Tony J. Simon

22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia

Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. These studies have highlighted a strong link between this genetic lesion and schizophrenia. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by the microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with cognitive dysfunction and psychiatric disorders.

Reconceptualizing the origins of number knowledge: A “non-numerical” account

This paper presents a new conceptualization of the origins of numerical competence in humans. I first examine the existing claim that infants are innately provided with a system of specifically numerical knowledge, consisting of both cardinal and ordinal concepts. I suggest instead that the observed behaviors require only simple perceptual discriminations based on domain-independent competencies. At most, these involve the formal equivalent of cardinal information. Finally, I present a “non-numerical” account that characterizes infants’ competencies with regard to numerosity as emerging primarily from some general characteristics of the human perception and attention system.

Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study

Chromosome 22q11.2 deletion syndrome is a highly prevalent genetic disorder whose manifestations include developmental disability and sometimes mental retardation. The few studies that have examined brain morphology in different samples from this population have found similar general patterns, mostly using region of interest measures. We employed voxel-based techniques to concurrently examine specific morphologic changes in multiple brain tissue measures. Results were similar to previous findings of volumetric reductions in the posterior brain. They also extended them in two ways. First, our methods provided greater specificity in the localization of changes detected. Second, the combination of our measures of gray and white matter along with cerebrospinal fluid volume and fractional anisotropy, which indicates the structure of white matter, showed a posterior displacement of and morphologic changes to the corpus callosum in affected children.

Neural Evidence Linking Visual Object Enumeration and Attention

Visual object enumeration is rapid and accurate for four or fewer items but slow and error-prone for over four items. This dichotomy has recently been linked to visual attentional phenomena by findings suggesting that subitizing of small sets of objects is preattentive whereas counting of over four items demands spatial shifts of attention. We evaluated this link at a neural level, using H215O positron emission tomography to measure changes in regional cerebral blood flow while subjects enumerated the number of target vertical bars that popped outof a 16-bar visual display consisting of both horizontal and vertical bars. Relative to a condition with a single target, subitizing (one to four targets) activated foci in the occipital extras-triate cortex, consistent with involvement of early, preattentive visual processes. Relative to subitizing, counting (five to eight targets) activated a widespread network of brain regions, including multiple foci implicated in shifting visual attention large regions of the superior parietal cortex bilaterally and a focus in the right inferior frontal cortex. These results offer the first direct neural support for mapping the subitizing-counting dichotomy onto separable processes mediating preattentive vision and shifts of visual attention.

Structure-Specific Statistical Mapping of White Matter Tracts

This paper describes a new statistical analysis framework for diffusion-based white matter studies. The framework is based on a recent unbiased normalization algorithm for diffusion tensor images. Taking advantage of the fact that most human white matter tracts are thin sheet-like structures, this framework uses deformable medial models to represent six of the major tracts in a white matter atlas derived for a given set of images. The medial representation allows one to average tensor-based features along directions perpendicular to the tracts, thus reducing data dimensionality and accounting for errors in normalization. Unlike earlier work in the area of tract-based spatial statistics (Smith et al, 2006), this framework enables the analysis of individual white matter structures, and provides a range of possibilities for computing statistics and visualizing differences between cohorts. The framework is demonstrated in a study of white matter differences in pediatric chromosome 22q deletion syndrome.

VISUOSPATIAL AND NUMERICAL COGNITIVE DEFICITS IN CHILDREN WITH CHROMOSOME 22Q11.2 DELETION SYNDROME

This article presents some of the earliest evidence of visuospatial and numerical cognitive deficits in children with the chromosome 22q11.2 deletion syndrome; a common but ill-understood genetic disorder resulting in medical complications, cognitive impairment, and brain morphologic changes. Relative to a group of typically developing controls, deleted children performed more poorly on tests of visual attentional orienting, visual enumeration and relative numerical magnitude judgment. Results showed that performance deficits in children with the deletion could not be explained by a global deficit in psychomotor speed. Instead, our findings are supportive of the hypothesis that visuospatial and numerical deficits in children with the chromosome 22q11.2 deletion are due, at least in part, to posterior parietal dysfunction.

Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism.

Increased Rate of Amygdala Growth in Children Aged 2 to 4 Years With Autism Spectrum Disorders: A Longitudinal Study

CONTEXT Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear. OBJECTIVE To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs). DESIGN Longitudinal structural magnetic resonance imaging study. SETTING Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community. PARTICIPANTS Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later. MAIN OUTCOME MEASURE Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated. RESULTS The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group. CONCLUSIONS Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.

The foundations of numerical thinking in a brain without numbers

Clearly, much more work needs to be done to establish firmly the neural substrates of quantification processing in visuospatial circuitry, but it already looks like a promising enterprise. Dehaene et al. have presented data that provide strong new evidence for the dichotomy between perceptually and conceptually based quantitative competence. However, the findings pose new questions about which common cultural experiences are necessary to stimulate our brains to organize themselves in such a way as to add these, initially unspecified, functional capabilities. The fact that societies still exist without requirements to go beyond a number system of three items19xYanomamo: The Last Days of Eden. Chagnon, N.A. See all References19, indicates that Dehaene et al.’s findings characterize a pattern of ontogenetic brain organization that has responded to ecological demands. Questions of how environmental stimulation transforms cognitive competence from one level to another are central to the field of developmental cognitive science. Unfortunately, these are not the kinds of investigations that many of us are experienced at tackling. With the powerful new tools of brain imaging to add to our experimental methods we have reached the point where we should be able to discover how mathematical thinking arises from a brain without numbers. These new findings of Dehaene et al. and Sathian et al. should stimulate us to do so with renewed zeal.

Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

IMPORTANCE Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.