Eric Courchesne | University of California, San Diego (original) (raw)

Papers by Eric Courchesne

Brain and Cognition, Jul 1, 2007

It has been suggested that spindle neurons, an evolutionarily unique type of neuron, might be inv... more It has been suggested that spindle neurons, an evolutionarily unique type of neuron, might be involved in higher-order social, emotional, and cognitive functions. As such, it was hypothesized that these neurons may be particularly important to the pathophysiology of autism, a disease characterized in part by disruption of higher-order social and emotional processing. Therefore, we conducted the first stereological investigation of the number of spindle neurons in autism, using the optical fractionator technique. Our results did not provide evidence of a reduction in spindle neuron number in frontoinsular cortex in autism. However, this study provides the first quantitative stereological data on spindle neuron number in autism. Future postmortem studies with larger sample sizes will likely be critical in elucidating the spared and defective neural systems underlying the autistic phenotype.

JAMA, Jul 16, 2003

Context Autism most commonly appears by 2 to 3 years of life, at which time the brain is already ... more Context Autism most commonly appears by 2 to 3 years of life, at which time the brain is already abnormally large. This raises the possibility that brain overgrowth begins much earlier, perhaps before the first clinically noticeable behavioral symptoms. Objectives To determine whether pathological brain overgrowth precedes the first clinical signs of autism spectrum disorder (ASD) and whether the rate of overgrowth during the first year is related to neuroanatomical and clinical outcome in early childhood. Design, Setting, and Participants Head circumference (HC), body length, and body weight measurements during the first year were obtained from the medical records of 48 children with ASD aged 2 to 5 years who had participated in magnetic resonance imaging studies. Of these children, 15 (longitudinal group) had measurements at 4 periods during infancy: birth, 1 to 2 months, 3 to 5 months, and 6 to 14 months; and 33 (partial HC data group) had measurements at birth and 6 to 14 months (n=7), and at birth only (n=28). Main Outcome Measures Age-related changes in infants with ASD who had multiple-age measurements, and the relationship of these changes to brain anatomy and clinical and diagnostic outcome at 2 to 5 years were evaluated by using 2 nationally recognized normative databases: cross-sectional normative data from a national survey and longitudinal data of individual growth. Results Compared with normative data of healthy infants, birth HC in infants with ASD was significantly smaller (z=-0.66, PϽ.001); after birth, HC increased 1.67 SDs and mean HC was at the 84th percentile by 6 to 14 months. Birth HC was related to cerebellar gray matter volume at 2 to 5 years, although the excessive increase in HC between birth and 6 to 14 months was related to greater cerebral cortex volume at 2 to 5 years. Within the ASD group, every child with autistic disorder had a greater increase in HC between birth and 6 to 14 months (mean [SD], 2.19 [0.98]) than infants with pervasive developmental disorder-not otherwise specified (0.58 [0.35]). Only 6% of the individual healthy infants in the longitudinal data showed accelerated HC growth trajectories (Ͼ2.0 SDs) from birth to 6 to 14 months; 59% of infants with autistic disorder showed these accelerated growth trajectories. Conclusions The clinical onset of autism appears to be preceded by 2 phases of brain growth abnormality: a reduced head size at birth and a sudden and excessive increase in head size between 1 to 2 months and 6 to 14 months. Abnormally accelerated rate of growth may serve as an early warning signal of risk for autism.

Scientific Reports, Mar 11, 2022

Few clinically validated biomarkers of ASD exist which can rapidly, accurately, and objectively i... more Few clinically validated biomarkers of ASD exist which can rapidly, accurately, and objectively identify autism during the first years of life and be used to support optimized treatment outcomes and advances in precision medicine. As such, the goal of the present study was to leverage both simple and computationally-advanced approaches to validate an eye-tracking measure of social attention preference, the GeoPref Test, among 1,863 ASD, delayed, or typical toddlers (12-48 months) referred from the community or general population via a primary care universal screening program. Toddlers participated in diagnostic and psychometric evaluations and the GeoPref Test: a 1-min movie containing side-by-side dynamic social and geometric images. Following testing, diagnosis was denoted as ASD, ASD features, LD, GDD, Other, typical sibling of ASD proband, or typical. Relative to other diagnostic groups, ASD toddlers exhibited the highest levels of visual attention towards geometric images and those with especially high fixation levels exhibited poor clinical profiles. Using the 69% fixation threshold, the GeoPref Test had 98% specificity, 17% sensitivity, 81% PPV, and 65% NPV. Sensitivity increased to 33% when saccades were included, with comparable validity across sex, ethnicity, or race. The GeoPref Test was also highly reliable up to 24 months following the initial test. Finally, fixation levels among twins concordant for ASD were significantly correlated, indicating that GeoPref Test performance may be genetically driven. As the GeoPref Test yields few false positives (~ 2%) and is equally valid across demographic categories, the current findings highlight the ability of the GeoPref Test to rapidly and accurately detect autism before the 2nd birthday in a subset of children and serve as a biomarker for a unique ASD subtype in clinical trials. Autism spectrum disorder (ASD) begins during prenatal life 1,2 , yet most children do not receive a diagnosis and start treatment until 3-4 years later 3,4. Although genetic, neural, metabolomic, and molecular systems are adversely impacted in ASD 2,5,6 , it is nevertheless detected and diagnosed using clinical judgement. There has been a recent surge in research designed to discover biologically-based markers of ASD which can increase the pace of diagnosis, remove the requirement for highly-trained professionals, provide prognostic information, guide treatment plans, or be used as outcome measures in clinical trials 7. Currently, only two ASD biomarkers are being considered for the FDA Biomarker Qualification Program 8,9. However, they were established at "late" ages in children and therefore may not be generalizable to toddlers and infants, for whom biomarkers are of greatest utility. Moreover, these biomarkers only identify a subset of ASD children, indicating that additional biomarkers for other ASD subtypes are needed. Dramatically reduced attention to social information is a key feature of ASD noted since its discovery in 1943 10. Unsurprisingly, considerable effort has been leveraged to understand and quantify social visual attention abnormalities, most recently using eye-tracking 11-29. Despite varying stimuli and participant age, a meta-analysis

Brain, Apr 1, 2000

Certain cognitive and behavioural deficits suggest that that frontal lobe cortex volume is increa... more Certain cognitive and behavioural deficits suggest that that frontal lobe cortex volume is increased in a subset of patients with autism and that this increase correlates the frontal lobe functions abnormally in patients with autism, but little anatomical research is available with the degree of cerebellar abnormality. This evidence of concurrent structural abnormalities in both the frontal to either verify or refute this. In contrast, several neuropathological and neuroimaging studies have lobe and the cerebellum has important implications for understanding the development and persistence of the demonstrated anatomical abnormalities in the cerebellum in autistic patients. The current study shows autistic disorder.

Mental Retardation and Developmental Disabilities Research Reviews, 2004

Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of chil... more Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies have now shown that abnormal brain overgrowth occurs during the first 2 years of life in children with autism. By 2-4 years of age, the most deviant overgrowth is in cerebral, cerebellar, and limbic structures that underlie higher-order cognitive, social, emotional, and language functions. Excessive growth is followed by abnormally slow or arrested growth. Deviant brain growth in autism occurs at the very time when the formation of cerebral circuitry is at its most exuberant and vulnerable stage, and it may signal disruption of this process of circuit formation. The resulting aberrant connectivity and dysfunction may lead to the development of autistic behaviors. To discover the causes, neural substrates, early-warning signs and effective treatments of autism, future research should focus on elucidating the neurobiological defects that underlie brain growth abnormalities in autism that appear during these critical first years of life.

medRxiv (Cold Spring Harbor Laboratory), Jul 9, 2021

Since ASD is genetically and clinical heterogeneous, can a single blood-based molecular classifie... more Since ASD is genetically and clinical heterogeneous, can a single blood-based molecular classifier accurately diagnose ASD at the age of first symptoms? Findings: To address heterogeneity, we developed an ASD classifier method testing 42,840 models. An ensemble of 1,076 models using 191 different feature routes and 2,764 gene features, weighted by Bayesian model averaging, demonstrated excellent performance in Discovery and Replication datasets producing ASD classification with the area under the receiver operating characteristic curve (AUC-ROC) scores of 84% to 88%. Features include genes with immune/inflammation, response to cytokines, transcriptional regulation, mitotic cell cycle, and PI3K-AKT, RAS and Wnt signaling pathways. Meaning: An ensemble gene expression ASD classifier has high accuracy across the spectrum of ASD clinical characteristics and across toddlers aged 1 to 4 years. .

American Journal of Neuroradiology, Jul 1, 1989

Correlation of thin (5-mm) sagittal high-field (1.5-T) MR images of three brain specimens and 11 ... more Correlation of thin (5-mm) sagittal high-field (1.5-T) MR images of three brain specimens and 11 normal volunteers with microtome sections of the human cerebellar vermis and hemispheres demonstrates that proton-density-weighted (long TR/short TE) and T2-weighted (long TR/Iong TE) spin-echo pulse sequences provide the greatest contrast between gray and white matter. These images also can display (1) the corpus medullare and primary white-matter branches to the vermian lobules, including the lingula, centralis, culmen, declive, folium, tuber, pyramis, uvula, and nodulus; and (2) several finer secondary branches to individual folia within the lobules. Surface features of the vermis including the deeper fissures (e.g., preculminate, primary, horizontal, and prepyramidal) and shallower sulci are best delineated by T1-weighted (short TR/short TE) and T2weighted images, which provide greatest contrast between CSF and parenchyma. Given that the width of the normal vermis varied from 6 to 12 mm in our volunteers, the acquisition of thin slices (:S5 mm) was required to minimize volume averaging of the cerebellar hemispheres with the vermis on a midline sagittal MR section. Knowledge of the detailed normal anatomy of the cerebellar vermis on sagittal MR images can assist in the identification of various pathologic alterations.

Brain Research, Jul 1, 2008

Impaired language is a prominent behavioral marker of autism spectrum disorders (ASD), but its ne... more Impaired language is a prominent behavioral marker of autism spectrum disorders (ASD), but its neurobiological underpinnings are incompletely understood. We studied letter and category fluency in 14 high functioning ASD individuals and 14 age-matched controls. Each fluency condition was compared to self-paced repetition of the word "nothing." Responses were recorded to monitor performance. In letter fluency, the ASD group had significantly greater activation than controls in the right frontal and right superior temporal lobe. Between-group differences were not observed in left prefrontal cortex. By examining functional asymmetry in frontal cortex, we found that the ASD group had significantly reduced lateralization of activation patterns in letter fluency compared to the controls. In category fluency, no between-group differences in lateralization were found, in light of greater bilateral activation in controls. These findings indicate reduced hemispheric differentiation for certain verbal fluency tasks in ASD, consistent with some previous evidence of atypical functional and structural asymmetries in autism. Abnormal functional organization may contribute to the language impairment seen in ASD.

Journal of Autism and Developmental Disorders, Sep 19, 2006

This study examined the nature and frequency of neurological and EEG abnormalities in 60 young ch... more This study examined the nature and frequency of neurological and EEG abnormalities in 60 young children (ages 2-6 years) with pervasive developmental disorders. A number of standard neurological functions could not be adequately assessed due to the young age of the children and/or limited comprehension and cooperation. The most common neurological deficits were hyporeflexia, stereotypies, and hypotonia. EEG abnormalities were identified in 32% of the children while only two children were known to have clinical seizures. The frequency of cases with hypotonia or hyporeflexia was more common than in older children with this diagnosis. Results also indicate that EEG abnormalities are common in this young population but clinical seizures are rare, confirming other studies.

Biological Psychiatry, Oct 1, 2008

Background-A failure to develop normal language is one of the most common first signs that a todd... more Background-A failure to develop normal language is one of the most common first signs that a toddler might be at risk for autism. Currently the neural bases underlying this failure to develop language are unknown. Methods-In this study, functional magnetic resonance imaging (fMRI) was utilized to identify the brain regions involved in speech perception in 12 2-3 year-old children with autism spectrum disorder (ASD) during natural sleep. We also recorded fMRI data from two typically developing control groups: a mental age-matched (MA) (n=11) and a chronological age-matched (CA) (n=12) group. During fMRI data acquisition, forward and backward speech stimuli were presented with intervening periods of no sound presentation. Results-Direct statistical comparison between groups revealed significant differences in regions recruited to process speech. In comparison to their MA-matched controls, the ASD group showed reduced activity in an extended network of brain regions, which are recruited in typical early language acquisition. In comparison to their CA-matched controls, ASD participants showed greater activation primarily within right and medial frontal regions. Laterality analyses revealed a trend towards greater recruitment of right hemisphere regions in the ASD group and left hemisphere regions in the CA group during the forward speech condition. Furthermore, correlation analyses revealed a significant positive relationship between right hemisphere frontal and temporal activity to forward speech and receptive language skill. Conclusions-These findings suggest that at 2-3 years, children with ASD may be on a deviant developmental trajectory characterized by a greater recruitment of right hemisphere regions during speech perception.

BMC Genomics, Sep 10, 2011

Background: Gene expression assays have been shown to yield high quality genome-wide data from pa... more Background: Gene expression assays have been shown to yield high quality genome-wide data from partially degraded RNA samples. However, these methods have not yet been applied to postmortem human brain tissue, despite their potential to overcome poor RNA quality and other technical limitations inherent in many assays. We compared cDNA-mediated annealing, selection, and ligation (DASL)-and in vitro transcription (IVT)-based genomewide expression profiling assays on RNA samples from artificially degraded reference pools, frozen brain tissue, and formalin-fixed brain tissue. Results: The DASL-based platform produced expression results of greater reliability than the IVT-based platform in artificially degraded reference brain RNA and RNA from frozen tissue-based samples. Although data associated with a small sample of formalin-fixed RNA samples were poor when obtained from both assays, the DASL-based platform exhibited greater reliability in a subset of probes and samples. Conclusions: Our results suggest that the DASL-based gene expression-profiling platform may confer some advantages on mRNA assays of the brain over traditional IVT-based methods. We ultimately consider the implications of these results on investigations of neuropsychiatric disorders.

Research Square (Research Square), Jan 31, 2023

Identifying prognostic early brain alterations is crucial for autism spectrum disorder (ASD). Lev... more Identifying prognostic early brain alterations is crucial for autism spectrum disorder (ASD). Leveraging structural MRI data from 166 ASD and 109 typical developing (TD) toddlers and controlling for brain size, we found that, compared to TD, ASD toddlers showed larger or thicker lateral temporal regions; smaller or thinner frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most of these differences were replicated in an independent cohort of 38 ASD and 37 TD toddlers. Moreover, the identi ed brain alterations were related to ASD symptom severity and cognitive impairments at intake, and, remarkably, they improved the accuracy for predicting later language outcome beyond intake clinical and demographic variables. In summary, brain regions involved in language, social, and face processing were altered in ASD toddlers. These early-age brain alterations may be the result of dysregulation in multiple neural processes and stages and are promising prognostic biomarkers for future language ability.

bioRxiv (Cold Spring Harbor Laboratory), Nov 3, 2022

medRxiv (Cold Spring Harbor Laboratory), Aug 2, 2022

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

bioRxiv (Cold Spring Harbor Laboratory), Jun 29, 2021

Background Predicting outcomes on human genetic studies is difficult because the number of variab... more Background Predicting outcomes on human genetic studies is difficult because the number of variables (genes) is often much larger than the number of observations (human subject tissue samples). We investigated means for improving model performance on the types of under-constrained problems that are typical in human genetics, where the number of strongly correlated genes (features) may exceed 10,000, and the number of study participants (observations) may be limited to under 1,000. Methods We created 'train', 'validate' and 'test' datasets from 240 microarray observations from 127 subjects diagnosed with autism spectrum disorder (ASD) and 113 'typically developing' (TD) subjects. We trained a neural network model (a.k.a., the 'naive' model) on 10,422 genes using the 'train' dataset, composed of 70 ASD and 65 TD subjects, and we restricted the model to one, fully-connected hidden layer to minimize the number of trainable parameters, including a dropout layer to help prevent overfitting. We experimented with alternative network architectures and tuned the hyperparameters using the 'validate' dataset, and performed a single, final evaluation using the holdout 'test' dataset. Next, we trained a neural network model using the identical architecture and identical genes to predict tissue type in GTEx data. We transferred that learning by replacing the top layer of the GTEx model with a layer to predict ASD outcome and we retrained the new layer on the ASD dataset, again using the identical 10,422 genes.

Encyclopedia of Cognitive Science, Jan 15, 2006

Brain and Language, Nov 1, 1992

American journal of medical genetics, Mar 18, 2002

Hyperserotonemia in autism is one of the longest-standing biochemical findings in a psychiatric d... more Hyperserotonemia in autism is one of the longest-standing biochemical findings in a psychiatric disorder. This well-replicated finding and subsequent studies of platelet serotonin receptors in autism indicate that the serotonin 2A receptor gene (HTR2A) on chromosome 13q is a primary candidate gene in autism. Converging data from recent genome screens also implicates the genomic region containing HTR2A. Based on these lines of evidence, the transmission/disequilibrium test (TDT) was used to assess transmission disequilibrium between autism and haplotypes of three polymorphisms, including the promoter -1438 G/A single nucleotide polymorphism (SNP) in perfect linkage disequilibrium with the 102 T/C SNP in previous studies, a newly identified SNP in intron 1 near exon 2, and the SNP responsible for the His452Tyr amino acid change in exon 3. Because expression studies have shown HTR2A to be polymorphically imprinted in the brain, secondary analyses were split into maternal and paternal transmissions. No evidence was found for unequal transmission of haplotypes; however, power analysis reveals low power to detect a parent-of-origin effect in this sample size.

Archives of General Psychiatry, Apr 1, 2000

You are seeing this message because your Web browser does not support basic Web standards. Find o... more You are seeing this message because your Web browser does not support basic Web standards. Find out more about why this message is appearing and what you can do to make your experience on this site better. ... Add to CiteULike Add to Connotea Add to ...