Brain developm adhd2


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Brain developm adhd2

  1. 1. Brain development and ADHD Author : Amy L. Krain, F. Xavier Castellanos Clinical Psychology Review 26 (2006) 433–444
  2. 2. ADHD characteristcs • excessive inattention, • hyperactivity, • impulsivity, either alone or in combination Neuropsychological 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
  3. 3. 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 ADHD and how specific phenotypes may be related to alterations in brain structure
  4. 4. 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
  5. 5. Anatomic MRI -Principle technology to study Pediatric Brain Advantage 1.Spacial resolution 2.No ionizing radiation Disadvantage 1.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.
  6. 6. Current methods Hand-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
  7. 7. 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 analysis Age related decrease-thalamus, lenticular neucleus Increase>lentricular size, after controlling TCV
  8. 8. 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
  9. 9. 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
  10. 10. Gray matter development More 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
  11. 11. 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
  12. 12. Symmetry in normal development Cerebral hemisphere Prefrontal Cortex Right > Left Left >Right Lateral Ventricle CSF volume Right>Left Left>Right Caudate Nucleus Lenticular Nucleus Putamen • Left sided • Right sided • Laterality
  13. 13. Neuroanatomical correlation in ADHD ADHD 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
  14. 14. 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 naïve 104 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 regionNo difference in Parietal,Temporal,Occipital region
  15. 15. 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
  16. 16. 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
  17. 17. 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- nglia+II
  18. 18. 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
  19. 19. 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
  20. 20. 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%
  21. 21. Cerebellum coordination of motor movements non-motor functions such as timing and attentional shifting through connections with frontal regionsTotal Volume smaller cerebellar hemispheric volumes (by up to 6%) sustained throughout adolescence Total Volume and Area Cerebellar Vermis and lobes remain significant even after adjusting 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
  22. 22. Gray and White matter Study > 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 in right side in the posterior cingulate gyrus, superior frontal gyrus, and putamen, and bilaterally in the globus pallidus in children 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
  23. 23. 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
  24. 24. Association between brain structure and functioning Behavioral 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 attention problems Semrud-Clikeman et al. (2000) smaller left caudate head and white matter volumes associated with higher Child Behavior Checklist (CBCL) Externalizing scores.
  25. 25. ADHD girls smaller volumes to be associated with greater symptom severity smaller total cerebral volume greater attention problems smaller posterior inferior vermal volume global functioning and CBCL anxiety- depression scores Gray matter density left occipital lobe Negatively correlated with inattention scores in children with ADHD Size of the rostral body of the corpus callosum Negatively correlated with parent and teacher ratings of impulsivity and hyperactivity in children with ADHD and controls
  26. 26. 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)
  27. 27. 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
  28. 28. 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