Polygenic risk for psychiatric disorders correlates with executive function in typical development.

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome-wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.

Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children.

The neuregulin-1 (NRG1) gene is one of the best-validated risk genes for schizophrenia, and psychotic and bipolar disorders. The rs6994992 variant in the NRG1 promoter (SNP8NRG243177) is associated with altered frontal and temporal brain macrostructures and/or altered white matter density and integrity in schizophrenic adults, as well as healthy adults and neonates. However, the ages when these changes begin and whether neuroimaging phenotypes are associated with cognitive performance are not fully understood. Therefore, we investigated the association of the rs6994992 variant on developmental trajectories of brain macro- and microstructures, and their relationship with cognitive performance. A total of 972 healthy children aged 3-20 years had the genotype available for the NRG1-rs6994992 variant, and were evaluated with magnetic resonance imaging (MRI) and neuropsychological tests. Age-by-NRG1-rs6994992 interactions and genotype effects were assessed using a general additive model regression methodology, covaried for scanner type, socioeconomic status, sex and genetic ancestry factors. Compared with the C-carriers, children with the TT-risk-alleles had subtle microscopic and macroscopic changes in brain development that emerge or reverse during adolescence, a period when many psychiatric disorders are manifested. TT-children at late adolescence showed a lower age-dependent forniceal volume and lower fractional anisotropy; however, both measures were associated with better episodic memory performance. To our knowledge, we provide the first multimodal imaging evidence that genetic variation in NRG1 is associated with age-related changes on brain development during typical childhood and adolescence, and delineated the altered patterns of development in multiple brain regions in children with the T-risk allele(s).

Genome-wide association study of shared components of reading disability and language impairment.

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.

Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.

The serotonin transporter gene (SLC6A4, MIM 182138) is a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR.

Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study.

OBJECTIVE: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. METHODS: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. RESULTS: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. CONCLUSIONS: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.

Attention coordination and anticipatory control.

The coordination of the direction of selective attention is an adaptive function that may be one of the many anticipatory tools under cerebellar control. This chapter presents neurobehavioral, neurophysiological, and neuroimaging data to support our hypothesis that the cerebellum plays a role in attentional functions. We discuss the idea that the cerebellum is a master computational system that anticipates and adjusts responsiveness in a variety of brain systems (e.g., sensory, attention, memory, language, affect) to efficiently achieve goals determined by cerebral and other subcortical systems.

The influence of pattern type on children's block design performance.

This study sought to determine what factors contribute to normal developmental changes in performance on the block design task. The target models were systematically varied to emphasize global, intermediate, and local pattern structures. One hundred children between 4.5 and 9 years of age were tested in the first experiment. Correct performance and error types differed significantly as a function of age and pattern type. Broken configuration errors were particularly common for the global patterns. In the second experiment, 48 children between 4.5 and 8 years of age were tested using designs with a superimposed grid (cued condition). Error rates were lower in the cued condition and broken configuration errors were less frequent. These results suggest that children have more difficulty parsing more cohesive patterns, but they can modify their strategies when the square matrix is provided by the pattern structure.

Impairment in shifting attention in autistic and cerebellar patients.

MRI and autopsy evidence of early maldevelopment of cerebellar vermis and hemispheres in autism raise the question of how cerebellar maldevelopment contributes to the cognitive and social deficits characteristic of autism. Compared with normal controls, autistic patients and patients with acquired cerebellar lesions were similarly impaired in a task requiring rapid and accurate shifts of attention between auditory and visual stimuli. Neurophysiologic and behavioral evidence rules out motor dysfunction as the cause of this deficit. These findings are consistent with the proposal that in autism cerebellar maldevelopment may contribute to an inability to execute rapid attention shifts, which in turn undermines social and cognitive development, and also with the proposal that the human cerebellum is involved in the coordination of rapid attention shifts in a fashion analogous to its role in the coordination of movement.

ERP Evidence for a Shifting Attention Deficit in Patients with Damage to the Cerebellum.

Abstract In a previous study, we found that patients with damage to the neocerebellum were significantly impaired in the ability to rapidly shift their attention between ongoing sequences of auditory and visual stimuli (Akshoomoff & Courchesne, 1992). In the present study, young patients with damage to the neoccrebelluni were found to be impaired in rapidly shifting their mention between visual stimuli that occurred within a single location. Event-related potentials recorded during the shifting attention experiment suggested that this reflects a deficit in the. covert ability to selectively activate and deactivate attention. These results lend Further support to the hypothesis that the neocerebellum plays a role in the ability to rapidly shift attention.

A new role for the cerebellum in cognitive operations.

Over the last 2 centuries, the predominant view of the cerebellum has been that it is part of a motor control system. Evidence is now presented that the neocerebellum, the evolutionarily newest region of the cerebellum, may also be involved in a key mental operation: the voluntary shift of selective attention between sensory modalities. It is theorized that this newly recognized function may operate via previously described sensory modulation properties of the cerebellum and its many connections with areas known to be important for selective attention, such as the pulvinar, the superior colliculus, and the parietal and frontal cortices.

Contribution of the cerebellum to neuropsychological functioning: evidence from a case of cerebellar degenerative disorder.

A detailed neuropsychological evaluation was performed on a patient with an idiopathic cerebellar degenerative disorder. Significant deficits were found in verbal and nonverbal intelligence, verbal associative learning, and visuospatial skills. These deficits were not readily explained by motor control difficulties. In contrast to the patient's moderately impaired language abilities, he was severely impaired on a test of verbal fluency and demonstrated mild naming deficits. Severe cerebellar parenchymal volume loss was demonstrated by magnetic resonance examination. Supratentorial structures showed only minimal posterior parietal and occipital sulcal prominence. On neurological examination, this patient had signs of severe involvement of the cerebellar systems and mild-to-moderate dysfunction of the corticospinal tract. As is characteristic of patients with cerebellar degeneration, there was neurophysiological evidence of subclinical involvement of auditory and somatosensory pathways at the level of the brain stem. Since relatively little cerebral cortical atrophy was noted in this patient, these findings suggest that an intact cerebellum is important for normal cognitive functions.

Brainstem auditory evoked potentials in receptive developmental language disorder.

It has been hypothesized that receptive developmental language disorder (RDLD) may be explained by an auditory processing deficit. The neuroanatomical locus of this deficit is unknown. Brainstem auditory evoked potentials (BAEPs) reflect the functioning of the auditory nerve and auditory brainstem pathways to high-frequency acoustical stimulation in humans and reflect the first stages of auditory processing. These were studied in 12 subjects with RDLD (four females and eight males, ages 12 to 19) and twelve control subjects (three females and nine males, ages 14 to 24). Click intensity and rate of stimulation were varied. The BAEPs for the RDLD group were comparable to the control group as well as to hospital norms across intensity levels and stimulation rates. The evidence obtained suggests that a disorder in the neurophysiological systems underlying the BAEPs and reflecting initial stages of auditory processing is not essential for RDLD.

Brainstem and middle latency auditory evoked potentials in autism and developmental language disorder.

Brainstem auditory evoked potentials (BAEP) and middle latency responses (MLR) were studied in 8 nonretarded subjects with infantile autism (mean age = 23.3, SD = 2.8), 8 subjects with receptive developmental language disorder (mean age = 16.3, SD = 1.4), and normal control subjects matched to each group for age, gender, and Performance IQ. Click stimuli were delivered monaurally to the left and the right ear and binaurally for both the BAEPs (70-dB HL, 7/sec) and the MLRs (60-dB HL, 13/sec). Amplitudes and latencies (Waves I to VI), interwave latencies (III-V, I-V, and I-III), and Wave I/V amplitude ratio of the BAEPs were determined for each group. For the MLR study, Wave Na, Pa, and Nb latencies, and Wave Na-Pa and Pa-Nb amplitudes were calculated. There were no consistent differences in the BAEP and MLR characteristics of the control and the experimental groups. These results suggest that the abnormal cognitive processes indexed by the cognitive and attention-related event-related potential components in infantile autism and receptive developmental language disorder are not due to abnormal sensory processing in the brainstem and in areas central to the brainstem whose activity generates the BAEPs and MLRs.

Block constructions of chronic alcoholic and unilateral brain-damaged patients: a test of the right hemisphere vulnerability hypothesis of alcoholism.

A detailed analysis of the block construction performance of chronic alcoholics, unilateral brain-damaged patients, and normal control subjects was conducted to test two hypotheses: (a) that alcoholics perform similarly to right-hemisphere damaged (RHD) patients but not left-hemisphere damaged (LHD) patients; and (b) that unilateral brain-damaged patients display qualitatively different strategies and errors. Differences in performance without a time limit and broken configuration errors suggest that the alcoholics have not incurred the type of visuospatial impairment characteristic of RHD patients. The LHD and RHD patients showed qualitative differences in their strategies and errors. Implications of the findings for research and clinical assessment of visuospatial dysfunction are discussed.