Deana Crocetti

Reduced GABA Concentration in Attention-Deficit/Hyperactivity Disorder

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a deficit in behavioral inhibition. Recent evidence also suggests a deficit in cortical inhibition via the GABA (γ-aminobutyric acid)-ergic system. OBJECTIVE To investigate the GABAergic component of ADHD using magnetic resonance spectroscopy. DESIGN Cross-sectional study. SETTING Participants were recruited through local schools, local pediatric and other community clinics, and through advertisement in regional publications. Magnetic resonance spectroscopy was performed within the research institute. PARTICIPANTS Children (age range, 8-12 years) in a typically developing control group vs a group with ADHD were compared. MAIN OUTCOME MEASURES J-difference-edited magnetic resonance spectroscopy at 3 T was used to measure GABA concentration in a volume that included primary somatosensory and motor cortices. RESULTS GABA concentration is reduced in children with ADHD compared with typically developing control subjects. CONCLUSION Our finding of reduced GABA concentration in ADHD is concordant with recently reported deficits in short intracortical inhibition in ADHD and suggests a GABAergic deficit in ADHD.

Basal Ganglia Shapes Predict Social, Communication, and Motor Dysfunctions in Boys With Autism Spectrum Disorder

OBJECTIVE Basal ganglia abnormalities have been suggested as contributing to motor, social, and communicative impairments in autism spectrum disorder (ASD). Volumetric analyses offer limited ability to detect localized differences in basal ganglia structure. Our objective was to investigate basal ganglia shape abnormalities and their association with behavioral features of ASD, which may involve multiple frontal-subcortical circuits. METHOD Basal ganglia were manually delineated from MR images of 32 boys with ASD and 45 typically developing (TD) boys. Large deformation diffeomorphic metric mapping (LDDMM) was used to assess between-group differences in basal ganglia shape and to examine associations with motor, praxis, and reciprocal social and communicative impairments in ASD. RESULTS Boys with ASD showed changes in right basal ganglia shape as compared with TD boys; surface deformation was present in the caudate, putamen, and globus pallidus but did not stand up to correction for multiple comparisons. Brain-behavior correlation findings were more robust; analyses accounting for multiple comparisons revealed, in boys with ASD, surface inward deformation of the right posterior putamen predicted poorer motor skill, whereas surface inward deformation of the bilateral anterior and posterior putamen predicted poorer praxis. Surface outward deformation in the bilateral medial caudate head predicted greater reciprocal social and communicative impairment. CONCLUSIONS Motor, social, and communicative impairments in boys with ASD are associated with shape abnormalities in the basal ganglia. The findings suggest abnormalities within parallel frontal-subcortical circuits are differentially associated with impaired acquisition of motor and reciprocal social and communicative skills in ASD.

Behavioural and neural basis of anomalous motor learning in children with autism

Autism spectrum disorder is a developmental disorder characterized by deficits in social and communication skills and repetitive and stereotyped interests and behaviours. Although not part of the diagnostic criteria, individuals with autism experience a host of motor impairments, potentially due to abnormalities in how they learn motor control throughout development. Here, we used behavioural techniques to quantify motor learning in autism spectrum disorder, and structural brain imaging to investigate the neural basis of that learning in the cerebellum. Twenty children with autism spectrum disorder and 20 typically developing control subjects, aged 8-12, made reaching movements while holding the handle of a robotic manipulandum. In random trials the reach was perturbed, resulting in errors that were sensed through vision and proprioception. The brain learned from these errors and altered the motor commands on the subsequent reach. We measured learning from error as a function of the sensory modality of that error, and found that children with autism spectrum disorder outperformed typically developing children when learning from errors that were sensed through proprioception, but underperformed typically developing children when learning from errors that were sensed through vision. Previous work had shown that this learning depends on the integrity of a region in the anterior cerebellum. Here we found that the anterior cerebellum, extending into lobule VI, and parts of lobule VIII were smaller than normal in children with autism spectrum disorder, with a volume that was predicted by the pattern of learning from visual and proprioceptive errors. We suggest that the abnormal patterns of motor learning in children with autism spectrum disorder, showing an increased sensitivity to proprioceptive error and a decreased sensitivity to visual error, may be associated with abnormalities in the cerebellum.

Cerebellar gray matter and lobular volumes correlate with core autism symptoms.

Neuroanatomical differences in the cerebellum are among the most consistent findings in autism spectrum disorder (ASD), but little is known about the relationship between cerebellar dysfunction and core ASD symptoms. The newly-emerging existence of cerebellar sensorimotor and cognitive subregions provides a new framework for interpreting the functional significance of cerebellar findings in ASD. Here we use two complementary analyses — whole-brain voxel-based morphometry (VBM) and the SUIT cerebellar atlas — to investigate cerebellar regional gray matter (GM) and volumetric lobular measurements in 35 children with ASD and 35 typically-developing (TD) children (mean age 10.4 ± 1.6 years; range 8–13 years). To examine the relationships between cerebellar structure and core ASD symptoms, correlations were calculated between scores on the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview (ADI) and the VBM and volumetric data. Both VBM and the SUIT analyses revealed reduced GM in ASD children in cerebellar lobule VII (Crus I/II). The degree of regional and lobular gray matter reductions in different cerebellar subregions correlated with the severity of symptoms in social interaction, communication, and repetitive behaviors. Structural differences and behavioral correlations converged on right cerebellar Crus I/II, a region which shows structural and functional connectivity with fronto-parietal and default mode networks. These results emphasize the importance of the location within the cerebellum to the potential functional impact of structural differences in ASD, and suggest that GM differences in cerebellar right Crus I/II are associated with the core ASD profile.

Distinct frontal lobe morphology in girls and boys with ADHD

Objective This study investigated whether frontal lobe cortical morphology differs for boys and girls with ADHD (ages 8–12 years) in comparison to typically developing (TD) peers. Method Participants included 226 children between the ages of 8–12 including 93 children with ADHD (29 girls) and 133 TD children (42 girls) for which 3T MPRAGE MRI scans were obtained. A fully automated frontal lobe atlas was used to generate functionally distinct frontal subdivisions, with surface area (SA) and cortical thickness (CT) assessed in each region. Analyses focused on overall diagnostic differences as well as examinations of the effect of diagnosis within boys and girls. Results Girls, but not boys, with ADHD showed overall reductions in total prefrontal cortex (PFC) SA. Localization revealed that girls showed widely distributed reductions in the bilateral dorsolateral PFC, left inferior lateral PFC, right medial PFC, right orbitofrontal cortex, and left anterior cingulate; and boys showed reduced SA only in the right anterior cingulate and left medial PFC. In contrast, boys, but not girls, with ADHD showed overall reductions in total premotor cortex (PMC) SA. Further localization revealed that in boys, premotor reductions were observed in bilateral lateral PMC regions; and in girls reductions were observed in bilateral supplementary motor complex. In line with diagnostic group differences, PMC and PFC SAs were inversely correlated with symptom severity in both girls and boys with ADHD. Conclusions These results elucidate sex-based differences in cortical morphology of functional subdivisions of the frontal lobe and provide additional evidence of associations among SA and symptom severity in children with ADHD.

A Preliminary Neuroimaging Study of Preschool Children with ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that, by current definition, has onset prior to age 7 years. MRI studies have provided some insight into brain differences associated with ADHD, but thus far have almost exclusively focused on children ages 7 years and older. To better understand the neurobiological development of ADHD, cortical and subcortical brain development should be systematically examined in younger children presenting with symptoms of the disorder. High-resolution anatomical (MPRAGE) images, acquired on a 3.0T scanner, were analyzed in a total of 26 preschoolers, ages 4–5 years (13 with ADHD, 13 controls, matched on age and sex). The ADHD sample was diagnosed using DSM-IV criteria, and screened for language disorders. Cortical regions were delineated and measured using automated methods in Freesurfer; basal ganglia structures were manually delineated. Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this age range. After controlling for age and total cerebral volume, left caudate volume was a significant predictor of hyperactive/impulsive, but not inattentive symptom severity. Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD.

Reduced GABA and altered somatosensory function in children with autism spectrum disorder

Background: Abnormal responses to tactile stimuli are a common feature of autism spectrum disorder (ASD). Several lines of evidence suggest that GABAergic function, which has a crucial role in tactile processing, is altered in ASD. In this study, we determine whether in vivo GABA levels are altered in children with ASD, and whether alterations in GABA levels are associated with abnormal tactile function in these children.

Manual MRI parcellation of the frontal lobe

The ability to examine associations between neuropsychiatric conditions and functionally relevant frontal lobe sub-regions is a fundamental goal in neuropsychiatry, but methods for identifying frontal sub-regions in MR (magnetic resonance) images are not well established. Prior published techniques have principally defined gyral regions that do not necessarily correspond to known functional divisions. We present a method in which sulcal-gyral landmarks are used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex, anterior cingulate, deep white matter, premotor cortex regions (supplementary motor complex (SMC), frontal eye field and lateral premotor cortex) and prefrontal cortex (PFC) regions (medial PFC, dorsolateral PFC (DLPFC), inferior PFC, lateral orbitofrontal cortex (OFC) and medial OFC). Feasibility was tested by applying the protocol to brain MR data from 15 boys with attention-deficit/hyperactivity disorder (ADHD) and 15 typically developing controls, 8-12 years old. Intra- and inter-rater intraclass correlation coefficients were calculated using parcellation volumes from a subset of that group. Inter-rater results for the 22 hemisphere specific sub-regions ranged from 0.724 to 0.997, with all but seven values above 0.9. Boys with ADHD showed significantly smaller left hemisphere SMC and DLPFC volumes after normalization for total cerebral volume. These findings support the method as a reliable and valid technique for parcellating the frontal lobe into functionally relevant sub-regions.

Comprehensive examination of frontal regions in boys and girls with attention-deficit/hyperactivity disorder

The current study examined regional frontal lobe volumes based on functionally relevant subdivisions in contemporaneously recruited samples of boys and girls with and without attention-deficit/hyperactivity disorder (ADHD). Forty-four boys (21 ADHD, 23 control) and 42 girls (21 ADHD, 21 control), ages 8-13 years, participated. Sulcal-gyral landmarks were used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex, anterior cingulate, deep white matter, premotor regions [supplementary motor complex (SMC), frontal eye field, lateral premotor cortex (LPM)], and prefrontal cortex (PFC) regions [medial PFC, dorsolateral PFC (DLPFC), inferior PFC, lateral orbitofrontal cortex (OFC), and medial OFC]. Compared to sex-matched controls, boys and girls with ADHD showed reduced volumes (gray and white matter) in the left SMC. Conversely, girls (but not boys) with ADHD showed reduced gray matter volume in left LPM; while boys (but not girls) with ADHD showed reduced white matter volume in left medial PFC. Reduced left SMC gray matter volumes predicted increased go/no-go commission rate in children with ADHD. Reduced left LPM gray matter volumes predicted increased go/no-go variability, but only among girls with ADHD. Results highlight different patterns of anomalous frontal lobe development among boys and girls with ADHD beyond that detected by measuring whole lobar volumes.

Segmentation of brain magnetic resonance images based on multi-atlas likelihood fusion: testing using data with a broad range of anatomical and photometric profiles

We propose a hierarchical pipeline for skull-stripping and segmentation of anatomical structures of interest from T1-weighted images of the human brain. The pipeline is constructed based on a two-level Bayesian parameter estimation algorithm called multi-atlas likelihood fusion (MALF). In MALF, estimation of the parameter of interest is performed via maximum a posteriori estimation using the expectation-maximization (EM) algorithm. The likelihoods of multiple atlases are fused in the E-step while the optimal estimator, a single maximizer of the fused likelihoods, is then obtained in the M-step. There are two stages in the proposed pipeline; first the input T1-weighted image is automatically skull-stripped via a fast MALF, then internal brain structures of interest are automatically extracted using a regular MALF. We assess the performance of each of the two modules in the pipeline based on two sets of images with markedly different anatomical and photometric contrasts; 3T MPRAGE scans of pediatric subjects with developmental disorders vs. 1.5T SPGR scans of elderly subjects with dementia. Evaluation is performed quantitatively using the Dice overlap as well as qualitatively via visual inspections. As a result, we demonstrate subject-level differences in the performance of the proposed pipeline, which may be accounted for by age, diagnosis, or the imaging parameters (particularly the field strength). For the subcortical and ventricular structures of the two datasets, the hierarchical pipeline is capable of producing automated segmentations with Dice overlaps ranging from 0.8 to 0.964 when compared with the gold standard. Comparisons with other representative segmentation algorithms are presented, relative to which the proposed hierarchical pipeline demonstrates comparative or superior accuracy.