Structural and Functional Connectivity of Frontostriatal and Frontoparietal Networks as Endophenotypes of ADHD
Condition: Attention Deficit/Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Observational

Summary: 
      Attention deficit/hyperactivity disorder (ADHD) is a common, impairing, clinically and
      genetically heterogeneous neuropsychiatric disorder with lifelong executive dysfunctions. The
      ultimate goal of this 3-year case-control imaging genomic study with unaffected siblings and
      typically developing (TD) children as controls is to identify useful imaging endophenotype
      for ADHD by investigating the structural connectivity, as assessed by diffusion spectrum
      imaging (DSI), and functional connectivity, as assessed by resting-state fMRI (rsfMRI) of
      brain regions related to cognitive/executive controls with regards to the ADHD status and the
      presence of dopamine transporter gene variants (DAT1).

      Specific Aims:

        1. to validate the executive functions, visuospatial memory, and structural and functional
           connectivity in frontostriatal, and frontoparietal circuitries as effective
           neurocognitive endophenotypes;

        2. to correlate the data from structural and functional connectivity, neuropsychology, and
           ADHD core symptoms stratifying by the presence of ADHD, proband-unaffected sibling
           dyads, and the presence of DAT1 variant; and

        3. To investigate reported candidate genes, in addition to DAT1 variant, related to
           dopamine and noradrenergic neurotransmitter systems in the association with
           neurocognitive endophenotypes such as DRD1, DRD2, DRD4, DRD5, DBH, MAO-A, ADRA2A,
           ADRA2C, NET, and COMT.
    

Detailed description: 
      The sample (n=240, 8 groups, ages 10-20, IQ > 80) consists of (1) 30 ADHD probands with DAT1
      variants, (2) 30 same-sex unaffected siblings, (3) 30 ADHD probands without DAT1 gene
      variants, who were age-, sex-, and IQ-matched to Group 1, (4) 30 same-sex unaffected siblings
      of Group 3, (5) 30 age-, sex- and IQ-matched TD controls for each of 4 groups (Groups 1, 2, 3
      & 4).

      The assessments include psychiatric interviews, self-administered questionnaires (CBCL and
      SNAP-IV for ADHD and behavioral problems; the SAICA for school and social function),
      neurocognitive assessments (WISC-III-R or WAIS-III for intelligence, Conner's CPT for
      sustained attention, inhibition, and vigilance, CANTAB for executive functions and
      visuo-spatial memory), and MRI assessments (Structural MRI, DSI and rsfMRI).

      Brain Imaging: (1) Structural MRI (T1- and T2-weighted images), DSI and rsfMRI data will be
      acquired on a 3T MRI system with a 32-channel head coil. DSI employs a pulsed-gradient
      spin-echo echo planar imaging (EPI) sequence by applying 102 diffusion gradient vectors and
      the maximum diffusion sensitivity = 4000 s/mm2, and rsfMRI is a 6-minute scan using a
      gradient-echo EPI sequence with 180 volumes. (2) Structural connectivity analysis: DSI
      tractography will be performed using in-house software (DSI studio,
      http://dsi-studio.labsolver.org/Home). Tracts-of-interest in the frontostriatal circuit and
      the frontoparietal circuit will be identified, and tract-specific analysis will be used to
      analyze the microstructural integrity along individual tract bundles. (3) Functional
      connectivity analysis: SPM8 program and in-house MATLAB codes will be used for analyses of
      rsfMRI data. Region-of-interests (ROIs) will be placed in the nodes of the corresponding
      circuits according to an anatomical template (WFU_PickAtlas 3.03). These ROIs will serve for
      tract determination in the tractography procedure and for seed regions in which BOLD signals
      are extracted for regression analysis among nodes.
    

Observational model: Other
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        The sample (n=240, 8 groups, ages 10-20, IQ > 80) consists of (1) 30 ADHD probands with
        DAT1 variants, (2) 30 same-sex unaffected siblings, (3) 30 ADHD probands without DAT1 gene
        variants, who were age-, sex-, and IQ-matched to Group 1, (4) 30 same-sex unaffected
        siblings of Group 3, (5) 30 age-, sex- and IQ-matched TD controls for each of 4 groups
        (Groups 1, 2, 3 & 4).
      
Keywords: ADHD; endophenotype; executive function; diffusion spectrum imaging; resting-state fMRI; frontostriatal and frontoparietal circuitries; DAT1