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Effects of the dopamine transporter gene on striatal functional connectivity in youths with attention-deficit/hyperactivity disorder

Published online by Cambridge University Press:  07 January 2020

Chi-Yung Shang ,
Hsiang-Yuan Lin  and
Susan Shur-Fen Gau Open the ORCID record for Susan Shur-Fen Gau [Opens in a new window]
Chi-Yung Shang
Affiliation:
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
Hsiang-Yuan Lin
Affiliation:
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
Susan Shur-Fen Gau*
Affiliation:
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan Graduate Institute of Brain and Mind Sciences and Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
*
Author for correspondence: Susan Shur-Fen Gau, E-mail: [email protected]
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Abstract

Background

The dopamine transporter gene (DAT1), striatal network dysfunction, and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine the effects of the DAT1 rs27048 (C)/rs429699 (T) haplotype on striatal functional connectivity and visual memory performance in youths with ADHD.

Method

After excluding those who had excessive head motion, a total of 96 drug-naïve youths with ADHD and 114 typically developing (TD) youths were assessed with the resting-state functional magnetic resonance imaging and the delayed matching to sample (DMS) task for visual memory. We examined the effects of ADHD, DAT1 CT haplotype, and the ADHD × CT haplotype interaction on the functional connectivity of five striatal seeds. We also correlated visual memory performance with the functional connectivity of striatal subregions, which showed significant diagnosis × genotype interactions.

Results

Compared with TD youths, ADHD youths showed significant hypoconnectivity of the left dorsal caudate (DC) with bilateral sensorimotor clusters. Significant diagnosis × genotype interactions were found in the connectivity between the left DC and the right sensorimotor cluster, and between the right DC and the left dorsolateral prefrontal/bilateral anterior cingulate clusters. Furthermore, the connectivity of the left DC showing significant diagnosis × genotype interactions was associated with DMS performance in youths with ADHD who carried the DAT1 CT haplotype.

Conclusions

A novel gene-brain-behavior association between the left DC functional connectivity and visual memory performance in ADHD youths with the DAT1 rs27048 (C)/rs429699 (T) haplotype suggests a differential effect of DAT1 genotype altering specific brain function causing neuropsychological dysfunction in ADHD.

Keywords

Attention deficit hyperactivity disorderdopamine transporter genefunctional connectivityresting brain imagingstriatumvisual memory
Type
Original Article
Information
Psychological Medicine , Volume 51 , Issue 5 , April 2021 , pp. 835 - 845
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Copyright
Copyright © Cambridge University Press 2020

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References

Barnett, R., Maruff, P., & Vance, A. (2009). Neurocognitive function in attention-deficit-hyperactivity disorder with and without comorbid disruptive behaviour disorders. The Australian and New Zealand Journal of Psychiatry, 43, 722–730.CrossRefGoogle ScholarPubMed
Bartres-Faz, D., Junque, C., Serra-Grabulosa, J. M., Lopez-Alomar, A., Moya, A., Bargallo, N., … Clemente, I. C. (2002). Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects. Neuroreport, 13, 1121–1125.CrossRefGoogle ScholarPubMed
Behzadi, Y., Restom, K., Liau, J., & Liu, T. T. (2007). A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. NeuroImage, 37, 90–101.CrossRefGoogle ScholarPubMed
Cao, Q., Zang, Y., Sun, L., Sui, M., Long, X., Zou, Q., & Wang, Y. (2006). Abnormal neural activity in children with attention deficit hyperactivity disorder: A resting-state functional magnetic resonance imaging study. Neuroreport, 17, 1033–1036.CrossRefGoogle ScholarPubMed
Cao, X., Cao, Q., Long, X., Sun, L., Sui, M., Zhu, C., … Wang, Y. (2009). Abnormal resting-state functional connectivity patterns of the putamen in medication-naive children with attention deficit hyperactivity disorder. Brain Research, 1303, 195–206.CrossRefGoogle ScholarPubMed
Castellanos, F. X., & Proal, E. (2012). Large-scale brain systems in ADHD: Beyond the prefrontal-striatal model. Trends in Cognitive Sciences, 16, 17–26.CrossRefGoogle ScholarPubMed
Chen, X., Lu, B., & Yan, C. G. (2018). Reproducibility of R-fMRI metrics on the impact of different strategies for multiple comparison correction and sample sizes. Human Brain Mapping, 39, 300–318.CrossRefGoogle ScholarPubMed
Davis, J. D., Filoteo, J. V., Kesner, R. P., & Roberts, J. W. (2003). Recognition memory for hand positions and spatial locations in patients with Huntington's disease: Differential visuospatial memory impairment? Cortex, 39, 239–253.CrossRefGoogle ScholarPubMed
Di Martino, A., Kelly, C., Grzadzinski, R., Zuo, X. N., Mennes, M., Mairena, M. A., … Milham, M. P. (2011). Aberrant striatal functional connectivity in children with autism. Biological Psychiatry, 69, 847–856.CrossRefGoogle ScholarPubMed
Di Martino, A., Scheres, A., Margulies, D. S., Kelly, A. M., Uddin, L. Q., Shehzad, Z., … Milham, M. P. (2008). Functional connectivity of human striatum: A resting state FMRI study. Cerebral Cortex, 18, 2735–2747.CrossRefGoogle ScholarPubMed
Draganski, B., Kherif, F., Kloppel, S., Cook, P. A., Alexander, D. C., Parker, G. J., … Frackowiak, R. S. (2008). Evidence for segregated and integrative connectivity patterns in the human Basal Ganglia. The Journal of Neuroscience, 28, 7143–7152.CrossRefGoogle ScholarPubMed
Egerhazi, A., Berecz, R., Bartok, E., & Degrell, I. (2007). Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease. Progress in Neuropsychopharmacology and Biological Psychiatry, 31, 746–751.CrossRefGoogle ScholarPubMed
Eklund, A., Nichols, T. E., & Knutsson, H. (2016). Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proceedings of the National Academy of Sciences of the United States of America, 113, 7900–7905.CrossRefGoogle ScholarPubMed
Fair, D. A., Nigg, J. T., Iyer, S., Bathula, D., Mills, K. L., Dosenbach, N. U., … Milham, M. P. (2012). Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data. Frontiers in Systems Neuroscience, 6, 80.Google ScholarPubMed
Faraone, S. V., Perlis, R. H., Doyle, A. E., Smoller, J. W., Goralnick, J. J., Holmgren, M. A., & Sklar, P. (2005). Molecular genetics of attention-deficit/hyperactivity disorder. Biological Psychiatry, 57, 1313–1323.CrossRefGoogle ScholarPubMed
FitzGerald, T. H., Friston, K. J., & Dolan, R. J. (2012). Action-specific value signals in reward-related regions of the human brain. The Journal of Neuroscience, 32, 16417–16423.CrossRefGoogle ScholarPubMed
Gau, S. S., Chong, M. Y., Chen, T. H., & Cheng, A. T. (2005). A 3-year panel study of mental disorders among adolescents in Taiwan. American Journal of Psychiatry, 162, 1344–1350.CrossRefGoogle ScholarPubMed
Gau, S. S., Shang, C. Y., Liu, S. K., Lin, C. H., Swanson, J. M., Liu, Y. C., & Tu, C. L. (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, 35–44.CrossRefGoogle ScholarPubMed
Gerardin, E., Pochon, J. B., Poline, J. B., Tremblay, L., Van de Moortele, P. F., Levy, R., … Lehericy, S. (2004). Distinct striatal regions support movement selection, preparation and execution. Neuroreport, 15, 2327–2331.CrossRefGoogle ScholarPubMed
Gizer, I. R., Ficks, C., & Waldman, I. D. (2009). Candidate gene studies of ADHD: A meta-analytic review. Human Genetics, 126, 51–90.CrossRefGoogle ScholarPubMed
Gordon, E. M., Devaney, J. M., Bean, S., & Vaidya, C. J. (2015). Resting-state striato-frontal functional connectivity is sensitive to DAT1 genotype and predicts executive function. Cerebral Cortex, 25, 336–345.CrossRefGoogle ScholarPubMed
Harmer, C. J., McTavish, S. F., Clark, L., Goodwin, G. M., & Cowen, P. J. (2001). Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology, 154, 105–111.CrossRefGoogle ScholarPubMed
Hazy, T. E., Frank, M. J., & O'Reilly, R. C. (2007). Towards an executive without a homunculus: Computational models of the prefrontal cortex/basal ganglia system. Philosophical Transactions of the Royal Society of London, 362, 1601–1613.CrossRefGoogle ScholarPubMed
Hong, S. B., Harrison, B. J., Fornito, A., Sohn, C. H., Song, I. C., & Kim, J. W. (2015). Functional dysconnectivity of corticostriatal circuitry and differential response to methylphenidate in youth with attention-deficit/hyperactivity disorder. Journal of Psychiatry and Neuroscience, 40, 46–57.Google ScholarPubMed
Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage, 17, 825–841.CrossRefGoogle ScholarPubMed
Jokinen, P., Bruck, A., Aalto, S., Forsback, S., Parkkola, R., & Rinne, J. O. (2009). Impaired cognitive performance in Parkinson's disease is related to caudate dopaminergic hypofunction and hippocampal atrophy. Parkinsonism and Related Disorders, 15, 88–93.CrossRefGoogle ScholarPubMed
Klein, M., Onnink, M., van Donkelaar, M., Wolfers, T., Harich, B., Shi, Y., … Franke, B. (2017). Brain imaging genetics in ADHD and beyond – mapping pathways from gene to disorder at different levels of complexity. Neuroscience and Biobehavioral Reviews, 80, 115–155.CrossRefGoogle ScholarPubMed
Mennes, M., Vega Potler, N., Kelly, C., Di Martino, A., Castellanos, F. X., & Milham, M. P. (2011). Resting state functional connectivity correlates of inhibitory control in children with attention-deficit/hyperactivity disorder. Frontiers in Psychiatry, 2, 83.Google ScholarPubMed
Mier, D., Kirsch, P., & Meyer-Lindenberg, A. (2010). Neural substrates of pleiotropic action of genetic variation in COMT: A meta-analysis. Molecular Psychiatry, 15, 918–927.CrossRefGoogle ScholarPubMed
Mostofsky, S. H., Newschaffer, C. J., & Denckla, M. B. (2003). Overflow movements predict impaired response inhibition in children with ADHD. Perceptual and Motor Skills, 97, 1315–1331.CrossRefGoogle ScholarPubMed
Mostofsky, S. H., & Simmonds, D. J. (2008). Response inhibition and response selection: Two sides of the same coin. Journal of Cognitive Neuroscience, 20, 751–761.CrossRefGoogle ScholarPubMed
O'Doherty, J., Dayan, P., Schultz, J., Deichmann, R., Friston, K., & Dolan, R. J. (2004). Dissociable roles of ventral and dorsal striatum in instrumental conditioning. Science, 304, 452–454.CrossRefGoogle ScholarPubMed
Oldehinkel, M., Beckmann, C. F., Pruim, R. H., van Oort, E. S., Franke, B., Hartman, C. A., … Mennes, M. (2016). Attention-deficit/hyperactivity disorder symptoms coincide with altered striatal connectivity. Biological Psychiatry : Cognitive Neuroscience and Neuroimaging, 1, 353–363.Google ScholarPubMed
Pamplona, G. S., Santos Neto, G. S., Rosset, S. R., Rogers, B. P., & Salmon, C. E. (2015). Analyzing the association between functional connectivity of the brain and intellectual performance. Frontiers in Human Neuroscience, 9, 61.CrossRefGoogle ScholarPubMed
Posner, J., Park, C., & Wang, Z. (2014). Connecting the dots: A review of resting connectivity MRI studies in attention-deficit/hyperactivity disorder. Neuropsychology Review, 24, 3–15.CrossRefGoogle ScholarPubMed
Posner, J., Rauh, V., Gruber, A., Gat, I., Wang, Z., & Peterson, B. S. (2013). Dissociable attentional and affective circuits in medication-naive children with attention-deficit/hyperactivity disorder. Psychiatry Research, 213, 24–30.CrossRefGoogle ScholarPubMed
Pruim, R. H., Mennes, M., van Rooij, D., Llera, A., Buitelaar, J. K., & Beckmann, C. F. (2015). ICA-AROMA: A robust ICA-based strategy for removing motion artifacts from fMRI data. NeuroImage, 112, 267–277.CrossRefGoogle ScholarPubMed
Rhodes, S. M., Coghill, D. R., & Matthews, K. (2004). Methylphenidate restores visual memory, but not working memory function in attention deficit-hyperkinetic disorder. Psychopharmacology, 175, 319–330.CrossRefGoogle Scholar
Rhodes, S. M., Coghill, D. R., & Matthews, K. (2005). Neuropsychological functioning in stimulant-naive boys with hyperkinetic disorder. Psychological Medicine, 35, 1109–1120.CrossRefGoogle ScholarPubMed
Robinson, J. L., Laird, A. R., Glahn, D. C., Blangero, J., Sanghera, M. K., Pessoa, L., … Fox, P. T. (2012). The functional connectivity of the human caudate: An application of meta-analytic connectivity modeling with behavioral filtering. NeuroImage, 60, 117–129.CrossRefGoogle ScholarPubMed
Rodi, C. P., Darnhofer-Patel, B., Stanssens, P., Zabeau, M., & van den Boom, D. (2002). A strategy for the rapid discovery of disease markers using the MassARRAY system. Biotechniques 62–66(Suppl), 68–69.Google Scholar
Rubia, K., Halari, R., Cubillo, A., Mohammad, A. M., Brammer, M., & Taylor, E. (2009). Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naive children with ADHD during a rewarded continuous performance task. Neuropharmacology, 57, 640–652.CrossRefGoogle ScholarPubMed
Sambataro, F., Podell, J. E., Murty, V. P., Das, S., Kolachana, B., Goldberg, T. E., … Mattay, V. S. (2015). A variable number of tandem repeats in the 3′-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span. The European Journal of Neuroscience, 42, 1912–1918.CrossRefGoogle ScholarPubMed
Shang, C. Y., Chiang, H. L., & Gau, S. S. (2015). A haplotype of the norepinephrine transporter gene (SLC6A2) is associated with visual memory in attention-deficit/hyperactivity disorder. Progress in Neuropsychopharmacology and Biological Psychiatry, 58, 89–96.CrossRefGoogle ScholarPubMed
Shang, C. Y., & Gau, S. S. (2011). Visual memory as a potential cognitive endophenotype of attention deficit hyperactivity disorder. Psychological Medicine, 41, 2603–2614.CrossRefGoogle ScholarPubMed
Shang, C. Y., & Gau, S. S. (2014). Association between the DAT1 gene and spatial working memory in attention deficit hyperactivity disorder. The International Journal of Neuropsychopharmacology, 17, 9–21.CrossRefGoogle ScholarPubMed
Shang, C. Y., Gau, S. S., Liu, C. M., & Hwu, H. G. (2011). Association between the dopamine transporter gene and the inattentive subtype of attention deficit hyperactivity disorder in Taiwan. Progress in Neuropsychopharmacology and Biological Psychiatry, 35, 421–428.CrossRefGoogle ScholarPubMed
Shang, C. Y., Wu, Y. H., Gau, S. S., & Tseng, W. Y. (2013). Disturbed microstructural integrity of the frontostriatal fiber pathways and executive dysfunction in children with attention deficit hyperactivity disorder. Psychological Medicine, 43, 1093–1107.CrossRefGoogle ScholarPubMed
Song, M., Zhou, Y., Li, J., Liu, Y., Tian, L., Yu, C., & Jiang, T. (2008). Brain spontaneous functional connectivity and intelligence. NeuroImage, 41, 1168–1176.CrossRefGoogle ScholarPubMed
Swanson, J. M., Kraemer, H. C., Hinshaw, S. P., Arnold, L. E., Conners, C. K., Abikoff, H. B., … Wu, M. (2001). Clinical relevance of the primary findings of the MTA: Success rates based on severity of ADHD and ODD symptoms at the end of treatment. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 168–179.CrossRefGoogle Scholar
Vilor-Tejedor, N., Caceres, A., Pujol, J., Sunyer, J., & Gonzalez, J. R. (2017). Imaging genetics in attention-deficit/hyperactivity disorder and related neurodevelopmental domains: State of the art. Brain Imaging and Behavior, 11, 1922–1931.CrossRefGoogle ScholarPubMed
von Rhein, D., Oldehinkel, M., Beckmann, C. F., Oosterlaan, J., Heslenfeld, D., Hartman, C. A., … Mennes, M. (2016). Aberrant local striatal functional connectivity in attention-deficit/hyperactivity disorder. Journal of Child Psychology and Psychiatry, 57, 697–705.CrossRefGoogle ScholarPubMed
Wahlstedt, C., Thorell, L. B., & Bohlin, G. (2009). Heterogeneity in ADHD: Neuropsychological pathways, comorbidity and symptom domains. Journal of Abnormal Child Psychology, 37, 551–564.CrossRefGoogle ScholarPubMed
Willcutt, E. G., Doyle, A. E., Nigg, J. T., Faraone, S. V., & Pennington, B. F. (2005). Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review. Biological Psychiatry, 57, 1336–1346.CrossRefGoogle ScholarPubMed
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