for TCV and vocabulary,
girls with ADHD had significantly smaller volumes in the posterior–inferior lobules of the cerebellar vermis
No other brain regions, even those previously reported in boys, were found to be significantly smaller in ADHD girls after covariance.
Exposure to stimulant no relationship with regional brain volumes in the ADHD sample
Association between brain structure and functioningBehavioral rating scale
Neuropsychological test
Regional brain volume
Smaller volume
Greater ADHD severity
Caudate
Frontal and Temporal Gray
Cerebellar Volume
significantly negatively correlated with global clinician ratings and parent ratings of child attentionproblems
Semrud-Clikeman et al. (2000)
smaller left caudate head and white matter volumes associated with higher Child Behavior Checklist (CBCL) Externalizing scores.
ADHD girls smaller volumes to be associated with greater symptom severity
smaller total cerebral volume greater attention problems
smaller posteriorinferior vermal volume
global functioning and CBCL anxiety-depression scores
Gray matter density left occipital lobe Negatively correlated with inattentionscores in children with ADHD
Size of the rostral body of the corpuscallosum
Negatively correlated with parent and teacher ratings of impulsivity and hyperactivity in children with ADHD and controls
Executive function deficits in ADHD children
study of 26 ADHD and 26 control boys
• ADHD task performance was positively correlated with prefrontal cortex, caudate, and globus pallidus volumes
• Correlations between sensory selection task performance and prefrontal and caudate volumes were predominantly localized to the right
• Response selection and response execution tasks were correlated with caudate symmetry and left globus pallidus size
• Prefrontal volumes were correlated with performance on the inhibitory conditions, while basal ganglia volumes related to both control and inhibitory conditions
study of 23 ADHD children and 24 normal controls
larger volumes in total superior prefrontal cortex and right superior prefrontal cortex were correlated with worse performance on a test of attention (Conners' Continuous Performance Test; CPT)
Proton magnetic resonance spectroscopy study
Conners' CPT Right dorsolateral volumes
Larger volumes poorer performance on the CPT composite,variability, and reaction time standard error scores
not found in healthy control Right dorsolateral region may be dysfunctional in ADHD
More tissue in right dorsolateral region leads to greater disruption in attention
Study comparing anatomic MRI measures with the performance of children with ADHD and normal controls on Executive function tests
Reversed normal asymmetry of the caudate
Poorer performance on the Stroop color–word test and Wisconsin Card Sorting Test (WCST)
Reversal of normal left-greater-than-right asymmetry
Greater disinhibition on the stroop and a higher incidence of loss of set on the WCST
Ability to name colors quickly compromised in the ADHD group
smaller volumes of white matter of the anterior–superior region
worse performance on rapid naming
Role in maintaining attention
Conclusion• ADHD is associated with globally decreased brain
volumes relative to age- and sex-matched typically developing controls
• structural neuroimaging literature implicates several key brain structures involved in ADHD
• Basal Ganglia are an important link in the circuits implicated in ADHD
• Caudate Nucleus, the volumetric abnormalities seem to be age-dependent
• Cerebellum's influence on cortico-striatal-thalamo-cortical (CSTC) which choose, initiate, and carry out complex motor and cognitive responses.
• Posterior–inferior Lobules of the Cerebellar Vermis differ from remaining cerebellar hemispheres and vermis in selectively containing dopamine-transporter-like immunore-active axons.
• Hypothesized role of dopamine in the pathophysiology of ADHD,
• Inconsistencies basal ganglia asymmetry> methodological differences and low statistical power
• Inattentive subtype of ADHD have a neural basis that is different from that of children with significant symptoms of hyperactivity and impulsivity