Memory and learning in children with 22q11.2 deletion syndrome: evidence for ventral and dorsal stream disruption?

This study examined memory functioning in children and adolescents with 22q11.2 Deletion Syndrome (DS; velocardiofacial syndrome). An overall verbal better than nonverbal memory pattern was evident on the Test of Memory and Learning (TOMAL), with children with 22q11.2 DS performing significantly below their siblings and children with low average IQ but similar to children with autism on facial memory. Children with 22q11 DS also performed significantly below their siblings on tests of verbal working memory. Children with autism performed significantly poorer than the siblings of children with 22q11.2 DS only on their recall of stories. Delayed recall was significantly poorer in children with 22q11.2 DS and children with autism, compared to sibling controls. Although there were no significant group differences on tests of multiple trial verbal or visual learning, a relative weakness was noted with multiple trial visual learning in children with 22q11.2 DS and their siblings, suggesting that an alternative or interactive factor other than the deletion may account for the relatively better verbal compared to nonverbal memory abilities. Deficits in facial memory in children with both 22q11.2 DS and autism suggest disruptions in ventral temporal pathways such as between fusiform gyrus and parahippocampal/hippocampal regions whereas deficits in verbal working memory in children with 22q11.2 DS implicates dorsolateral prefrontal regions, both intimating aberrant white matter pathways.     

Numerical magnitude processing impairments in genetic syndromes: a cross‐syndrome comparison of Turner and 22q11.2 deletion syndromes

Cross‐syndrome comparisons offer an important window onto understanding heterogeneity in mathematical learning disabilities or dyscalculia. The present study therefore investigated symbolic numerical magnitude processing in two genetic syndromes that are both characterized by mathematical learning disabilities: Turner syndrome and 22q11.2 deletion syndrome (22q11DS). We further verified whether the phenotypic outcomes of these syndromes emerged from the same or different cognitive processes and therefore examined whether numerical impairments were related to working memory deficits, often observed in these syndromes. Participants were 24 girls with Turner syndrome, 25 children with 22q11DS and 48 well‐matched typically developing control children. All children completed a symbolic numerical magnitude comparison task and four additional working memory tasks. Both groups of children with genetic syndromes showed similar impairments in symbolic numerical magnitude processing compared to typically developing controls. Importantly, in Turner syndrome, group differences in symbolic numerical magnitude processing disappeared when their difficulties in visual‐spatial working memory were taken into account. In contrast, the difficulties in 22q11DS were not explained by poor visual‐spatial working memory. These data suggest that different factors underlie the symbolic numerical magnitude processing impairments in both patient groups with mathematical learning disabilities and highlight the value of cross‐syndrome comparisons for understanding different pathways to mathematical learning disabilities or dyscalculia.     

Neuropsychological characteristics of children with the 22q11 Deletion Syndrome: a descriptive analysis.

Previous reports of cognitive functioning in children with the 22q11 Deletion Syndrome have reported marked variability in IQ and achievement subtest scores. Studies have begun to explore neuropsychological function in 22q11 DS however results are inconsistent and the profile incomplete. We assessed 40 children ages 5-12 with 22q11 DS. Consistent with past results, visual-spatial memory was significantly lower than verbal memory. Differentially lowered scores were found only in visual attention, working memory and motor function. Contrary with some past results quantitative, verbal ability, and visual spatial memory scores were within 1 SD from the standardization sample mean. Motor behavior, not typically discussed with regard to 22q11 DS school-age children, may be critical to incorporate in neurocognitive studies of children with 22q11 DS. Implications of these findings are considered with regard to past results.     

Gender-moderated dorsolateral prefrontal reductions in 22q11.2 Deletion Syndrome: implications for risk for schizophrenia.

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.     

Gender-Moderated Dorsolateral Prefrontal Reductions in 22q11.2 Deletion Syndrome: Implications for Risk for Schizophrenia

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.     

The Motor Profile of Primary School-Age Children with a 22q11.2 Deletion Syndrome (22q11.2DS) and an Age- and IQ-Matched Control Group

In the early publications on the 22q11.2 Deletion Syndrome (22q11.2DS) motor abnormalities have been frequently reported. However, systematic studies on the motor performance of children with the 22q11.2DS, and especially of school-age children, are scarce. In this study the motor performance of primary school-age children with a 22q11.2DS (n = 28) was compared with an age- and IQ-matched control group (n = 28) using the Movement Assessment Battery for Children (MABC), the Körperkoordinationstest für Kinder (KTK) and the Beery-Buctenica test of Visual-Motor Integration (Beery). Children with a 22q11.2DS scored significantly lower than the age- and IQ-matched control group on the subsection Manual Dexterity (MABC) and the Visual Perception and Motor Coordination subtests of the Beery. When investigating the correlations between Intelligence quotient (IQ) and motor performance, a specific profile was found in the 22q11.2DS group when compared with the age- and IQ-matched control group. Because an IQ-matched control group was adopted, the deficits in visual-perceptual and visuomotor integration skills cannot fully be attributed to a general developmental delay and thus may be specific for the 22q11.2DS. Future studies that investigate the specificity of the visual-perceptual problems — both on the behavioral and brain level (functional Magnetic Resonance Imaging [fMRI] and Diffusion Tensor Imaging [DTI]) — are necessary to answer this question. Nonetheless, the importance of incorporating motor functioning into the study of the neuropsychological profile of children with a 22q11.2DS has to be stressed.     

Executive functioning and its relation to ASD and ADHD symptomatology in 22q11.2 deletion syndrome*

Children with 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial-syndrome) are at risk for the developmental disorders, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this study, the relation between executive functioning (EF) and the severity of ADHD and ASD symptoms is examined, since EF is known to be important in relation to emotional and behavioral problems. The participants consist of 58 children (38 females) with a mean age of 13.5 years (SD 2.6). Standardized assessment was used to evaluate the severity of ASD and ADHD symptomatology. The major aspects of EF, i.e., cognitive flexibility, inhibition, sustained attention, distractibility, working memory and reaction speed, were evaluated. The profile of EF in 22q11DS was found to be characterized by weaker performance compared to the norms on all subdomains of EF. Poor cognitive flexibility and inhibition, as well as high distractibility, were found to be related to more severe ASD symptoms, while poor quality of sustained attention and high distractibility were found to be related to more severe ADHD symptoms. It is concluded that children with 22q11DS experience impairments in EF, and that the degree of impairment on specific EF subdomains is related to the severity of ASD and/or ADHD symptomatology. These results may help in defining the mediating role of neurocognitive dysfunctions in the development of social and behavioral problems in 22q11DS.     

Cognitive contributions to theory of mind ability in children with a traumatic head injury

The objective of the current study is to examine the contribution of intellectual abilities, executive functions (EF), and facial emotion recognition to difficulties in Theory of Mind (ToM) abilities in children with a traumatic head injury. Israeli children with a traumatic head injury were compared with their non-injured counterparts. Each group included 18 children (12 males) ages 7–13. Measurements included reading the mind in the eyes, facial emotion recognition, reasoning the other’s characteristics based on motive and outcome, Raven’s Coloured Progressive Matrices, similarities and digit span (Wechsler Intelligence Scale for Children – Revised 95 subscales), verbal fluency, and the Behaviour Rating Inventory of Executive Functions. Non-injured children performed significantly better on ToM, abstract reasoning, and EF measures compared with children with a traumatic head injury. However, differences in ToM abilities between the groups were no longer significant after controlling for abstract reasoning, working memory, verbal fluency, or facial emotion recognition. Impaired ToM recognition and reasoning abilities after a head injury may result from other cognitive impairments. In children with mild and moderate head injury, poorer performance on ToM tasks may reflect poorer abstract reasoning, a general tendency to concretize stimuli, working memory and verbal fluency deficits, and difficulties in facial emotion recognition, rather than deficits in the ability to understand the other’s thoughts and emotions. ToM impairments may be secondary to a range of cognitive deficits in determining social outcomes in this population.     

Peer Relationships and Emotional Well-Being of Children with Sickle Cell Disease: A Controlled Replication

This study investigated the effects of stimulus presentation modality on working memory performance in elementary school-age children ages 7–13. The experimental paradigm implemented a multitrial learning task incorporating three presentation modalities: Auditory, Visual, and simultaneous Auditory plus Visual. The first experiment compared the learning and memory performance of older and younger elementary school children. The second experiment compared verbal learning and memory performance in elementary school children with major depressive disorder (MDD) to the performance of nondepressed children. All participants benefited from the pictorial presentation of information during learning and recall of information as compared to the auditory presentation alone. Both age and socioeconomic status affected working memory performance in typically developing children. Children with depression demonstrated a more passive learning style during the auditory list acquisition. The present study supports the pictorial superiority hypothesis in verbal learning tasks and the theory that working memory matures during elementary school years. Furthermore, current results indicate that complex working memory measures are not entirely independent of previous experience.     

Stimulus modality and working memory performance in Greek children with reading disabilities: Additional evidence for the pictorial superiority hypothesis

This study investigated the effects of stimulus presentation modality on working memory performance in children with reading disabilities (RD) and in typically developing children (TDC), all native speakers of Greek. It was hypothesized that the visual presentation of common objects would result in improved learning and recall performance as compared to the auditory presentation of stimuli. Twenty children, ages 10–12, diagnosed with RD were matched to 20 TDC age peers. The experimental tasks implemented a multitrial verbal learning paradigm incorporating three modalities: auditory, visual, and auditory plus visual. Significant group differences were noted on language, verbal and nonverbal memory, and measures of executive abilities. A mixed-model MANOVA indicated that children with RD had a slower learning curve and recalled fewer words than TDC across experimental modalities. Both groups of participants benefited from the visual presentation of objects; however, children with RD showed the greatest gains during this condition. In conclusion, working memory for common verbal items is impaired in children with RD; however, performance can be facilitated, and learning efficiency maximized, when information is presented visually. The results provide further evidence for the pictorial superiority hypothesis and the theory that pictorial presentation of verbal stimuli is adequate for dual coding.     

Toddlers with Elevated Autism Symptoms Show Slowed Habituation to Faces

We explored social information processing and its relation to social and communicative symptoms in toddlers with Autism Spectrum Disorder (ASD) and their siblings. Toddlers with more severe symptoms of autism showed slower habituation to faces than comparison groups; slower face learning correlated with poorer social skills and lower verbal ability. Unaffected toddlers who were siblings of children with ASD also showed slower habituation to faces compared with toddlers without siblings with ASD. We conclude that slower rates of face learning may be an endophenotype of ASD and is associated with more severe symptoms among affected individuals.     

Atypical neuropsychological profile in a boy with 22q11.2 Deletion Syndrome.

In this article the general and specific cognitive impairments of the boy R.H. with a de novo deletion 22q11.2 are described. His full-scale IQ was 73, and he obtained only slightly better verbal than non-verbal subtest scores. Neuropsychological assessment revealed specific impairments in perceptual categorization of objects presented suboptimal, matching of unfamiliar faces, and verbal learning and memory. In contrast, he performed in accordance with his intelligence level on other visual perceptual tasks, on non-verbal learning and memory tasks, and on attention tasks. Voxel-wise statistical comparison of a high-resolution T1-weighted magnetic resonance image of R.H's brain with similar images obtained from 14 normal control children revealed as major abnormalities a reduction of the right inferior parietal and superior occipital lobe, and a bilateral reduction of deep white matter behind the inferior frontal gyrus. These cognitive impairments and MRI abnormalities are not commonly described in 22q11.2 Deletion Syndrome and may indicate a larger heterogeneity in the neurocognitive phenotype than currently evidenced. At least in this boy the microdeletion seems to have interfered with the development and functioning of particular neural subsystems, while the structure and functioning of other subsystems was left intact.     

Atypical Neuropsychological Profile in a Boy with 22q11.2 Deletion Syndrome Keywords:

In this article the general and specific cognitive impairments of the boy R.H. with a de novo deletion 22q11.2 are described. His full-scale IQ was 73, and he obtained only slightly better verbal than non-verbal subtest scores. Neuropsychological assessment revealed specific impairments in perceptual categorization of objects presented suboptimal, matching of unfamiliar faces, and verbal learning and memory. In contrast, he performed in accordance with his intelligence level on other visual perceptual tasks, on non-verbal learning and memory tasks, and on attention tasks. Voxel-wise statistical comparison of a high-resolution T1-weighted magnetic resonance image of R.H’s brain with similar images obtained from 14 normal control children revealed as major abnormalities a reduction of the right inferior parietal and superior occipital lobe, and a bilateral reduction of deep white matter behind the inferior frontal gyrus. These cognitive impairments and MRI abnormalities are not commonly described in 22q11.2 Deletion Syndrome and may indicate a larger heterogeneity in the neurocognitive phenotype than currently evidenced. At least in this boy the microdeletion seems to have interfered with the development and functioning of particular neural subsystems, while the structure and functioning of other subsystems was left intact.     

The Effect of Morphological Complexity on Verbal Working Memory: Results from Arabic Speaking Children

To examine the role of morphology in verbal working memory. Forty nine children, all native speakers of Arabic from the same region and of the same dialect, performed a Listening Word Span Task, whereby they had to recall Arabic uninflected words (i.e., base words), inflected words with regular (possessive) morphology, or inflected words with irregular (broken plural) morphology. Each of these words was at the end of a sentence (henceforth, target word). The participant’s task was to listen to a series of sentences and then recall the target words. Recall of inflected words was significantly poorer than uninflected words, and recall of words with regular morphology was significantly poorer than recall of words with irregular morphology. These findings, albeit preliminary, suggest a role of morphology in verbal working memory. They also suggest that, at least in Arabic, regular morphological forms are decomposed into their component elements and hence impose an extra load on the central executive and episodic buffer components of working memory. Furthermore, in concert with findings from other studies, they suggest that the effect of morphology on working memory is probably language-specific. The clinical implications of the present findings are addressed.     

Listening comprehension and working memory are impaired in attention-deficit hyperactivity disorder irrespective of language impairment

This study investigated listening comprehension and working memory abilities in children with attention-deficit hyperactivity disorder (ADHD), presenting with and without language impairments (LI). A 4-group design classified a community sample (n = 77) of boys aged 9–12 into ADHD, ADHD + LI, LI, and Normal groups. Children completed tests of basic language and cognitive skills, verbal and spatial working memory, and passage-level listening comprehension. Multivariate analyses and post hoc comparisons indicated that ADHD children who did not have co-occurring LI comprehended factual information from spoken passages as well as normal children, but were poorer at comprehending inferences and monitoring comprehension of instructions. ADHD children did not differ from normal children in verbal span, but showed significantly poorer verbal working memory, spatial span, and spatial working memory. The ADHD + LI and LI groups were most impaired in listening comprehension and working memory performance, but did not differ from each other. Listening comprehension skills were significantly correlated with both verbal and spatial working memory, and parent–teacher ratings of inattention and hyperactivity/impulsivity. Findings that children with ADHD but no LI showed subtle higher-level listening comprehension deficits have implications for both current diagnostic practices and conceptualizations of ADHD.     

Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome

Dopamine plays a critical role in regulating neural activity in prefrontal cortex (PFC) and modulates cognition via a hypothesized inverse U function. We investigated PFC function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in which one copy of catechol-O-methyltransferase (COMT) is deleted, thereby shifting them toward the lower end of dopamine turnover on the nonlinear function. A common polymorphism with valine to methionine substitution alters COMT activity that results in higher enzyme activity in the valine variant. Twenty-seven children with 22q11.2DS between 7 and 14 years old, and 21 age-matched typically developing children, performed a modified version of the Attention Network Test. Children with a single valine allele showed a reduction in response times when trials with incongruent flankers were repeated, whereas those who were hemizygous for the methionine allele did not show the same context-based response facilitation. Our results support that a single gene, COMT, could modulate PFC-dependent cognition.     

How does the severity of a learning disability affect working memory performance?

Working memory performance was examined in children aged 11-12 years who had borderline, mild, and moderate learning disabilities. Comparisons with children of average abilities were used to determine whether those with more severe learning disabilities had greater impairments in working memory. Seven measures of working memory span were used to assess temporary phonological short-term storage (digit span, word span), temporary visuo-spatial short-term storage (pattern span, spatial span), and temporary short-term storage with additional processing, or central executive, demands (listening span. odd one out span, reverse digit span). Children with mild and moderate learning disabilities were impaired on all measures of working memory compared to children of average abilities. Children with borderline learning disabilities were just as good as children with average abilities on visuo-spatial and complex span tasks, but showed an impairment on phonological span tasks. Children with moderate learning disabilities were indistinguishable from children with mild learning disabilities on simple span tasks, but were significantly poorer than the mild group on the more demanding complex span tasks. For the group as a whole, working memory was strongly related to mental age.     

How does the severity of a learning disability affect working memory performance?

Working memory performance was examined in children aged 11-12 years who had borderline, mild, and moderate learning disabilities. Comparisons with children of average abilities were used to determine whether those with more severe learning disabilities had greater impairments in working memory. Seven measures of working memory span were used to assess temporary phonological short-term storage (digit span, word span), temporary visuo-spatial short-term storage (pattern span, spatial span), and temporary short-term storage with additional processing, or central executive, demands (listening span, odd one out span, reverse digit span). Children with mild and moderate learning disabilities were impaired on all measures of working memory compared to children of average abilities. Children with borderline learning disabilities were just as good as children with average abilities on visuo-spatial and complex span tasks, but showed an impairment on phonological span tasks. Children with moderate learning disabilities were indistinguishable from children with mild learning disabilities on simple span tasks, but were significantly poorer than the mild group on the more demanding complex span tasks. For the group as a whole, working memory was strongly related to mental age.     

Maladaptive conflict monitoring as evidence for executive dysfunction in children with chromosome 22q11.2 deletion syndrome

Using an adaptation of the Attentional Networks Test, we investigated aspects of executive control in children with chromosome 22q11.2 deletion syndrome (DS22q11.2), a common but not well understood disorder that produces non-verbal cognitive deficits and a marked incidence of psychopathology. The data revealed that children with DS22q11.2 demonstrated greater difficulty than controls in locating and processing target items in the presence of distracters. Importantly, children with DS22q11.2 showed a deficit in the ability to monitor and adapt to stimulus conflict. These data provide evidence of inadequate conflict adaptation in children with DS22q11.2, a problem that is also present in schizophrenia. The findings of specific executive dysfunction in this group may provide a linkage between particular genetic abnormalities and the development of psychopathology.     

Domain specific attentional impairments in children with chromosome 22q11.2 deletion syndrome

One of the defining cognitive characteristics of the chromosome 22q deletion syndrome (DS22q11.2) is visuospatial processing impairments. The purpose of this study was to investigate and extend the specific attentional profile of children with this disorder using both an object-based attention task and an inhibition of return task. A group of children with the disorder was compared in these tasks with a group of age-matched typically developing children. The children with DS22q11.2 demonstrated impaired spatially based orienting which is consistent with previous findings in this group. Strikingly, the children with DS22q11.2 also demonstrated an improved ability to use object-based cues, relative to the typically developing group. Finally, the children with DS22q11.2 demonstrated an intact inhibition of return system, however, it appears to be delayed developmentally.