Developmental Brain Anomalies in Children With Attention-Deficit Hyperactivity Disorder

Abstract

The pathoetiology of attention-deficit hyperactivity disorder (ADHD) has been considered to be neurodevelopmental, yet the timing and processes involved are not clearly identified. Neurodevelopmental brain anomalies have been associated with a variety of psychiatric conditions. However, they have never been evaluated in a population of patients with ADHD. This study was designed to determine the frequency of specific developmental brain anomalies in a group of children with ADHD (n = 85; mean age, 10.9 years) and healthy control children (n = 95; mean age, 11.7 years) by visually inspecting brain magnetic resonance imaging scans. Compared to controls, the ADHD group showed an increase in frequency of two developmental anomalies: (1) gray-matter heterotopia, a neuronal migration anomaly, in 2 of 85 patients versus 0 of 95 controls; and (2) posterior fossa abnormality (excess cerebrospinal fluid in the posterior fossa) in 8 of 85 patients versus 2 of 95 controls. There were no differences in frequency of enlarged cavum septi pellucidi between the two groups. These findings support and extend the idea that ADHD is of developmental origin, and further suggest that the timing of aberrant brain development could be in early gestation.

Neuronal Heterotopias Affect the Activities of Distant Brain Areas and Lead to Behavioral Deficits

“…ities in our Reelin-induced heterotopia model (Weeber et al, 2002;Niu et al, 2004;Pujadas et al, 2010).…”

“…If the former were true, it would be interesting to investigate how these GABAergic neurons migrated toward the heterotopias. Cortical GABAergic neurons are known to be born mainly in the ganglionic eminences and to migrate tangentially into the cortex (Nakajima, 2007). When they enter the cortex, they move through the subventricular zone/intermediate zone or through the marginal zone into the developing cortex (Tanaka and Nakajima, 2012).…”

“…In human cases of periventricular nodular heterotopia caused by mutation in the X-linked gene Filamin A (FLNA), there is a possibility that the neurons located outside the heterotopias (not only the overlying sister neurons but also other neurons) also show impairments in their dendrites and spines (Nagano et al, 2004). Thus, the impaired neurons located outside the heterotopias may also be involved in the development of various clinical symptoms in human cases.…”

“…The gray-painted maze has three arms, each arm being 40-cm-long, 15-cm-high, 3-cm-wide at the bottom and 12-cm-wide at the top. The test was conducted as described previously (Sarter et al, 1988;Maurice et al, 1994), with minor modifications. Each mouse (CA-Fyn, n ϭ 13; control, n ϭ 14; hM3Dq-control, n ϭ 27; hM3Dq-CA-Fyn, n ϭ 15; P6W male mice in each group were randomly selected from 4 -7 dams) was placed at the end of one arm and allowed to explore freely for 8 min.…”

“…To produce heterotopias in the somatosensory cortex, we ectopically overexpressed one of the following three molecules by in utero electroporation (Tabata and Nakajima, 2001;: (1) Reelin, a protein involved in laminar formation and neuronal migration in the developing cortex (Bar et al, 1995;D'Arcangelo et al, 1995;Ogawa et al, 1995;Nakajima et al, 1997;Honda et al, 2011;Sekine et al, 2014); (2) a constitutive-active form of Fyn (CA-Fyn), a member of the Src family kinase (Arnaud et al, 2003); and (3) a dominant-negative form of Cdk5 (DN-Cdk5), a cyclin-dependent kinase known to be important during neuronal migration (Ohshima et al, 1996). Behavioral analyses revealed that the mice with heterotopias showed spatial working memory deficit and low competitive dominance behavior relative to the control mice.…”