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White matter endophenotype candidates for ADHD: a diffusion imaging tractography study with sibling design

  • Huey-Ling Chiang (a1) (a2), Yung-Chin Hsu (a3) (a4), Chi-Yuan Shang (a1), Wen-Yih Isaac Tseng (a3) (a5) and Susan Shur-Fen Gau (a1) (a6)...

Abstract

Background

Brain structural alterations are frequently observed in probands with attention-deficit/hyperactivity disorder (ADHD). Here we examined the microstructural integrity of 76 white matter tracts among unaffected siblings of patients with ADHD to evaluate the potential familial risk and its association with clinical and neuropsychological manifestations.

Methods

The comparison groups included medication-naïve ADHD probands (n = 50), their unaffected siblings (n = 50) and typically developing controls (n = 50, age-and-sex matched with ADHD probands). Whole brain tractography was reconstructed automatically by tract-based analysis of diffusion spectrum imaging (DSI). Microstructural properties of white matter tracts were represented by the values of generalized fractional anisotropy (GFA), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD).

Results

Compared to the control group, ADHD probands showed higher AD values in the perpendicular fasciculus, superior longitudinal fasciculus I, corticospinal tract, and corpus callosum. The AD values of unaffected siblings were in the intermediate position between those of the ADHD and control groups. These AD values were significantly associated with ADHD symptoms, sustained attention and working memory, for all white matter tracks evaluated except for the perpendicular fasciculus. Higher FA and lower RD values in the right frontostriatal tract connecting ventrolateral prefrontal cortex (FS-VLPFC) were associated with better performance in spatial span only in the unaffected sibling group.

Conclusions

Abnormal AD values of specific white matter tracts among unaffected siblings of ADHD probands suggest the presence of familial risk in this population. The right FS-VLPFC may have a role in preventing the expression of the ADHD-related behavioral phenotype.

ClinicalTrials.gov number

NCT01682915

Copyright

Corresponding author

Author for correspondence: Susan Shur-Fen Gau, E-mail: gaushufe@ntu.edu.tw; and Wen-Yih Isaac Tseng, E-mail: wytseng@ntu.edu.tw

References

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Alexander, AL, Lee, JE, Lazar, M and Field, AS (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4, 316329.
Aoki, Y, Yoncheva, YN, Chen, B, Nath, T, Sharp, D, Lazar, M, Velasco, P, Milham, MP and Di Martino, A (2017) Association of white matter structure with autism spectrum disorder and attention-deficit/hyperactivity disorder. JAMA Psychiatry 74, 11201128.
Aoki, Y, Cortese, S and Castellanos, FX (2018) Research review: diffusion tensor imaging studies of attention-deficit/hyperactivity disorder: meta-analyses and reflections on head motion. Journal of Child Psychology and Psychiatry 59, 193202.
Ashburner, J and Friston, KJ (2011) Diffeomorphic registration using geodesic shooting and Gauss-Newton optimisation. Neuroimage 55, 954967.
Barber, AD, Jacobson, LA, Wexler, JL, Nebel, MB, Caffo, BS, Pekar, JJ and Mostofsky, SH (2015) Connectivity supporting attention in children with attention deficit hyperactivity disorder. NeuroImage: Clinical 7, 6881.
Basser, PJ, Mattiello, J and LeBihan, D (1994) Estimation of the effective self-diffusion tensor from the NMR spin echo. Journal of Magnetic Resonance, Series B 103, 247254.
Bralten, J, Greven, CU, Franke, B, Mennes, M, Zwiers, MP, Rommelse, NN, Hartman, C, van der Meer, D, O'Dwyer, L, Oosterlaan, J, Hoekstra, PJ, Heslenfeld, D, Arias-Vasquez, A and Buitelaar, JK (2016) Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings. Journal of Psychiatry & Neuroscience 41, 272279.
Casals, M, Girabent-Farres, M and Carrasco, JL (2014) Methodological quality and reporting of generalized linear mixed models in clinical medicine (2000–2012): a systematic review. PLoS One 9, e112653.
Chamberlain, SR, Robbins, TW, Winder-Rhodes, S, Muller, U, Sahakian, BJ, Blackwell, AD and Barnett, JH (2011) Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery. Biological Psychiatry 69, 11921203.
Chen, YJ, Lo, YC, Hsu, YC, Fan, CC, Hwang, TJ, Liu, CM, Chien, YL, Hsieh, MH, Liu, CC, Hwu, HG and Tseng, WY (2015) Automatic whole brain tract-based analysis using predefined tracts in a diffusion spectrum imaging template and an accurate registration strategy. Human Brain Mapping 36, 34413458.
Chen, YL, Shen, LJ and Gau, SS (2017) The mandarin version of the kiddie-schedule for affective disorders and Schizophrenia-epidemiological version for DSM-5 - a psychometric study. Journal of the Formosan Medical Association 116, 671678.
Chiang, HL, Chen, YJ, Lo, YC, Tseng, WY and Gau, SS (2015) Altered white matter tract property related to impaired focused attention, sustained attention, cognitive impulsivity and vigilance in attention-deficit/ hyperactivity disorder. Journal of Psychiatry & Neuroscience 40, 325335.
Chiang, HL, Chen, YJ, Shang, CY, Tseng, WY and Gau, SS (2016) Different neural substrates for executive functions in youths with ADHD: a diffusion spectrum imaging tractography study. Psychological Medicine 46, 12251238.
Chiang, HL, Chen, YJ, Lin, HY, Tseng, WI and Gau, SS (2017) Disorder-specific alteration in white matter structural property in adults with autism spectrum disorder relative to adults with adhd and adult controls. Human Brain Mapping 38, 384395.
Chmielewski, WX, Muckschel, M, Dippel, G and Beste, C (2016) Concurrent information affects response inhibition processes via the modulation of theta oscillations in cognitive control networks. Brain Structure & Function 221, 39493961.
Cohen-Adad, J, El Mendili, MM, Lehericy, S, Pradat, PF, Blancho, S, Rossignol, S and Benali, H (2011) Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI. Neuroimage 55, 10241033.
Davey, J, Thompson, HE, Hallam, G, Karapanagiotidis, T, Murphy, C, De Caso, I, Krieger-Redwood, K, Bernhardt, BC, Smallwood, J and Jefferies, E (2016) Exploring the role of the posterior middle temporal gyrus in semantic cognition: integration of anterior temporal lobe with executive processes. Neuroimage 137, 165177.
Duan, K, Chen, J, Calhoun, VD, Lin, D, Jiang, W, Franke, B, Buitelaar, JK, Hoogman, M, Arias-Vasquez, A, Turner, JA and Liu, J (2018) Neural correlates of cognitive function and symptoms in attention-deficit/hyperactivity disorder in adults. NeuroImage: Clinical 19, 374383.
Fassbender, C and Schweitzer, JB (2006) Is there evidence for neural compensation in attention deficit hyperactivity disorder? A review of the functional neuroimaging literature. Clinical Psychology Review 26, 445465.
Francx, W, Zwiers, MP, Mennes, M, Oosterlaan, J, Heslenfeld, D, Hoekstra, PJ, Hartman, CA, Franke, B, Faraone, SV, O'Dwyer, L and Buitelaar, JK (2015) White matter microstructure and developmental improvement of hyperactive/impulsive symptoms in attention-deficit/hyperactivity disorder. Journal of Child Psychology and Psychiatry 56, 12891297.
Gau, SS and Huang, WL (2014) Rapid visual information processing as a cognitive endophenotype of attention deficit hyperactivity disorder. Psychological Medicine 44, 435446.
Gau, SS and Shang, CY (2010) Executive functions as endophenotypes in ADHD: evidence from the Cambridge Neuropsychological Test Battery (CANTAB). Journal of Child Psychology and Psychiatry 51, 838849.
Gau, SF and Soong, WT (1999) Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a case-control study. Australian & New Zealand Journal of Psychiatry 33, 734739.
Gau, SS, Chong, MY, Chen, TH and Cheng, AT (2005) A 3-year panel study of mental disorders among adolescents in Taiwan. American Journal of Psychiatry 162, 13441350.
Gau, SS, Shang, CY, Liu, SK, Lin, CH, Swanson, JM, Liu, YC and Tu, CL (2008) Psychometric properties of the Chinese version of the Swanson, Nolan, and Pelham, version IV scale - parent form. International Journal of Methods in Psychiatric Research 17, 3544.
Glahn, DC, Knowles, EE, McKay, DR, Sprooten, E, Raventos, H, Blangero, J, Gottesman, II and Almasy, L (2014) Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 165B, 122130.
Gottesman, II and Gould, TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636645.
Greven, CU, Bralten, J, Mennes, M, O'Dwyer, L, van Hulzen, KJ, Rommelse, N, Schweren, LJ, Hoekstra, PJ, Hartman, CA, Heslenfeld, D, Oosterlaan, J, Faraone, SV, Franke, B, Zwiers, MP, Arias-Vasquez, A and Buitelaar, JK (2015) Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings. JAMA Psychiatry 72, 490499.
Han, GT, Chen, YL, Tsai, FJ and Gau, SS (2018) Temporal and reciprocal relations between ADHD symptoms and emotional problems in school-age children. Journal of Attention Disorders, doi: 10.1177/1087054718787891.
Hsu, YC and Tseng, WY (2018) An efficient regularization method for diffusion MAP-MRI estimation. 2018 ISMRM-ESMRMB Joint Annual Meeting.
Hsu, YC, Hsu, CH and Tseng, WY (2012) A large deformation diffeomorphic metric mapping solution for diffusion spectrum imaging datasets. NeuroImage 63, 818834.
Hsu, YC, Lo, YC, Chen, YJ, Wedeen, VJ and Tseng, WY (2015) NTU-DSI-122: a diffusion spectrum imaging template with high anatomical matching to the ICBM-152 space. Human Brain Mapping 36, 35283541.
Jones, DK, Knosche, TR and Turner, R (2013) White matter integrity, fiber count, and other fallacies: the do's and don'ts of diffusion MRI. Neuroimage 73, 239254.
Kuo, LW, Chen, JH, Wedeen, VJ and Tseng, WY (2008) Optimization of diffusion spectrum imaging and q-ball imaging on clinical MRI system. Neuroimage 41, 718.
Larsson, H, Chang, Z, D'Onofrio, BM and Lichtenstein, P (2014) The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychological Medicine 44, 22232229.
Lawrence, KE, Levitt, JG, Loo, SK, Ly, R, Yee, V, O'Neill, J, Alger, J and Narr, KL (2013) White matter microstructure in subjects with attention-deficit/hyperactivity disorder and their siblings. Journal of the American Academy of Child and Adolescent Psychiatry 52, 431440.e434.
Lin, CP, Wedeen, VJ, Chen, JH, Yao, C and Tseng, WY (2003) Validation of diffusion spectrum magnetic resonance imaging with manganese-enhanced rat optic tracts and ex vivo phantoms. Neuroimage 19, 482495.
Luciana, M and Nelson, CA (1998) The functional emergence of prefrontally-guided working memory systems in four- to eight-year-old children. Neuropsychologia 36, 273293.
Mous, SE, Muetzel, RL, El Marroun, H, Polderman, TJ, van der Lugt, A, Jaddoe, VW, Hofman, A, Verhulst, FC, Tiemeier, H, Posthuma, D and White, T (2014) Cortical thickness and inattention/hyperactivity symptoms in young children: a population-based study. Psychological Medicine 44, 32033213.
Mulder, MJ, Baeyens, D, Davidson, MC, Casey, BJ, van den Ban, E, van Engeland, H and Durston, S (2008) Familial vulnerability to ADHD affects activity in the cerebellum in addition to the prefrontal systems. Journal of the American Academy of Child and Adolescent Psychiatry 47, 6875.
Muster, R, Choudhury, S, Sharp, W, Kasparek, S, Sudre, G and Shaw, P (2019) Mapping the neuroanatomic substrates of cognition in familial attention deficit hyperactivity disorder. Psychological Medicine 49, 18.
Orinstein, AJ and Stevens, MC (2014) Brain activity in predominantly-inattentive subtype attention-deficit/hyperactivity disorder during an auditory oddball attention task. Psychiatry Research 223, 121128.
Ozarslan, E, Koay, CG, Shepherd, TM, Komlosh, ME, Irfanoglu, MO, Pierpaoli, C and Basser, PJ (2013) Mean apparent propagator (MAP) MRI: a novel diffusion imaging method for mapping tissue microstructure. Neuroimage 78, 1632.
Parlatini, V, Radua, J, Dell'Acqua, F, Leslie, A, Simmons, A, Murphy, DG, Catani, M and Thiebaut de Schotten, M (2017) Functional segregation and integration within fronto-parietal networks. Neuroimage 146, 367375.
Pironti, VA, Lai, MC, Muller, U, Dodds, CM, Suckling, J, Bullmore, ET and Sahakian, BJ (2014) Neuroanatomical abnormalities and cognitive impairments are shared by adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives. Biological Psychiatry 76, 639647.
Reese, TG, Heid, O, Weisskoff, RM and Wedeen, VJ (2003) Reduction of eddy-current-induced distortion in diffusion MRI using a twice-refocused spin echo. Magnetic Resonance in Medicine 49, 177182.
Shang, CY, Lin, HY, Tseng, WY and Gau, SS (2018) A haplotype of the dopamine transporter gene modulates regional homogeneity, gray matter volume, and visual memory in children with attention-deficit/hyperactivity disorder. Psychological Medicine 48, 25302540.
Shaw, P, Eckstrand, K, Sharp, W, Blumenthal, J, Lerch, JP, Greenstein, D, Clasen, L, Evans, A, Giedd, J and Rapoport, JL (2007) Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proceedings of the National Academy of Sciences of the United States of America 104, 1964919654.
Simmonds, DJ, Hallquist, MN, Asato, M and Luna, B (2014) Developmental stages and sex differences of white matter and behavioral development through adolescence: a longitudinal diffusion tensor imaging (DTI) study. Neuroimage 92, 356368.
Song, SK, Sun, SW, Ramsbottom, MJ, Chang, C, Russell, J and Cross, AH (2002) Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17, 14291436.
Streiner, DL and Norman, GR (2011) Correction for multiple testing: is there a resolution? Chest 140, 1618.
Sudre, G, Choudhuri, S, Szekely, E, Bonner, T, Goduni, E, Sharp, W and Shaw, P (2017) Estimating the heritability of structural and functional brain connectivity in families affected by attention-deficit/hyperactivity disorder. JAMA Psychiatry 74, 7684.
Tamm, L, Barnea-Goraly, N and Reiss, AL (2012) Diffusion tensor imaging reveals white matter abnormalities in attention-deficit/hyperactivity disorder. Psychiatry Research 202, 150154.
Tomasino, B and Gremese, M (2016) The cognitive side of M1. Frontiers in Human Neuroscience 10, 298.
Tzourio-Mazoyer, N, Landeau, B, Papathanassiou, D, Crivello, F, Etard, O, Delcroix, N, Mazoyer, B and Joliot, M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15, 273289.
van Ewijk, H, Heslenfeld, DJ, Zwiers, MP, Faraone, SV, Luman, M, Hartman, CA, Hoekstra, PJ, Franke, B, Buitelaar, JK and Oosterlaan, J (2014) Different mechanisms of white matter abnormalities in attention-deficit/hyperactivity disorder: a diffusion tensor imaging study. Journal of the American Academy of Child and Adolescent Psychiatry 53, 790799.e3.
Vangberg, TR, Skranes, J, Dale, AM, Martinussen, M, Brubakk, AM and Haraldseth, O (2006) Changes in white matter diffusion anisotropy in adolescents born prematurely. Neuroimage 32, 15381548.
van Rooij, D, Hartman, CA, Mennes, M, Oosterlaan, J, Franke, B, Rommelse, N, Heslenfeld, D, Faraone, SV, Buitelaar, JK and Hoekstra, PJ (2015 a) Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings. NeuroImage: Clinical 7, 325335.
van Rooij, D, Hoekstra, PJ, Mennes, M, von Rhein, D, Thissen, AJ, Heslenfeld, D, Zwiers, MP, Faraone, SV, Oosterlaan, J, Franke, B, Rommelse, N, Buitelaar, JK and Hartman, CA (2015 b) Distinguishing adolescents with ADHD from their unaffected siblings and healthy comparison subjects by neural activation patterns during response inhibition. American Journal of Psychiatry 172, 674683.
Veazie, PJ (2006) When to combine hypotheses and adjust for multiple tests. Health Services Research 41, 804818.
Waddell, J and McCarthy, MM (2012) Sexual differentiation of the brain and ADHD: what is a sex difference in prevalence telling us? Current Topics in Behavioral Neurosciences 9, 341360.
Wedeen, VJ, Wang, RP, Schmahmann, JD, Benner, T, Tseng, WY, Dai, G, Pandya, DN, Hagmann, P, D'Arceuil, H and de Crespigny, AJ (2008) Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers. Neuroimage 41, 12671277.

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