A Magnetic Resonance Imaging Study of the Cerebellar Vermis in Chronically Treated and Treatment-Naïve Children with Attention-Deficit/Hyperactivity Disorder Combined Type

doi:10.1016/j.biopsych.2008.11.030

Biological Psychiatry

Volume 65, Issue 7, 1 April 2009, Pages 620-624

https://doi.org/10.1016/j.biopsych.2008.11.030 Get rights and content

Background

Because of its dense connections to the prefrontal cortex and basal ganglia, the cerebellum is thought to play an important role in cognition. Numerous magnetic resonance imaging (MRI) studies have found abnormalities in the cerebellum in children with attention-deficit/hyperactivity disorder (ADHD). While some studies in animal and human models suggest that certain brain structures are affected by chronic stimulant medication, it is unclear whether the cerebellum is also affected. The purpose of the current study was to determine if cerebellar morphology was different in treatment-naïve versus chronically treated children with ADHD.

Methods

There were 32 boys and 15 girls total (N = 47) that comprised three groups: ADHD-combined type (ADHD-C) children with no history of stimulant medication treatment (n = 14), ADHD-C children chronically treated with stimulant medication (n = 18), and typically developing control children (n = 15).

Results

Treatment-naïve children with ADHD had significantly smaller area in the posterior inferior vermis (lobules VIII–X) than both chronically treated children with ADHD (p = .004) and typically developing control children (p = .001). No differences were observed between chronically treated children with ADHD and control children.

Conclusions

The results from this study suggest that chronic stimulant treatment may normalize the development of important areas of the cerebellar vermis in children with ADHD.

Section snippets

Methods and Materials

All subjects (N = 47) were right-handed and consisted of 15 girls and 32 boys with a mean age of (11.34 ± 2.42 years). There were three groups: ADHD-C children with no history of stimulant medication treatment (n = 14), ADHD-C children chronically treated with stimulant medication (n = 18), and typically developing control children (n = 15). Chronically treated children with ADHD-C had taken medication for at least 1 year (range of 2.3–5 years). The treatment-naïve ADHD-C group had never

Results

Initial analysis of Conners' Global Index RI indicated, as expected, group differences in both ADHD groups versus control subjects (F = 7.648, df = 2, 43, p = .001) but no differences between the ADHD groups (p = .742). This suggests that the ADHD groups did not differ on the level of symptom severity. Demographic and clinical variables are presented in Table 1.

Discussion

As hypothesized, treatment-naïve children with ADHD had significantly smaller area measures in the posterior inferior vermis (lobules VIII–X) than either the chronically treated children with ADHD or control subjects. No differences were observed between chronically treated and typically developing control subjects in any vermal area measurement. This finding is important given recent accounts of cerebellar abnormalities in children with ADHD.

Numerous studies have reported that children with

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Very few studies have investigated longitudinal clinical cohorts of attention-deficit/hyperactivity disorder (ADHD). Moreover, how baseline brain changes could affect the development of ADHD symptoms later in life remains elusive. Therefore, we aimed to fill this gap by exploring brain and clinical changes in youth with ADHD using a longitudinal design.
This prospective study consisted of 74 children and adolescents with ADHD and 50 age-, sex-, intelligence-matched typically developing controls (TDC), evaluated at baseline (aged 7–19 years) and re-evaluated 5.3 years later (a mean follow-up latency). We applied voxel-based morphometry to characterize brain structures, followed by both mass-univariate and multivariate structural covariance statistics to identify brain regions with significant diagnosis-by-time interactions from late childhood/adolescence to early adulthood. We used the cross-lagged panel model to investigate the longitudinal association between structural brain metrics and core ADHD symptoms.
The mass-univariate statistic revealed significant diagnosis-by-time interactions in the right striatum and the sixth lobule of the cerebellum. This was expressed by increased striatal and decreased cerebellar volume in ADHD, while TDC showed inverse volume changes over time. The multivariate method showed significant diagnosis-by-time interactions in a structural covariance network consisting of the regions involved in the functional sensory-motor and default-mode networks. Higher baseline right striatal and cerebellar volumes were associated with elevated ADHD symptoms at follow-up.
Our findings suggest a temporal association between the divergent development of striatal and cerebellar regions and dynamical ADHD phenotypic expression through young adulthood. These results highlight a potential brain marker of future outcomes.
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Gray matter (GM) abnormalities have been reported in both adults and children/adolescents with histories of childhood maltreatment (CM). A comparison of effects in youth and adulthood may be informative regarding life-span effects of CM. Voxel-wise meta-analyses of whole-brain voxel-based morphometry studies were conducted in all datasets and age-based subgroups respectively, followed by a quantitative comparison of the subgroups. Thirty VBM studies (31 datasets) were included. The pooled meta-analysis revealed increased GM in left supplementary motor area, and reduced GM in bilateral cingulate/paracingulate gyri, left occipital lobe, and right middle frontal gyrus in maltreated individuals compared to the controls. Maltreatment-exposed youth showed less GM in the cerebellum, and greater GM in bilateral middle cingulate/paracingulate gyri and bilateral visual cortex than maltreated adults. Opposite GM alterations in bilateral middle cingulate/paracingulate gyri were found in maltreatment-exposed adults (decreased) and children/adolescents (increased). Our findings demonstrate different patterns of GM changes in youth closer to maltreatment events than those seen later in life, suggesting detrimental effects of CM on the developmental trajectory of brain structure.
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Although there is some evidence for a normalization of brain structure following exposure to ADHD medication, literature on the effects of duration and dose of continued use on the brain is scarce. Here, we investigated the association between cumulative exposure to medication (range 1 week to 4.69 years) and cortical structures and subcortical volumes in a clinical sample of children with ADHD taking medication (n = 109). To the best of our knowledge, this is the first structural MRI study investigating the effects of cumulative exposure to medication on subregional volumes in children treated for ADHD.
Cumulative exposure to ADHD medication (CEM) was defined as the product of duration on medication (days) and dose (mg/day), yielding the area under the curve (total mg). Cortical thickness and surface area measurements (CIVET-1.1.12), and subcortical volumes in 51 regions (MAGeT-Brain) were analyzed using general linear modelling.
Significant effects of CEM were found in two subregions of the left hippocampus, the CA1 (df = 95; q = 0.003) and the strata radiatum/lacunosum/moleculare (df = 95; q = 0.003). Specifically, higher CEM was associated with smaller volumes within these subregions. No effects of medication exposure were detected on cortical thickness or surface area.
Although this study is cross-sectional, the results found within this sample of children show that prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions. More research is required to determine whether these results are reproduced in other samples of children of ADHD, and further, whether these are beneficial or off-target effects of the medication.
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Determinar si existen diferencias en el grosor macular y papilar mediante tomografía de coherencia óptica (OCT) en pacientes con trastorno por déficit de atención e hiperactividad (TDAH) comparando con un grupo control, evaluando además si existen diferencias entre pacientes con TDAH con y sin tratamiento.
Estudio transversal en el que se incluyó a 92 ojos de 46 pacientes, divididos en 2 grupos: 46 ojos de 23 pacientes con TDAH y un grupo control de 46 ojos de 23 sujetos. El grupo de pacientes con TDAH se subdividió en aquellos con tratamiento con metilfenidato o derivados (n = 28) y aquellos sin tratamiento (n = 18). Se midió el grosor macular, el complejo de células ganglionares (CCG) y la capa de fibras nerviosas de la retina (CFNR) a nivel papilar en 12 sectores.
Se observó un menor grosor macular central en los TDAH que en controles (257,4 ± 20 μm vs. 267,5 ± 20 μm; p = 0,013), no observándose diferencias en el CCG (p ≥ 0,566), ni en la CFNR (p ≥ 0,095). En los pacientes con TDAH con y sin tratamiento no se observaron diferencias en el grosor macular ni en el CCG (p ≥ 0,160 y 0,375, respectivamente), pero se objetivó un menor grosor foveal (p = 0,018) y de la CFNR en 5/12 sectores a nivel papilar (p ≤ 0,033) en aquellos sin tratamiento.
Se observó un menor grosor macular en los pacientes con TDAH que en controles. Además, los pacientes con TDAH sin tratamiento presentaron un menor grosor foveal y de la CFNR que aquellos pacientes en tratamiento.
To assess if there are any differences in macular and papillary thickness using optical coherence tomography (OCT) in patients with attention deficit hyperactivity disorder (ADHD) compared with a control group, including if there are differences between ADHD patients with and without treatment.
Prospective observational study including 92 eyes of 46 patients divided into 2 groups: 46 eyes of 23 patients with ADHD, and a control group of 46 eyes of 23 healthy patients. The group of patients with ADHD was subdivided into those on treatment with methylphenidate (n = 28) and those not on treatment (n = 18). The macular thickness, the ganglion cell complex (GCC), and the retinal nerve fibre layer (RNFL) at the papillary level were measured in 12 sectors.
A lower central macular thickness was observed in the ADHD patients than in the controls (257.4 ± 20 μm versus 267.5 ± 20 μm, P=.013), with no differences observed in the GCC (P=.566), or in the RNFL (P=.095). There were no differences in the patients with ADHD with and without treatment, as regards macular thickness and the GCC (P=.160 and P=.375 respectively), but a lower foveal thickness (P=.018) and RNFL in 5/12 sectors at the papillary level (P=.033) were observed in those without treatment.
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The role of cerebellum in the child neuropsychological functioning
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This chapter proposes a review of neuropsychologic and behavior findings in pediatric pathologies of the cerebellum, including cerebellar malformations, pediatric ataxias, cerebellar tumors, and other acquired cerebellar injuries during childhood. The chapter also contains reviews of the cerebellar mutism/posterior fossa syndrome, reported cognitive associations with the development of the cerebellum in typically developing children and subjects born preterm, and the role of the cerebellum in neurodevelopmental disorders such as autism spectrum disorders and developmental dyslexia. Cognitive findings in pediatric cerebellar disorders are considered in the context of known cerebellocerebral connections, internal cellular organization of the cerebellum, the idea of a universal cerebellar transform and computational internal models, and the role of the cerebellum in specific cognitive and motor functions, such as working memory, language, timing, or control of eye movements. The chapter closes with a discussion of the strengths and weaknesses of the cognitive affective syndrome as it has been described in children and some conclusions and perspectives.
Characterization of cortical and subcortical abnormalities in drug-naive boys with attention-deficit/hyperactivity disorder
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Citation Excerpt :
However, according to previous studies, patients with ADHD presenting with comorbidities, such as oppositional defiant disorder, simple phobia and dysthymic disorder, show a different cortical morphometry than patients with ADHD without comorbidities (Wolosin et al., 2009). In addition, compared to non-medicated patients with ADHD, medicated patients with ADHD have more normal volumes and/or morphology in ADHD-relevant brain regions, including the anterior cingulate cortex (Semrud-Clikeman et al., 2006), cerebellum (Bledsoe et al., 2009), and basal ganglia (Sobel et al., 2010). Finally, ADHD is diagnosed more frequently in males than in females (2–4 to 1), and evidence suggests that there are different underlying neuropathophysiological processes between boys and girls with ADHD (Davies, 2014; Qiu et al., 2009).
The current study was designed to investigate the anatomical differences in cortical and subcortical morphometry between drug-naive boys with attention-deficit/hyperactivity disorder (ADHD) and healthy controls (HCs) using three-dimensional T1-weighted imaging and to explore the effects of age on morphometric abnormalities.
Fifty-three drug-naive boys with ADHD and 53 HCs underwent high-resolution anatomical magnetic resonance (MR) imaging using a 3-T MR scanner. The FreeSurfer image analysis suite was used to obtain measures of cortical volume, thickness, and surface area, as well as the volumes of 14 subcortical structures. Statistically significant differences in measures between children with ADHD and HCs were evaluated using a least general linear model, with the intracranial volume and age as covariates.
Compared to HCs, boys with ADHD exhibited an increased cortical volume in the left frontal eye field (FEF), a decreased surface area in the left ventral frontal cortex (VFC), and a decreased volume in the right putamen (cluster-wise p < 0.05; Monte Carlo-corrected). Moreover, we also observed age-related differences in FEF and VFC between groups.
The cross-sectional study design limited inferences about the effects of age on regions displaying morphometric differences.
To our knowledge, this study is the first to characterize the cortical morphometry, including volume, thickness and surface area, of drug-naive boys with ADHD at the whole brain level; which provided detailed information about neuroanatomical alterations in attention systems beyond effects reported in previous studies at the lobe and sub-lobe levels. Based on our results, boys with ADHD presented significant alterations in cortical and subcortical morphology in several important nodes of the attention network.

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Research ReportA Magnetic Resonance Imaging Study of the Cerebellar Vermis in Chronically Treated and Treatment-Naïve Children with Attention-Deficit/Hyperactivity Disorder Combined Type

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

J Am Acad Child Adolesc Psychiatry

Biol Psychiatry

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Survey Replication

Am J Psychiatry

Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD

Psychol Bull

Cognitive Neuroscience of Attention

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

JAMA

Brain morphology in developmental dyslexia and attention-deficit disorder/hyperactivity

Arch Neurol

Etiological subtypes of attention-deficit/hyperactivity disorder: Brain imaging, molecular genetics, and environmental factors and the dopamine hypothesis

Neuropsychol Rev

Brain morphometry in Tourette's syndrome: The influence of comorbid attention-deficit/hyperactivity disorder

Neurology

Research Report
A Magnetic Resonance Imaging Study of the Cerebellar Vermis in Chronically Treated and Treatment-Naïve Children with Attention-Deficit/Hyperactivity Disorder Combined Type