Cited by 207Attention Deficit Hyperactivity DisorderNeural and Behavioral Psychology StudiesAutism Spectrum Disorder Research

The DOI matches its Crossref record; 107 of the 107 references it cites were found in a registry or an index; none of the 150 sources its claims cite is checked for support yet.

Brain Gray Matter Deficits at 33-Year Follow-up in Adults With Attention-Deficit/Hyperactivity Disorder Established in Childhood

Open access
Proal, Erika·2011·Archives of General Psychiatry

Abstract

CONTEXT: Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder (ADHD) whose childhood status was retrospectively recalled. We present, to our knowledge, the first prospective study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood. OBJECTIVES: To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD. DESIGN: Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years. SETTING: Research outpatient center. PARTICIPANTS: We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively). MAIN OUTCOME MEASURES: Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses. RESULTS: The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions. CONCLUSIONS: Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry.

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TL;DR

In a 33-year prospective follow-up, adults diagnosed with combined-type ADHD in childhood showed thinner cortex and lower gray matter than comparison subjects, largely regardless of current ADHD diagnosis. Remitters and persistents did not differ at corrected thresholds, but exploratory uncorrected analyses suggested remitters had thicker cortex in some regions.

Key findings

  • Global mean cortical thickness was significantly lower in ADHD probands (n=59) than comparisons (n=80): 3.18±0.11 mm vs 3.24±0.11 mm, p<0.001, Cohen’s d=0.54. Probands with persistent ADHD differed from non-ADHD comparisons (3.14±0.13 mm vs 3.25±0.10 mm, p=0.0005, d=1.02); remitters also differed from non-ADHD comparisons (3.20±0.11 mm, p=0.04, d=0.48), while persistents and remitters did not differ significantly (p=0.10, d=0.51).
  • Vertex-wise analyses at FDR<0.05 found significantly thinner cortex in ADHD probands in the dorsal attentional network and limbic areas, with the largest cluster extending from right precuneus to precentral gyrus; no region was significantly thicker in probands. VBM showed significantly decreased gray matter in probands in right caudate, right thalamus, and bilateral cerebellar hemispheres, as well as cortical regions.
  • Persistents (n=17) did not differ significantly from remitters (n=26) at FDR<0.05. At uncorrected p<0.05, remitters had thicker cortex than persistents in medial occipital cortex, insula, parahippocampus, and prefrontal regions; no regions exceeded cluster threshold where remitters had thinner cortex than persistents.

Methods

  • Cross-sectional MRI analysis embedded in a 33-year prospective follow-up at mean age 41. The original ADHD group comprised 207 6–12-year-old Caucasian boys referred from 1970–1977 (mean age 8.3 years); male comparisons (n=178) were free of ADHD in childhood. MRI scans were obtained in 59 probands and 80 comparisons (28% and 45% of original samples, respectively).
  • Anatomic T1-weighted images were acquired on two 3T Siemens scanners and processed through the CIVET-MNI pipeline. Whole-brain VBM and vertex-wise cortical thickness analyses (81,924 vertices) controlled for age at scan and scanner model; results were thresholded at FDR<0.05, with post-hoc region-of-interest analyses and exploratory uncorrected p<0.05 analyses.
  • Current diagnostic subgroups included persistents (n=17), remitters (n=26), and ADHD-NOS probands (n=16); comparisons were dichotomized into non-ADHD comparisons (n=57) and comparisons with ADHD-NOS (n=23). Subgroup analyses excluded ADHD-NOS participants.

Limitations

  • Stated by the paper: imaging data were examined only cross-sectionally in middle adulthood despite the prospective longitudinal design; only 28% of initially diagnosed probands and 45% of comparisons had analyzable MRI scans; scanned probands had significantly higher rates of substance use disorders at 18FU than non-scanned probands, although no significant relationships were observed between brain measures and substance use disorders.
  • Stated by the paper: probands had significantly lower IQ than comparisons in childhood/adolescence and adulthood; all but four scanned probands were treated with methylphenidate in childhood, so effects of ADHD without medication treatment cannot be assessed; the sample was limited to Caucasian males; two scanners were used; and analyses were limited to cortical thickness and VBM.
  • Evident from the text: the high rate of ADHD-NOS in comparisons was comparable to that in probands, which the authors speculate may reflect secular changes in ADHD awareness or possible instrument-related error; the cross-sectional imaging design cannot establish whether anatomic differences precede or follow diagnostic remission.

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Crossref · 10.1001/archgenpsychiatry.2011.117

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  • The paper relies on this without support.

    The neurobiology of ADHD remission has not been previously examined in middle adulthood.

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    The parietal, temporal and posterior frontal regions and limbic areas underpin top-down control of attention and the regulation of emotion and motivation.

    “These regions underpin top-down control of attention and the regulation of emotion and motivation”
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  1. [9]Seidman LJ Valera EM Makris N Monuteaux MC Boriel DL Kelkar K Kennedy DN Caviness VS Bush G Aleardi M Faraone SV Biederman J Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging Biol Psychiatry 2006 60 10 1071 1080 16876137
  2. [18]Monuteaux MC Seidman LJ Faraone SV Makris N Spencer T Valera E Brown A Bush G Doyle AE Hughes S Helliesen M Mick E Biederman J A preliminary study of dopamine D4 receptor genotype and structural brain alterations in adults with ADHD Am J Med Genet B Neuropsychiatr Genet 2008 147B 8 1436 1441 18951431
  3. [19]Hesslinger B Tebartz van Elst L Thiel T Haegele K Hennig J Ebert D Frontoorbital volume reductions in adult patients with attention deficit hyperactivity disorder Neuroscience Letters 2002 328 3 319 321 12147334
  4. [27]Mannuzza S Klein RG Bonagura N Malloy P Giampino TL Addalli KA Hyperactive boys almost grown up. V. Replication of psychiatric status Arch Gen Psychiatry 1991 48 1 77 83 1984764
  5. [31]Makris N Biederman J Valera EM Bush G Kaiser J Kennedy DN Caviness VS Faraone SV Seidman LJ Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder Cereb Cortex 2007 17 6 1364 1375 16920883
  6. [34]Gittelman R Abikoff H Pollack E Klein DF Katz S Mattes JA Controlled trial of behavior modification and methylphenidate in hyperactive children Whalen CHB Hyperactive Children: The Ecology of Identification and Treatment New York Academic Press 1980 221 243
  7. [83]Cubillo A Halari R Ecker C Giampietro V Taylor E Rubia K Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood Attention-Deficit Hyperactivity Disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching J Psychiatr Res 2010 44 10 629 639 20060129

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Metadata

Authors
Proal, E.
Affiliations
NYU Langone Health (US)
Corresponding author
Proal, Erika
Venue
Archives of General Psychiatry
Published
2011-11-01
Volume
68
Issue
11
Pages
1122
ISSN
0003-990X (ISSN-L)
OpenAlex
W2158859522
Cited by
207
References
106
Citations by year
2026: 2 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 12 · 2021: 8 · 2020: 13 · 2019: 9 · 2018: 14 · 2017: 13 · 2016: 17 · 2015: 35 · 2014: 21 · 2013: 21 · 2012: 17
FWCI
13.35
Type
journal article
Language
en
Open access
Locations
  • Archives of General Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5t32mh067763-10)
  • National Institute of Mental Health (T32MH-067763)
  • National Institute on Drug Abuse (R01DA016979)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
attention deficit hyperactivity disorder, cortical thinning, adult ADHD, dorsal attention network, limbic system, caudate nucleus, thalamus, cerebellum, prefrontal cortex, emotion regulation
MeSH terms
Adult, Attention Deficit Disorder with Hyperactivity, Behavioral Symptoms, Cerebral Cortex, Child, Chronic Disease, Cross-Sectional Studies, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Organ Size, Remission Induction, Time, Age of Onset

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