John A. Sweeney
University of Cincinnati
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Featured researches published by John A. Sweeney.
Nature | 2009
Joseph T. Glessner; Kai Wang; Guiqing Cai; Olena Korvatska; Cecilia E. Kim; Shawn Wood; Haitao Zhang; Annette Estes; Camille W. Brune; Jonathan P. Bradfield; Marcin Imielinski; Edward C. Frackelton; Jennifer Reichert; Emily L. Crawford; Jeffrey Munson; Patrick Sleiman; Rosetta M. Chiavacci; Kiran Annaiah; Kelly Thomas; Cuiping Hou; Wendy Glaberson; James H. Flory; Frederick G. Otieno; Maria Garris; Latha Soorya; Lambertus Klei; Joseph Piven; Kacie J. Meyer; Evdokia Anagnostou; Takeshi Sakurai
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ∼550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Nature | 2009
Kai Wang; Haitao Zhang; Deqiong Ma; Maja Bucan; Joseph T. Glessner; Brett S. Abrahams; Daria Salyakina; Marcin Imielinski; Jonathan P. Bradfield; Patrick Sleiman; Cecilia E. Kim; Cuiping Hou; Edward C. Frackelton; Rosetta M. Chiavacci; Nagahide Takahashi; Takeshi Sakurai; Eric Rappaport; Clara M. Lajonchere; Jeffrey Munson; Annette Estes; Olena Korvatska; Joseph Piven; Lisa I. Sonnenblick; Ana I. Alvarez Retuerto; Edward I. Herman; Hongmei Dong; Ted Hutman; Marian Sigman; Sally Ozonoff; Ami Klin
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10-8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10-8 to 2.1 × 10-10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
NeuroImage | 2001
Beatriz Luna; Keith R. Thulborn; Douglas P. Munoz; Elisha P. Merriam; Krista E. Garver; Nancy J. Minshew; Matcheri S. Keshavan; Christopher R. Genovese; William F. Eddy; John A. Sweeney
Cognitive and brain maturational changes continue throughout late childhood and adolescence. During this time, increasing cognitive control over behavior enhances the voluntary suppression of reflexive/impulsive response tendencies. Recently, with the advent of functional MRI, it has become possible to characterize changes in brain activity during cognitive development. In order to investigate the cognitive and brain maturation subserving the ability to voluntarily suppress context-inappropriate behavior, we tested 8-30 year olds in an oculomotor response-suppression task. Behavioral results indicated that adult-like ability to inhibit prepotent responses matured gradually through childhood and adolescence. Functional MRI results indicated that brain activation in frontal, parietal, striatal, and thalamic regions increased progressively from childhood to adulthood. Prefrontal cortex was more active in adolescents than in children or adults; adults demonstrated greater activation in the lateral cerebellum than younger subjects. These results suggest that efficient top-down modulation of reflexive acts may not be fully developed until adulthood and provide evidence that maturation of function across widely distributed brain regions lays the groundwork for enhanced voluntary control of behavior during cognitive development.
Nature Reviews Drug Discovery | 2012
Mark J. Millan; Y. Agid; Martin Brüne; Edward T. Bullmore; Cameron S. Carter; Nicola S. Clayton; Richard C. Connor; Sabrina Davis; Bill Deakin; Robert J. DeRubeis; Bruno Dubois; Mark A. Geyer; G M Goodwin; Philip Gorwood; Thérèse M. Jay; Marian Joëls; Isabelle M. Mansuy; Andreas Meyer-Lindenberg; Declan Murphy; Edmund T. Rolls; Bernd Saletu; Michael Spedding; John A. Sweeney; Miles A. Whittington; Larry J. Young
Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.
Biological Psychiatry | 2000
John A. Sweeney; Julie Kmiec; David J. Kupfer
BACKGROUND Cognitive deficits associated with mood disorders, especially bipolar disorder, have been the focus of limited systematic investigation. METHODS We tested 35 bipolar (21 in depressed state and 14 in mixed or manic state) and 58 nonbipolar depressed consecutively admitted young adult inpatients and 51 matched healthy individuals on the Cambridge Neuropsychological Test Automated Battery, a computerized neurocognitive battery. RESULTS The mixed/manic bipolar patients demonstrated robust deficits in episodic and working memory, spatial attention, and problem solving. In contrast, depressed bipolar and nonbipolar patients demonstrated impairments only in episodic memory. CONCLUSIONS Neuropsychologic findings with the Cambridge Neuropsychological Test Automated Battery indicate widely distributed deficits in cognitive domains subserved by temporal, parietal, and frontostriatal systems in bipolar patients during mixed/manic states of illness. Significant deficits in bipolar and nonbipolar depressed patients were restricted to episodic memory, suggesting a more selective dysfunction in mesial temporal lobe function during episodes of depression. These findings highlight the different cognitive profiles of mania and depression, demonstrate similar patterns of neuropsychologic deficits in bipolar and nonbipolar depression, and point to a need for further research investigating the characteristics, causes, course, and treatment of severe cognitive deficits associated with mixed/manic phases of bipolar disorder.
Annals of the New York Academy of Sciences | 2004
Beatriz Luna; John A. Sweeney
Abstract: Adolescence marks the beginning of adult‐level cognitive control of behavior supported by the brain maturation processes of synaptic pruning and myelination. Cognitive development studies on adolescence indicate that this period is characterized by improvements in the performance of existing abilities including speed and capacity of information processing and the ability to have consistent cognitive control of behavior. Although adolescents can behave at adult levels in some ways, brain imaging studies indicate that the functional organization of brain systems that support higher‐cognitive processes are not fully mature. Synaptic pruning allows for more efficient local computations, enhancing the ability of discrete brain regions to support high‐level cognitive control of behavior including working memory. Myelination increases the speed of neuronal transmission supporting the collaboration of a widely distributed circuitry, integrating regions that support top‐down cognitive control of behavior. Functional brain imaging methods allow for the characterization of the relationship between cognitive development and brain maturation as we can map progressions in the establishment of distributed brain circuitry and its relation to enhanced cognitive control of behavior. We present a review on the maturation (as distinct from “development” in emphasizing the transition to maturity and stabilization) of response inhibition, brain structure, and brain function through adolescence. We also propose a model for brain‐behavior maturation that allows for the qualitative changes in cognitive processes that occur during adolescence.
PLOS Genetics | 2009
Maja Bucan; Brett S. Abrahams; Kai Wang; Joseph T. Glessner; Edward I. Herman; Lisa I. Sonnenblick; Ana I. Alvarez Retuerto; Marcin Imielinski; Dexter Hadley; Jonathan P. Bradfield; Cecilia Kim; Nicole Gidaya; Ingrid Lindquist; Ted Hutman; Marian Sigman; Vlad Kustanovich; Clara M. Lajonchere; Andrew Singleton; Junhyong Kim; Thomas H. Wassink; William M. McMahon; Thomas Owley; John A. Sweeney; Hilary Coon; John I. Nurnberger; Mingyao Li; Rita M. Cantor; Nancy J. Minshew; James S. Sutcliffe; Edwin H. Cook
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
NeuroImage | 2005
Fabio Babiloni; Febo Cincotti; Claudio Babiloni; Filippo Carducci; Donatella Mattia; Laura Astolfi; Alessandra Basilisco; P.M. Rossini; Lei Ding; Yicheng Ni; J Cheng; K. Christine; John A. Sweeney; Bin He
Nowadays, several types of brain imaging device are available to provide images of the functional activity of the cerebral cortex based on hemodynamic, metabolic, or electromagnetic measurements. However, static images of brain regions activated during particular tasks do not convey the information of how these regions communicate with each other. In this study, advanced methods for the estimation of cortical connectivity from combined high-resolution electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data are presented. These methods include a subjects multicompartment head model (scalp, skull, dura mater, cortex) constructed from individual magnetic resonance images, multidipole source model, and regularized linear inverse source estimates of cortical current density. Determination of the priors in the resolution of the linear inverse problem was performed with the use of information from the hemodynamic responses of the cortical areas as revealed by block-designed (strength of activated voxels) fMRI. We estimate functional cortical connectivity by computing the directed transfer function (DTF) on the estimated cortical current density waveforms in regions of interest (ROIs) on the modeled cortical mantle. The proposed method was able to unveil the direction of the information flow between the cortical regions of interest, as it is directional in nature. Furthermore, this method allows to detect changes in the time course of information flow between cortical regions in different frequency bands. The reliability of these techniques was further demonstrated by elaboration of high-resolution EEG and fMRI signals collected during visually triggered finger movements in four healthy subjects. Connectivity patterns estimated for this task reveal an involvement of right parietal and bilateral premotor and prefrontal cortical areas. This cortical region involvement resembles that revealed in previous studies where visually triggered finger movements were analyzed with the use of separate EEG or fMRI measurements.
The Cerebellum | 2012
S. Hossein Fatemi; Kimberly A. Aldinger; Paul Ashwood; Margaret L. Bauman; Gene J. Blatt; Abha Chauhan; Ved Chauhan; Stephen R. Dager; Price E. Dickson; Annette Estes; Dan Goldowitz; Detlef H. Heck; Thomas L. Kemper; Bryan H. King; Loren A. Martin; Kathleen J. Millen; Guy Mittleman; Matthew W. Mosconi; Antonio M. Persico; John A. Sweeney; Sara J. Webb; John P. Welsh
There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.
Neurology | 2002
Beatriz Luna; Nancy J. Minshew; Krista E. Garver; Nicole A. Lazar; Keith R. Thulborn; William F. Eddy; John A. Sweeney
Objective To test the hypothesis that deficits in spatial working memory in autism are due to abnormalities in prefrontal circuitry. Methods Functional MRI (fMRI) at 3 T was performed in 11 rigorously diagnosed non–mentally retarded autistic and six healthy volunteers while they performed an oculomotor spatial working memory task and a visually guided saccade task. Results Autistic subjects demonstrated significantly less task-related activation in dorsolateral prefrontal cortex (Brodmann area [BA] 9/46) and posterior cingulate cortex (BA 23) in comparison with healthy subjects during a spatial working memory task. In contrast, activation of autistic individuals was not reduced in other regions comprising the neural circuitry for spatial working memory including the cortical eye fields, anterior cingulate cortex, insula, basal ganglia, thalamus, and lateral cerebellum. Autistic subjects also did not demonstrate reduced activation in any brain regions while performing visually guided saccades. ConclusionImpairments in executive cognitive processes in autism may be subserved by abnormalities in neocortical circuitry as evidenced by decreased activation in prefrontal and posterior cingulate circuitry during a spatial working memory task.