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Quantitative Brain Magnetic Resonance Imaging in Attention-Deficit Hyperactivity Disorder
Abstract
BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit hyperactivity disorder (ADHD) have been limited by small samples or measurement of single brain regions. Since the neuropsychological deficits in ADHD implicate a network linking basal ganglia and frontal regions, 12 subcortical and cortical regions and their symmetries were measured to determine if these structures best distinguished ADHD. METHODS: Anatomic brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left asymmetries were examined along with midsagittal area measures of the cerebellum and corpus callosum. Interrater reliabilities were .82 or greater for all MRI measures. RESULTS: Subjects with ADHD had a 4.7% smaller total cerebral volume (P = .02). Analysis of covariance for total cerebral volume demonstrated a significant loss of normal right > left asymmetry in the caudate (P = .006), smaller right globus pallidus (P = .005), smaller right anterior frontal region (P = .02), smaller cerebellum (P = .05), and reversal of normal lateral ventricular asymmetry (P = .03) in the ADHD group. The normal age-related decrease in caudate volume was not seen, and increases in lateral ventricular volumes were significantly diminished in ADHD. CONCLUSION: This first comprehensive morphometric analysis is consistent with hypothesized dysfunction of right-sided prefrontal-striatal systems in ADHD.
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“several (Berquin et al., 1998; Castellanos et al., 1996; Castellanos, 2001; Castellanos et al., 2002a; Hill et al., 2003), but not all (Durston et al., 2004; Filipek et al., 1997; Hynd et al., 1990; Mostofsky et al., 2002), studies report reduced whole brain size in children with ADHD.”
From The influences of environmental enrichment, cognitive enhancement, and physical exercise on brain development: Can we alter the developmental trajectory of ADHD? (2011) · cites this paper as Castellanos et al., 1996
In the citing paper
“Studies have noted reduced volume in several parts of the cerebellum in ADHD (Castellanos et al., 2002a; Castellanos et al., 1996; Durston et al., 2004; Posner & Petersen, 1990) as well as posterior cortical anomalies (Durston et al., 2004; Filipek et al., 1997; Sowell et al., 2003).”
From The influences of environmental enrichment, cognitive enhancement, and physical exercise on brain development: Can we alter the developmental trajectory of ADHD? (2011) · cites this paper as Castellanos et al., 1996
In the citing paper
“Numerous structural MRI studies have reported smaller regions in the prefrontal cortex (PFC) of youth with ADHD (Castellanos et al., 1996; Castellanos et al., 2002a; Durston et al., 2004; Filipek et al., 1997; Hynd, Semrud-Clikeman, Lorys, Novey, & Eliopulos, 1990; Kates et al., 2002; Mostofsky, Cooper, Kates, Denckla, & Kaufmann, 2002; Sowell et al., 2003).”
From The influences of environmental enrichment, cognitive enhancement, and physical exercise on brain development: Can we alter the developmental trajectory of ADHD? (2011) · cites this paper as Castellanos et al., 1996
In the citing paper
“Earlier mental disorder onset shapes brain development (e.g., (123)) and relates to self-injurious behaviors (1).”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [123]
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BackgroundCo‐occurrence of bipolar and attention‐deficit hyperactivity disorders in children
Singh, M. K., DelBello, M. P., Kowatch, R. A., & Strakowski, S. M. (2006) · Bipolar Disorders · doi:10.1111/j.1399-5618.2006.00391.x · Cited by 163
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Striatal volume loss in HD as measured by MRI and the influence of CAG repeat
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“Third, structural MRI studies of individuals with AD/HD have reported volumetric reductions in the frontal lobes and striatum (Aylward et al., 1996; Castellanos et al., 1994, 1996; Durston et al., 2004; Filipek et al., 1997; Mataro et al., 1997; Mostofsky et al., 2002).”
BackgroundCharacteristic neurocognitive profile associated with adult attention-deficit/hyperactivity disorder
McLean, A., Dowson, J., Toone, B., Young, S., Bazanis, E., Robbins, T., & Sahakian, B. (2004) · Psychological Medicine · doi:10.1017/s0033291703001296 · Cited by 142
“Studies employing magnetic resonance imaging (MRI) indicated abnormalities in the size and shape of the caudate and pallidum (Hynd et al. 1991, 1993; Castellanos et al. 1994, 1996), and reductions in right frontal cortex volume (Hynd et al. 1990; Castellanos et al. 1996).”
MethodRegional cerebral perfusion abnormalities in attention deficit/hyperactivity disorder
Shin, M., Cho, S.-C., Lee, D., Lee, J., & Kim, B. (2002) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-002-0384-3 · Cited by 151
Preventive Interventions for ADHD: A Neurodevelopmental Perspective
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“…including mainly the frontocortical circuit, but also the parietal lobe and a reduced size of the anterior part of the corpus callosum as well as the vermal volume of the cerebellum (Bush et al. 1999; Castellanos et al. 1996; Filipek et al. 1997; Lou et al. 1998; Sieg et al. 1995; Tannock 1998).”
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“Many structural [7–14] and functional neuroimaging studies [15–17] have revealed abnormalities in the frontostriatal circuit.”
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“Findings of functional fronto-striatal abnormalities are also in line with studies showing reduced tissue volumes in DLPFC and caudate in pediatric populations with ADHD (Castellanos et al., 1994, 1996, 2002; Filipek et al., 1997; Seidman et al., 2006).”
BackgroundResultEffects of maternal smoking in pregnancy on prenatal brain development. The Generation R Study
Roza, S. J., Verburg, B. O., Jaddoe, V. W. V., Albert Hofman, D., Mackenbach, J. P., Steegers, E. A. P., Witteman, J. C. M., Verhulst, F. C., & Tiemeier, H. W. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05393.x · Cited by 148
“Our data suggest that the structural changes induced by prenatal exposure to tobacco smoke are similar to the structural changes found in ADHD.”
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Dysfunctions in Dopamine Systems and ADHD: Evidence From Animals and Modeling
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“Moreover, ADHD morphofunctional substrates are likely to be the same in rats and humans.”
BackgroundInfluentialEffects of stimulant medications on the EEG of girls with Attention-Deficit/Hyperactivity Disorder
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Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD
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“Furthermore, neuroimaging studies have consistently reported abnormalities in nigrostriatal dopaminergic brain structures (Aylward et al, 1996; Castellanos et al, 1996) and function (Zametkin et al, 1993; Vaidya et al, 1998; Zametkin and Liotta, 1998) in children with ADHD.”
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“Early structural neuroimaging work in children and adolescents with ADHD (aged 5–18 years) and controls indicated that over the course of development the right caudate and right prefrontal areas were observed to have reduced volume in ADHD participants compared to controls (Castellanos et al., 1996).”
ResultAbnormal T2 relaxation time in the cerebellar vermis of adults sexually abused in childhood:
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Neurobiology of Attention Deficit Hyperactivity Disorder
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Neuropsychological performance deficits in adults with attention deficit/hyperactivity disorder
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“Consequently, ADHD causality has been conceptualized in at least three different ways, as (1) frontal lobe dysfunction (Castellanos et al., 1996; Hynd, Semrud, Lorys, Novey, & Eliopulos, 1990), (2) delayed frontal maturation functioning (Chelune et al.”
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“…support of an inhibitory deficit in children with ADHD stems from MRI, fMRI, and ERP studies reporting reduced volumes in the right frontal lobe (Castellanos et al., 1996; Filipek et al., 1997), lower activation of right prefrontal areas (Rubia et al., 1998), and suggesting a deficit in…”
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Motion Artifact in Magnetic Resonance Imaging: Implications for Automated Analysis
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Dopamine D4Receptor-Deficient Mice Display Cortical Hyperexcitability
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“…with ADHD have revealed that the FC, dorsal striatum, and globus pallidus, the three areas richest in D4Rs (Mrzljak et al., 1996; Ariano et al., 1997), are significantly smaller in affected individuals compared with the corresponding structures in control subjects (Castellanos et al., 1996).”
ResultSchweitzer, J. B., Lee, D. O., Hanford, R. B., Zink, C. F., Ely, T. D., Tagamets, M. A., Hoffman, J. M., Grafton, S. T., & Kilts, C. D. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.07.011 · Cited by 135
“Comparisons between the ADHD and normal control groups showed that normal control articipants exhibited greater anterior cingulate cortex and temporal gyrus rCBF than ADHD participants under both conditions. xecutive functioning was associated with greater subcortical (basal ganglia and cerebellar…”
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“With the introduction of MRI, small (n_7–11) then larger samples (n_50–57) of ADHD boys were shown to have, on average, smaller anterior frontal cortices on the right - the opposite of what was expected [10, 12, 43].”
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Oculomotor abnormalities in attention deficit hyperactivity disorder
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Neuroimaging in Attention-Deficit Hyperactivity Disorder: Beyond the Frontostriatal Circuitry
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Childhood onset schizophrenia: support for a progressive neurodevelopmental disorder
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Attention-Deficit Hyperactivity Symptomatology After Traumatic Brain Injury: A Prospective Study
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“Multidimensionally Impaired Disorder”: Is It a Variant of Very Early-Onset Schizophrenia?
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“…of an executive function defi cit in ADHD is supported by the fi ndings of neuroimaging studies showing anomalies of prefrontal cortical regions and the basal ganglia in patients with ADHD (Hynd et al. 1993; Castellanos et al. 1996; Casey et al. 1997; Filipek et al. 1997; Vaidya et al. 1998).”
Executive Function Oculomotor Tasks in Girls With ADHD
Castellanos, F. X., Marvasti, F. F., Ducharme, J. L., WALTER, J. M., Israel, M. E., Krain, A. L., PAVLOVSKY, C., & Hommer, D. W. (2000) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200005000-00019 · Cited by 135
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Overview of attention deficit hyperactivity disorder in young children
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Common variants at 12q15 and 12q24 are associated with infant head circumference
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“…structural imaging studies have reported significantly reduced volume of the right frontal (particularly prefrontal) cortex in ADHD subjects (Castellanos et al., 1996b; Filipek et al., 1997; Casey et al., 1997; Pueyo et al., 2000; Mostofsky et al., 2002) in conjunction with right caudate…”
InfluentialToward developmental models of psychiatric disorders in zebrafish
Norton, W. H. J. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00079 · Cited by 127
“In some cases, environmental influences may ultimately reflect the interaction of the parent’s and child’s genomes in expression of mental illness (Castellanos et al., 1996; Laucht et al., 2007).”
BackgroundInfluentialNeurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder
Turner, D. C., Blackwell, A. D., Dowson, J. H., McLean, A., & Sahakian, B. J. (2005) · Psychopharmacology · doi:10.1007/s00213-004-1993-5 · Cited by 127
“Evidence from neuroimaging studies in children suggests that frontostriatal brain dysfunction in ADHD may underlie many of the neurocognitive deficits described above (Lou et al. 1984, 1989; Hynd et al. 1993, 1990, 1991; Castellanos et al. 1994, 1996; Vaidya et al. 1998).”
BackgroundSchneider, M., Retz, W., Coogan, A. N., Thome, J., & Rösler, M. (2006) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-006-1005-3 · Cited by 133
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Temporal Attention as a Scaffold for Language Development
de Diego‐Balaguer, R., Martinez‐Alvarez, A., & Pons, F. (2016) · Frontiers in Psychology · doi:10.3389/fpsyg.2016.00044 · Cited by 137
“Evidence from pathophysiology research has shown that ADHD physiology involves dopaminergic and noradrenergic pathway dysfunction in the prefrontal cortex and subcortical regions of the brain (Barkley et al., 1992; Castellanos et al., 1996; Faraone and Biederman, 1998; Konrad et al., 2006).”
BackgroundYordanova, J., Banaschewski, T., Kolev, V., Woerner, W., & Rothenberger, A. (2001) · Clinical Neurophysiology · doi:10.1016/s1388-2457(01)00524-7 · Cited by 126
Attention deficit/hyperactivity disorder and methylphenidate
Rapport, M. D., & Moffitt, C. E. (2002) · Clinical Psychology Review · doi:10.1016/s0272-7358(02)00129-0 · Cited by 125
Disproportionate increases of white matter in right frontal lobe in Tourette syndrome
Fredericksen, K., Cutting, L. E., Kates, W. R., Mostofsky, S. H., Singer, H. S., Cooper, K. L., Lanham, D. C., DENCKLA, M. B., & Kaufmann, W. E. (2002) · Neurology · doi:10.1212/wnl.58.1.85 · Cited by 124
Castellanos, F. X., Sharp, W. S., Gottesman, R. F., GREENSTEIN, D. K., Giedd, J. N., & Rapoport, J. L. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.9.1693 · Cited by 124
Early Markers in Infants and Toddlers for Development of ADHD
Gurevitz, M., Geva, R., Varon, M., & Leitner, Y. (2012) · Journal of Attention Disorders · doi:10.1177/1087054712447858 · Cited by 121
“…imaging (MRI) have indicated significantly smaller anterior right frontal regions, smaller size of the caudate nucleus, and smaller globus pallidus regions in children with ADHD compared with control participants (Aylward et al., 1996; Castellanos et al., 1996; Filipek et al., 1997; Pauls, 1991).”
ResultNeuroimaging of children following prenatal drug exposure
Derauf, C., Kekatpure, M., Neyzi, N., Lester, B., & Kosofsky, B. (2009) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2009.03.001 · Cited by 122
Attention Deficit Hyperactivity Disorder
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Animal models concerning the role of dopamine in attention-deficit hyperactivity disorder
van der Kooij, M. A., & Glennon, J. C. (2007) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.12.002 · Cited by 128
Theories of Attention-Deficit/Hyperactivity Disorder
Barkley, R. A. (1999) · Springer eBooks · doi:10.1007/978-1-4615-4881-2_13 · Cited by 126
Courvoisie, H. E., Hooper, S. R., Fine, C., Kwock, L., & Castillo, M. (2004) · Journal of Neuropsychiatry · doi:10.1176/jnp.16.1.63 · Cited by 119
Multisensory Integration and Child Neurodevelopment
Dionne-Dostie, E., Paquette, N., Lassonde, M. C., & Gallagher, A. (2015) · Brain Sciences · doi:10.3390/brainsci5010032 · Cited by 157
“prefrontal cortices [205–207].”
Regional differences of the prefrontal cortex in pediatric PTSD: an MRI study
Richert, K. A., Carrion, V. G., Karchemskiy, A., & Reiss, A. L. (2006) · Depression and Anxiety · doi:10.1002/da.20131 · Cited by 118
“…controlling for the variance associated with comorbid MDD and ADHD, conditions that have been associated with PFC morphology [Casey et al., 1997; Castellanos et al., 1996; Nolan et al., 2002] hoc analyses further controlled for the effects of comorbid ADHD and MDD, and confirmed that the…”
BackgroundRoth, R. M., & Saykin, A. J. (2004) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(03)00112-6 · Cited by 123
“At present, there is little evidence of structural abnormality in the medial temporal lobe, temporal neocortex, or parietal lobe in patients with ADHD, although there is a paucity of data [57].”
BackgroundTotally tubular: the mystery behind function and origin of the brain ventricular system
Lowery, L. A., & Sive, H. L. (2009) · BioEssays · doi:10.1002/bies.200800207 · Cited by 116
Putamen Lesions and the Development of Attention-Deficit/Hyperactivity Symptomatology
Max, J. E., Fox, P. T., Lancaster, J. L., Kochunov, P. V., Mathews, K. D., Manes, F. F., Robertson, B., Arndt, S. V., Robin, D. A., & Lansing, A. E. (2002) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200205000-00014 · Cited by 114
Rubia, K. (2002) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00437-5 · Cited by 117
Rafalovich, A. (2005) · Sociology of Health & Illness · doi:10.1111/j.1467-9566.2005.00444.x · Cited by 115
Mulhern, R. K., White, H. A., Glass, J. O., Kun, L. E., Leigh, L., Thompson, S. J., & Reddick, W. E. (2004) · Journal of the International Neuropsychological Society · doi:10.1017/s135561770410204x · Cited by 114
“…differences in brain volumes between healthy children and those diagnosed with ADHD, including decreased volume of the frontal and prefrontal regions, and, more relevant to the present study, reduced right frontal white matter volumes (Filipek et al., 1997; Castellanos et al., 1996, 2002).”
BackgroundThe neurobiological link between OCD and ADHD
Brem, S., Grünblatt, E., Drechsler, R., Riederer, P., & Walitza, S. (2014) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-014-0146-x · Cited by 109
“…corpus callosum (Giedd et al. 1994; Hill et al. 2003), prefrontal (Hill et al. 2003; Shaw et al. 2007; Sowell et al. 2003), temporal (Sowell et al. 2003), and cerebellar cortex (Cas- tellanos et al. 1996, 2002) did not reach significance in the most recent meta-analysis of Nakao et al. (2011).”
BackgroundSchrimsher, G. W., Billingsley, R. L., Jackson, E. F., & Moore, B. D. (2002) · Journal of Child Neurology · doi:10.1177/08830738020170122001 · Cited by 111
Sheppard, D. M., Bradshaw, J. L., Mattingley, J. B., & Lee, P. (1999) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.66.1.57 · Cited by 111
Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder
Fone, K. C. F., & Nutt, D. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.10.001 · Cited by 110
Émond, V., Joyal, C. C., & Poissant, H. (2008) · L Encéphale · doi:10.1016/j.encep.2008.01.005 · Cited by 113
“Cela pourrait rendre compte du paradoxe bservé chez les enfants avec un TDAH à savoir, leur bonne erformance lorsqu’ils sont motivés et leurs performances éficitaires quand la tâche est moins stimulante, ou que la écompense est trop éloignée dans le temps [7].”
BackgroundInfluentialAnimal models of attention deficit/hyperactivity disorder (ADHD): a critical review
Sontag, T. A., Tucha, O. M., Walitza, S., & Lange, K. W. (2010) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-010-0019-x · Cited by 120
Is attention-deficit/hyperactivity disorder an energy deficiency syndrome?
Todd, R. D., & Botteron, K. N. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01173-8 · Cited by 107
Timing, Space and ADHD: The Dopamine Theory Revisited
Lévy, F., & Swanson, J. M. (2001) · Australian & New Zealand Journal of Psychiatry · doi:10.1046/j.1440-1614.2001.00923.x · Cited by 115
“For example, if dopamine is associated with motor activity, why would a dopaminergic deficit result in hyperactivity, rather than hypoactivity? Neuroimaging studies [6,11,12] have directed attention to morphological and physiological differences in right-sided, prefrontal-striatal systems, which are rich in dopaminerg…”
BackgroundSeidman, L. J., Biederman, J., Monuteaux, M. C., Weber, W. J., & Faraone, S. V. (2000) · Journal of Abnormal Psychology · doi:10.1037/0021-843x.109.2.252 · Cited by 109
Viggiano, D., Ruocco, L. A., & Sadile, A. G. (2003) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2003.08.006 · Cited by 110
“[10] Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Vaituzis AC, Dickstein DP, Sarfatti SE, Vauss YC, Snell JW, Lange N, Kaysen D,”
BackgroundIctal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography
Silvestri, R., Gagliano, A., Calarese, T., Aricò, I., Cedro, C., Condurso, R., Germanò, E., Vita, G., & Tortorella, G. (2007) · Epilepsy Research · doi:10.1016/j.eplepsyres.2007.05.007 · Cited by 107
Dougherty, C. C., Evans, D. W., Myers, S. M., Moore, G. J., & Michael, A. M. (2016) · Neuropsychology Review · doi:10.1007/s11065-015-9300-2 · Cited by 104
“2006) and caudate and globus pallidus (Castellanos et al. 1996).”
Background
Metadata
- Authors
- Castellanos, F. X.
- Affiliations
- National Institute of Mental Health (US)
- Corresponding author
- Castellanos, F. Xavier
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 1996-07-01
- Volume
- 53
- Issue
- 7
- Pages
- 607
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2097559385
- Cited by
- 1,183
- References
- 102
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 4 · 2023: 14 · 2022: 11 · 2021: 11 · 2020: 20 · 2019: 21 · 2018: 18 · 2017: 19 · 2016: 31 · 2015: 37 · 2014: 40 · 2013: 39 · 2012: 52
- FWCI
- 25.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- 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, brain volumetry, brain volume, caudate nucleus, globus pallidus, cerebellum, corpus callosum, lateral ventricle, hemispheric lateralization, basal ganglia, children, brain structure
- MeSH terms
- Adolescent, Age Factors, Attention Deficit Disorder with Hyperactivity, Basal Ganglia, Body Height, Body Weight, Brain, Caudate Nucleus, Cerebellum, Cerebral Ventricles, Child, Child, Preschool, Frontal Lobe, Globus Pallidus, Humans, Intelligence Tests, Functional Laterality, Magnetic Resonance Imaging, Male, Discriminant Analysis, Prefrontal Cortex
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