Clinical Research

AD/HD

Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder.

Lancet. 2003 Nov 22;362(9397):1699-707. Sowell, E.R., Thompson, P.M., Welcome, S.E., Henkenius, A.L., Toga, A.W., Peterson, B.S.

University of California at Los Angeles, Laboratory of Neuro Imaging, Department of Neurology, 710 Westwood Plaza, Room 4-238, Los Angeles, CA 90095-1769.

Background: Results of structural brain imaging studies of patients with attention-deficit hyperactivity disorder have shown subtle reductions in total brain volume and in volumes of the right frontal lobe and caudate nucleus. Although various conventional volumetric and voxel-based methods of image analysis have been used in these studies, regional brain size and grey-matter abnormalities have not yet been mapped over the entire cortical surface in patients with this disorder. We aimed to map these features in patients with attention-deficit hyperactivity disorder.

Methods: We used high-resolution MRI and surface-based, computational image analytic techniques to map regional brain size and grey-matter abnormalities at the cortical surface in a group of 27 children and adolescents with attention-deficit hyperactivity disorder and 46 controls, who were group-matched by age and sex.

Findings: Abnormal morphology was noted in the frontal cortices of patients with attention-deficit hyperactivity disorder, with reduced regional brain size localized mainly to inferior portions of dorsal prefrontal cortices bilaterally. Brain size was also reduced in anterior temporal cortices bilaterally. Prominent increases in grey matter were recorded in large portions of the posterior temporal and inferior parietal cortices bilaterally.

Interpretation: The frontal, temporal, and parietal regions are heteromodal association cortices that constitute a distributed neural system, which subserves attention and behavioral inhibition. We have identified region-specific anatomical abnormalities in cortical components of attentional systems, which may help better account for the symptoms of attention-deficit hyperactivity disorder.

Structural and functional neuroanatomy of attention-deficit hyperactivity disorder (ADHD)

Encephale. 2009 Apr;35(2):107-14. Epub 2008 Jul 7. Original article in French.

Emond, V., Joyal, C., Poissant, H.

Université du Québec, succursale Centre-Ville, 8888 Montréal H3C 3P8, Québec, Canada.

Introduction: Attention-deficit hyperactivity disorder (ADHD) is a common and impairing neuropsychiatric disorder with preschool onset. ADHD occurs in approximately 3-9% of the childhood population. There is a much higher incidence rate in boys who are around three times more likely than girls to be diagnosed. Approximately 30-60% of individuals diagnosed with ADHD in youth have symptoms that persist into adulthood.

Literature Findings: Three subtypes of the disorder have been proposed in the current clinical view of ADHD: inattentive, hyperactive-impulsive and combined type. Numerous problems are associated with ADHD: poor academic performance, learning disorders, subtle cognitive deficits, conduct disorders, antisocial personality disorder, poor social relationships, and a higher incidence of anxiety and depression symptoms into adulthood. Researchers have emphasized poor behavioural inhibition as the central impairment of the disorder. From the neuropsychological viewpoint, impairment of the "hot" affective aspects of executive functions, like behavioural inhibition and attention and the more cognitive, "cool" aspects of executive functions like self-regulation, working memory, planning, and cognitive flexibility, are often reported by studies on ADHD. The hot executive functions are associated with ventral and medial regions of the prefrontal cortex (including the anterior cingulated cortex) and named "hotbrain" and the cool executive functions are associated with the dorsolateral prefrontal cortex and are called "coolbrain".

Discussion: Convergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex, the caudate nucleus and putamen. Moreover, a growing literature demonstrates abnormalities affecting other cortical regions and the cerebellum. The exploratory brain regions of interest in which abnormalities have been identified, but that were not predicted by cognitive models of ADHD, are the temporal lobe, parietal lobe, occipital lobe and lateral ventricles. Anatomical studies suggest widespread reductions in volume throughout the cerebrum and cerebellum, while functional imaging studies suggest that affected individuals activate more diffuse areas than controls during the performance of cognitive tasks. More precisely, reductions in volume have been observed in the total cerebral volume, the prefrontal cortex, the basal ganglia (striatum), the dorsal anterior cingulate cortex, the corpus callosum and the cerebellum. Furthermore, hypoactivation of the dorsal anterior cingulate cortex, the frontal cortex and the basal ganglia (striatum) have also been reported. The paradigms mostly used in functional magnetic resonance imaging (fMRI) are tasks of motor inhibition, interference and attention such as the go/no-go, "stop-signal" and the Stroop.

Conclusion: This review provides an overview of the main imaging studies that investigated the neurobiological substrate of ADHD. Some guidelines for future functional magnetic imaging studies are also suggested.

The neurobiology of attention deficit/hyperactivity disorder.

Eur J Paediatr Neurol. 2009 Jul;13(4):299-304. Epub 2008 Jul 21.

Curatolo, P., Paloscia, C., D'Agati, E., Moavero, R., Pasini, A.

Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata University of Rome, Rome, Italy.

ADHD is a brain based disorder with structural and functional abnormalities in widespread but specific areas of the brain. The most significant and consistent structural imaging findings include smaller total brain volumes, and reduced volumes in the right frontal lobe, right parietal cortex, caudate nucleus, cerebellar hemispheres, and posterior-inferior lobules of the cerebellar vermis. ADHD involves hypofunction of catecholaminergic circuits, particularly those that project to the prefrontal cortex. A minimum of 18 genes have been reported to be associated with the disorder; among them the DRD4 7-repeat allele has been found associated with a thinner prefrontal and posterior parietal cortex. Epigenetic factors acting during critical periods of prenatal and postnatal development may interact with genetic determinants. Methylphenidate, as well as the catecholaminergic nonstimulant atomoxetine, are effective in improving ADHD symptoms.

Cerebellum and psychiatric disorders.

Rev Bras Psiquiatr. 2008 Sep;30(3):281-9.

Baldaçara, L., Borgio, J.G., Lacerda, A.L., Jackowski, A.P.

Laboratório Interdisciplinar de Neurociências Clínicas, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brazil.

Objective: The objective of this update article is to report structural and functional neuroimaging studies exploring the potential role of cerebellum in the pathophysiology of psychiatric disorders.

Method: A non-systematic literature review was conducted by means of Medline using the following terms as a parameter: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" and "attention deficit hyperactivity disorder". The electronic search was done up to April 2008.

Discussion: Structural and functional cerebellar abnormalities have been reported in many psychiatric disorders, namely schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia and attention deficit hyperactivity disorder. Structural magnetic resonance imaging studies have reported smaller total cerebellar and vermal volumes in schizophrenia, mood disorders and attention deficit hyperactivity disorder. Functional magnetic resonance imaging studies using cognitive paradigms have shown alterations in cerebellar activity in schizophrenia, anxiety disorders and attention deficit hyperactivity disorder. In dementia, the cerebellum is affected in later stages of the disease.

Conclusion: Contrasting with early theories, cerebellum appears to play a major role in different brain functions other than balance and motor control, including emotional regulation and cognition. Future studies are clearly needed to further elucidate the role of cerebellum in both normal and pathological behavior, mood regulation, and cognitive functioning.

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder.

JAMA. 2002 Oct 9;288(14):1740-8.

Castellanos, F.X., Lee, P.P., Sharp, W., Jeffries, N.O., Greenstein, D.K., Clasen, L.S., Blumenthal, J.D., James, R.S., Ebens, C.L., Walter, J.M., Zijdenbos, A., Evans, A.C., Giedd, J.N., Rapoport, J.L.

Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

Context: Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure. OBJECTIVE: To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls.

Design, Setting, and Participants: Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, MD, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images.

Main Outcome Measures: Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls.

Results: On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F(1,280) = 8.30, P =.004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F(1,280) = 12.29, P =.001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F(2,288) = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P =.002) and cerebellar volumes (-6.2%, F( 2,288) = 8.97, P is less than .001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F(2,288) = 11.65) compared with controls (-10.7%, P is less than .001) and with medicated children with ADHD (-8.9%, P is less than .001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P =.002) and in the cerebellum (P =.003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P =.05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were less than .05).

Conclusions: Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.