CoChat
Sign Up
Cited by 42Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorGenetics and Neurodevelopmental Disorders

Why is there selective subcortical vulnerability in ADHD? Clues from postmortem brain gene expression data

Open access
Hess, J L, Akutagava-Martins, G C, Patak, J D, Glatt, S J, Faraone, S V·2018·Molecular Psychiatry
DOI 10.1038/mp.2017.242PMC PMC6985986
Open this paper in CoChat — free account

Abstract

Sub-cortical volumetric differences were associated with attention-deficit/hyperactivity disorder (ADHD) in a recent multi-site, mega-analysis of 1713 ADHD persons and 1529 controls. As there was a wide range of effect sizes among the sub-cortical volumes, it is possible that selective neuronal vulnerability has a role in these volumetric losses. To address this possibility, we used data from Allen Brain Atlas to investigate variability in gene expression profiles between subcortical regions of typically developing brains. We tested the hypothesis that the expression of genes in a set of curated ADHD candidate genes and five a priori selected, biological pathways would be associated with the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) findings. Across the subcortical regions studied by ENIGMA, gene expression profiles for three pathways were significantly correlated with ADHD-associated volumetric reductions: apoptosis, oxidative stress and autophagy. These correlations were strong and significant for children with ADHD, but not for adults. Although preliminary, these data suggest that variability of structural brain anomalies in ADHD can be explained, in part, by the differential vulnerability of these regions to mechanisms mediating apoptosis, oxidative stress and autophagy.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/mp.2017.242

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. [2]Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for attention-deficit hyperactivity disorder. Acta Pediatrica 2007; 96(9): 1269– 1274. 17718779
  2. [3]Rubia K, Alegria AA, Brinson H. Brain abnormalities in attention-deficit hyperactivity disorder: a review. Rev Neurol 2014; 58 Suppl 1: S3– 16. 25252664
  3. [5]Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies. J Clin Psychiatry 2013; 74(9): 902– 917. 24107764 PMC3801446
  4. [6]Hoogman M, Bralten J, Hibar DP, Mennes M, Zwiers MP, Schweren LS Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry 2017. PMC5933934 28219628
  5. [7]Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2010; 2: 12. 20552050 PMC2874397
  6. [8]Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 2011; 71(1): 35– 48. 21745636
  7. [9]Roselli F, Caroni P. From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases. Neuron 2015; 85(5): 901– 910. 25741719
  8. [10]Joseph N, Zhang-James Y, Perl A, Faraone SV. Oxidative Stress and Attention Deficit Hyperactivity Disorder: A Meta-Analysis J Atten Disord 2015; 19(11): 915– 924. 24232168 PMC5293138
  9. [11]Reus GZ, Scaini G, Jeremias GC, Furlanetto CB, Morais MO, Mello-Santos LM Brain apoptosis signaling pathways are regulated by methylphenidate treatment in young and adult rats. Brain Res 2014; 1583: 269– 276. 25128604
  10. [12]Thapar A, Martin J, Mick E, Arias Vasquez A, Langley K, Scherer SW Psychiatric gene discoveries shape evidence on ADHD’s biology. Mol Psychiatry 2016; 21(9): 1202– 1207. 26573769 PMC4820035
  11. [13]Poelmans G, Pauls DL, Buitelaar JK, Franke B. Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. Am J Psychiatry 2011; 168(4): 365– 377. 21324949
  12. [17]Demmontis D, Walters RK, Matrin J, Mattheisen M, Als TD, Agerbro E Discovery Of The First Genome-Wide Significant Risk Loci For ADHD. BiorXiv 2017. PMC6481311 30478444
  13. [18]de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol 2015; 11(4): e1004219. 25885710 PMC4401657
  14. [20]Chen YC, Sudre G, Sharp W, Donovan F, Chandrasekharappa SC, Hansen N Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder. Mol Psychiatry 2017. PMC5914518 28322272
  15. [21]Lushchak VI. Free Radicals, Reactive Oxygen Species, Oxidative Stresses and Their Classifications. Ukr Biochem J 2015; 87(6): 11– 18. 27025055
  16. [22]Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003; 552(Pt 2): 335– 344. 14561818 PMC2343396
  17. [23]Halliwell B Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med 1991; 91(3C): 14S– 22S. 1928205
  18. [26]Chovanova Z, Muchova J, Sivonova M, Dvorakova M, Zitnanova I, Waczulikova I Effect of polyphenolic extract, Pycnogenol, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder. Free Radic Res 2006; 40(9): 1003– 1010. 17015282
  19. [27]Garcia RJ, Francis L, Dawood M, Lai ZW, Faraone SV, Perl A. Attention deficit and hyperactivity disorder scores are elevated and respond to NAC treatment in patients with SLE. Arthritis Rheum 2013. PMC4034122 23400548
  20. [28]Leffa DT, Bellaver B, de Oliveira C, de Macedo IC, de Freitas JS, Grevet EH Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder. Neurochem Res 2017. 28664398
  21. [29]Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010; 2010: 214074. 20182529 PMC2825543
  22. [31]Maday S Mechanisms of neuronal homeostasis: Autophagy in the axon. Brain Res 2016. PMC5045311 27038755
  23. [32]Lee JA. Neuronal autophagy: a housekeeper or a fighter in neuronal cell survival? Exp Neurobiol 2012; 21(1): 1– 8. 22438673 PMC3294068
  24. [33]Lv X, Jiang H, Li B, Liang Q, Wang S, Zhao Q The crucial role of Atg5 in cortical neurogenesis during early brain development. Sci Rep 2014; 4: 6010. 25109817 PMC4127499
  25. [34]Gao Q, Liu L, Chen Y, Li H, Yang L, Wang Y Synaptosome-related (SNARE) genes and their interactions contribute to the susceptibility and working memory of attention-deficit/hyperactivity disorder in males. Prog Neuropsychopharmacol Biol Psychiatry 2015; 57: 132– 139. 25445064
  26. [35]Fekadu J, Rami A. Beclin-1 Deficiency Alters Autophagosome Formation, Lysosome Biogenesis and Enhances Neuronal Vulnerability of HT22 Hippocampal Cells. Mol Neurobiol 2015. 26456737
  27. [36]Elmore S Apoptosis: a review of programmed cell death. Toxicol Pathol 2007; 35(4): 495– 516. 17562483 PMC2117903
  28. [37]Haanen C, Vermes I. Apoptosis and inflammation. Mediators Inflamm 1995; 4(1): 5– 15. 18475609 PMC2365613
  29. [38]Awasaki T, Tatsumi R, Takahashi K, Arai K, Nakanishi Y, Ueda R Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis. Neuron 2006; 50(6): 855– 867. 16772168
  30. [39]Snigdha S, Smith ED, Prieto GA, Cotman CW. Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 2012; 28(1): 14– 24. 22233886 PMC3838299
  31. [40]Gilman CP, Mattson MP. Do apoptotic mechanisms regulate synaptic plasticity and growth-cone motility? Neuromolecular Med 2002; 2(2): 197– 214. 12428811
  32. [41]Lo SC, Wang Y, Weber M, Larson JL, Scearce-Levie K, Sheng M. Caspase-3 deficiency results in disrupted synaptic homeostasis and impaired attention control. J Neurosci 2015; 35(5): 2118– 2132. 25653368 PMC6705356
  33. [42]Valbonesi S, Magri C, Traversa M, Faraone SV, Cattaneo A, Milanesi E Copy number variants in attention-deficit hyperactive disorder: identification of the 15q13 deletion and its functional role. Psychiatr Genet 2015; 25(2): 59– 70. 25370694
  34. [43]Xu P, Gu R, Broster LS, Wu R, Van Dam NT, Jiang Y Neural basis of emotional decision making in trait anxiety. J Neurosci 2013; 33(47): 18641– 18653. 24259585 PMC3834062
  35. [44]Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy 2010; 6(3): 322– 329. 20224296 PMC2914492
  36. [45]Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014; 15(2): 81– 94. 24401948 PMC3970201
  37. [46]Rubinstein AD, Kimchi A. Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci 2012; 125(Pt 22): 5259– 5268. 23377657
  38. [47]Hou W, Han J, Lu C, Goldstein LA, Rabinowich H. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 2010; 6(7): 891– 900. 20724831 PMC3039736
  39. [48]Tanaka K, Whelan KA, Chandramouleeswaran PM, Kagawa S, Rustgi SL, Noguchi C ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds. Am J Cancer Res 2016; 6(4): 781– 796. 27186430 PMC4859883
  40. [49]Rodney GG, Pal R, Abo-Zahrah R. Redox regulation of autophagy in skeletal muscle. Free Radic Biol Med 2016. PMC4975974 27184957
  41. [50]Zhang L, Wang K, Lei Y, Li Q, Nice EC, Huang C. Redox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response. Free Radic Biol Med 2015; 89: 452– 465. 26454086
  42. [51]Huang J, Lam GY, Brumell JH. Autophagy signaling through reactive oxygen species. Antioxid Redox Signal 2011; 14(11): 2215– 2231. 20874258
  43. [52]Cabal-Hierro L, Lazo PS. Signal transduction by tumor necrosis factor receptors. Cell Signal 2012; 24(6): 1297– 1305. 22374304
  44. [53]Sriram K, O’Callaghan JP. Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol 2007; 2(2): 140– 153. 18040839
  45. [55]Instanes JT, Halmoy A, Engeland A, Haavik J, Furu K, Klungsoyr K. Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases. Biol Psychiatry 2017; 81(5): 452– 459. 26809250
  46. [56]Onnink AM, Zwiers MP, Hoogman M, Mostert JC, Dammers J, Kan CC Deviant white matter structure in adults with attention-deficit/hyperactivity disorder points to aberrant myelination and affects neuropsychological performance. Prog Neuropsychopharmacol Biol Psychiatry 2015; 63: 14– 22. 25956761 PMC4515357
  47. [57]Kondo N, Takahashi A, Ono K, Ohnishi T. DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids 2010; 2010: 543531. 21113301 PMC2989456

Cited by

Sorted by citations

Authors
Hess, J. L., Akutagava-Martins, G. C., Patak, J. D., Glatt, S. J., & Faraone, S. V.
Affiliations
SUNY Upstate Medical University (US)
Corresponding author
Faraone, S V
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-11-28
Volume
23
Issue
8
Pages
1787-1793
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2017.242
PMC
PMC6985986
OpenAlex
W2768561058
Cited by
42
References
10
Citations by year
2025: 6 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 3
FWCI
3.60
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (U01MH109536, R01MH101519)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
attention deficit hyperactivity disorder, subcortical volume, neuronal vulnerability, gene expression, apoptosis, oxidative stress, autophagy, brain development, children versus adults
MeSH terms
Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Brain, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Organ Size, Meta-Analysis as Topic, Gene Expression, Microarray Analysis, Young Adult, Genetic Association Studies, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review