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