Edward S Brodkin

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (42)213.74 Total impact

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    ABSTRACT: Dysfunction in sensory information processing is a hallmark of many neurological disorders, including autism spectrum disorders, schizophrenia and Rett syndrome (RTT). Using mouse models of RTT, a monogenic disorder caused by mutations in MECP2, we found that the large-scale loss of MeCP2 from forebrain GABAergic interneurons led to deficits in auditory event-related potentials and seizure manifestation, whereas the restoration of MeCP2 in specific classes of interneurons ameliorated these deficits.
    Nature Neuroscience 04/2014; · 15.25 Impact Factor
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    ABSTRACT: Autism spectrum disorders (ASD) comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3) is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and behavioral (social approach and zero maze) tests at 3 different time points (30, 50 and 70 days-of-age) on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD.
    PLoS ONE 01/2014; 9(10):e109872. · 3.53 Impact Factor
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    ABSTRACT: Violence is increasingly viewed as a public health issue that may be ameliorated by health‐based interventions. The Healthy Brains and Behavior Study (HBBS) aims to identify environmental and biological risk factors for aggression in late childhood and to reduce aggression through psychological and nutritional treatments. Utilizing a cross‐disciplinary collaborative research approach, the HBBS has both human and animal components. The human component has two stages consisting of risk assessment followed by treatment. The risk assessment is based on 451 community‐residing children aged 11–12 years and their caregivers, during which genetic, brain imaging, neuroendocrine, psychophysiology, environment toxicology, neurocognitive, nutrition, psychological, social and demographic risk variables are collected. Children who met criteria (N = 219) for problematic aggressive behaviors were assigned to one of four treatment groups: cognitive‐behavior therapy (CBT) alone, nutritional supplements alone, both CBT and nutrition, or treatment‐as‐usual. Treatment duration was 12 weeks and all children whether in treatment or not were followed‐up at three, six, and 12 months. The animal component assessed the effects of dietary omega‐3 fatty acids on the development of aggression. This study contributes knowledge on how biological factors interact with social factors in shaping proactive and reactive aggression and assesses the efficacy of treatment approaches to reduce childhood aggression. Copyright © 2013 John Wiley & Sons, Ltd.
    International Journal of Methods in Psychiatric Research 01/2013; 22(3). · 1.76 Impact Factor
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    ABSTRACT: Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.
    Proceedings of the National Academy of Sciences 12/2012; · 9.81 Impact Factor
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    ABSTRACT: BALB/cJ and C57BL/6J inbred mouse strains have been proposed as useful models of low and high levels of sociability (tendency to seek social interaction), respectively, based primarily on behaviors of ∼30-day-old mice in the Social Approach Test (SAT). In the SAT, approach and sniffing behaviors of a test mouse toward an unfamiliar stimulus mouse are measured in a novel environment. However, it is unclear whether such results generalize to a familiar environment with a familiar social partner, such as with a littermate in a home cage environment. We hypothesized that C57BL/6J mice would show higher levels of social behaviors than BALB/cJ mice in the home cage environment, particularly at 30 days-of-age. We measured active and passive social behaviors in home cages by pairs of BALB/cJ or C57BL/6J littermates at ages 30, 41, and 69 days. The strains did not differ robustly in their active social behaviors. C57BL/6J mice were more passively social than BALB/cJ mice at 30 days, and C57BL/6J levels of passive social behaviors declined to BALB/cJ levels by 69 days. The differences in passive social behaviors at 30 days-of-age were primarily attributable to differences in huddling. These results indicate that different test conditions (SAT conditions vs. home cage conditions) elicit strain differences in distinct types of behaviors (approach/sniffing vs. huddling behaviors, respectively). Assessment of the more naturalistic social interactions in the familiar home cage environment with a familiar littermate will provide a useful component of a comprehensive assessment of social behaviors in mouse models relevant to autism.
    Behavioural brain research 09/2012; 237C:338-347. · 3.22 Impact Factor
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    ABSTRACT: Diffusion tensor imaging (DTI) is highly sensitive in detecting brain structure and connectivity phenotypes in autism spectrum disorders (ASD). Since one of the core symptoms of ASD is reduced sociability (reduced tendency to seek social interaction), we hypothesized that DTI will be sensitive in detecting neural phenotypes that correlate with decreased sociability in mouse models. Relative to C57BL/6J (B6) mice, juvenile BALB/cJ mice show reduced sociability. We performed social approach test in a three-chambered apparatus and in-vivo longitudinal DTI at post-natal days 30, 50 and 70 days-of-age in BALB/cJ (n=32) and B6 (n=15) mice to assess the correlation between DTI and sociability and to evaluate differences in DTI parameters between these two strains. Fractional anisotropy (FA) and mean diffusivity (MD) values from in-vivo DTI data were analyzed from white matter (corpus callosum, internal and external capsule) and gray matter (cerebral cortex, frontal motor cortex, hippocampus, thalamus and amygdaloid) regions based on their relevance to ASD. A moderate but significant (p<0.05) negative correlation between sociability and FA in hippocampus and frontal motor cortex was noted for BALB/cJ mice at 30 days-of-age. Significant differences in FA and MD values between BALB/cJ and B6 mice were observed in most white and gray matter areas at all three time points. Significant differences in developmental trajectories of FA and MD values from thalamus and frontal motor cortex were also observed between BALB/cJ and B6, indicating relative under-connectivity in BALB/cJ mice. These results indicate that DTI may be used as an in-vivo, non-invasive imaging method to assess developmental trajectories of brain connectivity in mouse models of neurodevelopmental and behavioral disorders.
    Brain research 03/2012; 1455:56-67. · 2.46 Impact Factor
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    ABSTRACT: The idea that social motivation deficits play a central role in Autism Spectrum Disorders (ASD) has recently gained increased interest. This constitutes a shift in autism research, which has traditionally focused more intensely on cognitive impairments, such as theory-of-mind deficits or executive dysfunction, and has granted comparatively less attention to motivational factors. This review delineates the concept of social motivation and capitalizes on recent findings in several research areas to provide an integrated account of social motivation at the behavioral, biological and evolutionary levels. We conclude that ASD can be construed as an extreme case of diminished social motivation and, as such, provides a powerful model to understand humans' intrinsic drive to seek acceptance and avoid rejection.
    Trends in Cognitive Sciences 03/2012; 16(4):231-9. · 16.01 Impact Factor
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    ABSTRACT: Sociability--the tendency to seek social interaction--propels the development of social cognition and social skills, but is disrupted in autism spectrum disorders (ASD). BALB/cJ and C57BL/6J inbred mouse strains are useful models of low and high levels of juvenile sociability, respectively, but the neurobiological and developmental factors that account for the strains' contrasting sociability levels are largely unknown. We hypothesized that BALB/cJ mice would show increasing sociability with age but that C57BL/6J mice would show high sociability throughout development. We also hypothesized that littermates would resemble one another in sociability more than non-littermates. Finally, we hypothesized that low sociability would be associated with low corpus callosum size and increased brain size in BALB/cJ mice. Separate cohorts of C57BL/6J and BALB/cJ mice were tested for sociability at 19-, 23-, 31-, 42-, or 70-days-of-age, and brain weights and mid-sagittal corpus callosum area were measured. BALB/cJ sociability increased with age, and a strain by age interaction in sociability between 31 and 42 days of age suggested strong effects of puberty on sociability development. Sociability scores clustered according to litter membership in both strains, and perinatal litter size and sex ratio were identified as factors that contributed to this clustering in C57BL/6J, but not BALB/cJ, litters. There was no association between corpus callosum size and sociability, but smaller brains were associated with lower sociability in BALB/cJ mice. The associations reported here will provide directions for future mechanistic studies of sociability development.
    Behavioural brain research 12/2011; 228(2):299-310. · 3.22 Impact Factor
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    ABSTRACT: Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations among depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes.
    Psychiatry Research 09/2011; 193(3):161-7. · 2.68 Impact Factor
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    ABSTRACT: Reduced sociability is a core feature of autism spectrum disorders (ASD) and is highly disabling, poorly understood, and treatment refractory. To elucidate the biological basis of reduced sociability, multiple laboratories are developing ASD-relevant mouse models in which sociability is commonly assessed using the Social Choice Test. However, various measurements included in that test sometimes support different conclusions. Specifically, measurements of time the "test" mouse spends near a confined "stimulus" mouse (chamber scores) sometimes support different conclusions from measurements of time the test mouse sniffs the cylinder containing the stimulus mouse (cylinder scores). This raises the question of which type of measurements are best for assessing sociability. We assessed the test-retest reliability and ecological validity of chamber and cylinder scores. Compared with chamber scores, cylinder scores showed higher correlations between test and retest measurements, and cylinder scores showed higher correlations with time spent in social interaction in a more naturalistic phase of the test. This suggests that cylinder scores are more reliable and valid measures of sociability in mouse models. Cylinder scores are reported less commonly than chamber scores, perhaps because little work has been done to establish automated software systems for measuring the former. In this study, we found that a particular automated software system performed at least as well as human raters at measuring cylinder scores. Our data indicate that cylinder scores are more reliable and valid than chamber scores, and that the former can be measured very accurately using an automated video analysis system in ASD-relevant models.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 09/2011; 294(10):1713-25. · 1.34 Impact Factor
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    ABSTRACT: This study estimated the ASD prevalence in a psychiatric hospital and evaluated the Social Responsiveness Scale (SRS) combined with other information for differential diagnosis. Chart review, SRS and clinical interviews were collected for 141 patients at one hospital. Diagnosis was determined at case conference. Receiver operating characteristic (ROC) curves were used to evaluate the SRS as a screening instrument. Chi-squared Automatic Interaction Detector (CHAID) analysis estimated the role of other variables, in combination with the SRS, in separating cases and non-cases. Ten percent of the sample had ASD. More than other patients, their onset was prior to 12 years of age, they had gait problems and intellectual disability, and were less likely to have a history of criminal involvement or substance abuse. Sensitivity (0.86) and specificity (0.60) of the SRS were maximized at a score of 84. Adding age of onset <12 years and cigarette use among those with SRS <80 increased sensitivity to 1.00 without lowering specificity. Adding a history substance abuse among those with SRS >80 increased specificity to 0.90 but dropped sensitivity to 0.79. Undiagnosed ASD may be common in psychiatric hospitals. The SRS, combined with other information, may discriminate well between ASD and other disorders.
    Autism 08/2011; · 2.27 Impact Factor
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    ABSTRACT: The purpose of this study was to use high-resolution diffusion tensor imaging (DTI) to investigate the association between DTI metrics and sociability in BALB/c inbred mice. The sociability of prepubescent (30-day-old) BALB/cJ mice was operationally defined as the time that the mice spent sniffing a stimulus mouse in a social choice test. High-resolution ex vivo DTI data on 12 BALB/cJ mouse brains were acquired using a 9.4-T vertical-bore magnet. Regression analysis was conducted to investigate the association between DTI metrics and sociability. Significant positive regression (p < 0.001) between social sniffing time and fractional anisotropy was found in 10 regions located in the thalamic nuclei, zona incerta/substantia nigra, visual/orbital/somatosensory cortices and entorhinal cortex. In addition, significant negative regression (p < 0.001) between social sniffing time and mean diffusivity was found in five areas located in the sensory cortex, motor cortex, external capsule and amygdaloid region. In all regions showing significant regression with either the mean diffusivity or fractional anisotropy, the tertiary eigenvalue correlated negatively with the social sniffing time. This study demonstrates the feasibility of using DTI to detect brain regions associated with sociability in a mouse model system.
    NMR in Biomedicine 05/2011; 25(1):104-12. · 3.45 Impact Factor
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    ABSTRACT: Aggressive behaviors are disabling, treatment refractory, and sometimes lethal symptoms of several neuropsychiatric disorders. However, currently available treatments for patients are inadequate, and the underlying genetics and neurobiology of aggression is only beginning to be elucidated. Inbred mouse strains are useful for identifying genomic regions, and ultimately the relevant gene variants (alleles) in these regions, that affect mammalian aggressive behaviors, which, in turn, may help to identify neurobiological pathways that mediate aggression. The BALB/cJ inbred mouse strain exhibits relatively high levels of intermale aggressive behaviors and shows multiple brain and behavioral phenotypes relevant to neuropsychiatric syndromes associated with aggression. The A/J strain shows very low levels of aggression. We hypothesized that a cross between BALB/cJ and A/J inbred strains would reveal genomic loci that influence the tendency to initiate intermale aggressive behavior. To identify such loci, we conducted a genomewide scan in an F2 population of 660 male mice bred from BALB/cJ and A/J inbred mouse strains. Three significant loci on chromosomes 5, 10 and 15 that influence aggression were identified. The chromosome 5 and 15 loci are completely novel, and the chromosome 10 locus overlaps an aggression locus mapped in our previous study that used NZB/B1NJ and A/J as progenitor strains. Haplotype analysis of BALB/cJ, NZB/B1NJ and A/J strains showed three positional candidate genes in the chromosome 10 locus. Future studies involving fine genetic mapping of these loci as well as additional candidate gene analysis may lead to an improved biological understanding of mammalian aggressive behaviors.
    Genes Brain and Behavior 02/2011; 10(1):57-68. · 3.60 Impact Factor
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    ABSTRACT: Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized, in part, by deficits in social behaviors. Many studies have associated ASDs with hyperserotonemia and abnormal regulation of brain serotonin, and serotonergic neurotransmission has been implicated in a variety of social behaviors in humans and animals. The serotonergic system also mediates various forms of anxiety, and several of these are heightened in patients with ASDs. The role of serotonin in the development of sociability (tendency to seek social interaction) and anxiety during prepubescence is not well understood. Previous work has demonstrated that prepubescent BALB/cJ mice show reduced sociability relative to prepubescent C57BL/6J mice. Objectives: We systemically manipulated the serotonergic system with the selective serotonin reuptake inhibitor (SSRI) citalopram and the serotonin depletor p-chlorophenylalanine (PCPA) in prepubescent C57BL/6J and BALB/cJ mice. We assessed the acute effects of these pharmacological agents in a social choice test and the elevated zero maze test (EZM). We hypothesized that acute citalopram would decrease sociability in the social choice test and increase non-social anxiety-related behaviors (anxiogenesis) in the EZM. We further hypothesized that PCPA would increase sociability and decrease anxiety-related behaviors (anxiolysis). Methods: In the first experiment, 31-day-old male and female BALB/cJ and C57BL/6J mice received a single i.p. injection of citalopram (10 mg/kg) or saline, and a half-hour later were tested for sociability towards an unfamiliar, gonadectomized A/J stimulus' mouse. In a second experiment, 29-to-33-day-old male BALB/cJ mice received a single i.p. injection of citalopram (1 or 10 mg/kg) or saline, and were then tested for sociability a half-hour later. The following day, they received another injection of citalopram at the same dose or of saline, and were then tested on the EZM a half-hour later. In a third experiment, male BALB/cJ and C57BL/6J mice received 3 days of twice-daily injections of PCPA (100 or 300 mg/kg/day) or saline. On the fourth day, the 29-to-33-day-old mice were tested for sociability, then received a final injection of PCPA at the same dose or of saline. On the fifth day, mice were tested on the EZM. Results: In the first experiment, the experimental groups did not differ in their locomotor activity or their exploratory behaviors prior to exposure to the stimulus mouse. Citalopram-treated mice showed lower sociability than saline-treated mice, and this effect was more pronounced in the BALB/cJ mice than the C57BL/6J mice (social investigation time, Wilcoxon-Mann-Whitney tests: C57BL/6J saline vs. citalopram, U = 59, p < 0.001; BALB/cJ saline vs. citalopram, U = 49, p < 0.01). No differences due to sex were detected. The results of the second and third experiments will be presented. Conclusions: The results of these experiments will clarify the relationship between sociability and non-social anxiety during the little-studied developmental period of prepubescence in mice. These experiments will also elucidate the role that serotonin plays in these processes during prepubescence, and this may provide insights into the neural mechanisms of reduced sociability and heightened anxiety-related behaviors, two behavioral endophenotypes highly relevant to ASDs.
    International Meeting for Autism Research 2010; 05/2010
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    ABSTRACT: Background: Previous studies suggest that autism spectrum disorders (ASD) are over-represented and under-diagnosed in adult psychiatric populations. Adults in state psychiatric hospitals, many of whom received their diagnoses prior to the changing conceptualization and increased awareness of ASD, may have undiagnosed ASD. ASD symptoms may appear similar to the negative symptoms of schizophrenia. Four studies have estimated the prevalence of ASD in adult psychiatric populations (inpatient and outpatient) to be between 0.6% and 5.3%; no more than 10% of subjects in these studies who were found to have ASD were previously diagnosed as such. Instead, they were most commonly diagnosed with schizophrenia. Objectives: The objective of this study was two-fold: to validate the previous prevalence estimates of ASD among psychiatric inpatients and to identify characteristics that discriminate between severely impaired adults with ASD and other psychiatric disorders. Methods: The sample included 322 civilly-committed patients in one state psychiatric hospital in Pennsylvania. Nursing staff completed the Social Responsiveness Scale (SRS) for each patient as part of standard of care. All patients with scores ≥ 100 on the SRS and a stratified random sample of those with lower scores were consented to conduct in-depth chart reviews and contact family members to conduct the Autism Diagnostic Interview-Revised (ADI-R). Chart reviews focused on developmental history, paying particular attention to age of onset and clinical features indicative of ASD. Data on medications, self-injurious behaviors, and physical/mechanical restraints were collected for each consented patient. Patients also completed clinical interviews and a neurobehavioral battery to assess the presence and severity of psychotic symptoms and cognitive impairment. Case conferences with two psychiatrists and the team of assessing psychologists were held for all patients. Results: Eighteen percent of patients received a SRS score ≥100. ADI-R administration and case conferences are ongoing. Of the patients with completed case conferences (n=108), 9% meet criteria for certain or highly probable ASD. Formal analysis of characteristics that discriminate between severely impaired adults with ASD and other psychiatric disorders is ongoing. Preliminary results indicate that unresponsiveness to medications, lack of recreational drug use, and documentation in charts indicating that the patient “responds to internal stimuli” but no clear documentation of hallucinations/delusions discriminate between the presence of ASD and other psychiatric disorders. Conclusions: Almost one in 10 adults in this state psychiatric hospital met criteria for ASD, a much larger proportion than has been found in most previous studies. Previously validated screening and diagnostic instruments including the Social Responsiveness Scale (SRS) and the Autism Diagnostic Interview-Revised (ADI-R), did not demonstrate the same accuracy in this sample as they have in the general population. Improved screening and diagnostic assessments for more severely impaired adults with ASD, especially those that discriminate ASD from other psychiatric disorders, may have important implications for their treatment and supports. The results of this study will aid in efforts to determine the prevalence of ASD among institutionalized adults, increase understanding of the prevalence of ASD in adults, and guide policy and practice regarding diagnostic practices and service delivery to adults with ASD.
    International Meeting for Autism Research 2010; 05/2010
  • A. S. Kreibich, M. Torre, E. S. Brodkin
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    ABSTRACT: Background: Many individuals with autism spectrum disorders (ASD) show both reduced sociability (reduced tendency to seek social interaction), and disabling anxiety symptoms, but the biological relationship between sociability and anxiety is not well understood. Mouse model systems are useful for experimentally testing the relationship between sociability and anxiety. Relative to C57BL/6J mice, BALB/cJ mice show certain behavioral endophenotypes relevant to ASD, including low levels of sociability and high levels of anxiety-related behaviors in non-social tests. Objectives: We hypothesized that the low sociability of BALB/cJ mice is related to their generalized high level of anxiety, and that pharmacologically reducing anxiety in BALB/cJ mice would increase their level of social interaction. Methods: To test this hypothesis, we treated BALB/cJ mice with the anxiolytic chlordiazepoxide (CDP), and then measured levels of sociability in a social choice test and anxiety-related behaviors in a non-social paradigm, the elevated zero maze. Results: Contrary to our original hypothesis, we found that treatment with an anxiolytic medication, CDP (a benzodiazepine), reduces anxiety-related behavior in a nonsocial task, but also significantly decreases sociability. In contrast, treatment with a GABA inverse agonist, beta-carboline does not affect sociability or anxiety. Conclusions: These findings indicate that decreasing generalized anxiety does not increase sociability in this model system, suggesting that sociability and nonsocial anxiety-related behaviors are subserved by distinct neural circuitry. Future studies will use this mouse model system to further elucidate the neural circuitry and mechanisms that subserve sociability vs. nonsocial anxiety-related behaviors. These mechanistic studies may provide new pharmacologic targets for treating social withdrawal and/or anxiety symptoms in ASD.
    International Meeting for Autism Research 2010; 05/2010
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    ABSTRACT: Background: Limited research has been conducted on diagnosing adults with autism spectrum disorders (ASD). Previous studies have shown that diagnosing adults is difficult due to scarce and inconsistent information relating to the manifestation of ASD in adulthood. Symptoms of ASD in an individual may change over the life course due to maturation, environmental influences, and treatments and services. Life experiences may also cause individuals to appear to have ASD in adulthood. Current diagnostic instruments have not been validated in adult use and do not take into account the effect life occurrences may have on the presentation of ASD in adults. This may lead to a potential mistake in diagnosis of ASD in adults. Objectives: To identify characteristics, among adults who meet ADI-R criteria for an ASD, that discriminate between true and false positives. Methods: The sample included 322 civilly-committed patients in one state psychiatric hospital in Pennsylvania. Nursing staff completed the Social Responsiveness Scale (SRS) for each patient as part of standard of care. All patients with scores ≥ 100 on the SRS and a stratified random sample of those with lower scores were consented to conduct in-depth chart reviews and contact family members to conduct the Autism Diagnostic Interview-Revised (ADI-R) and Conflict Tactics Scales: Parent-Child Version (CTS-PC). Chart reviews focused on developmental history, paying particular attention to age of onset and clinical features indicative of ASD. Data on medications, self-injurious behaviors, and physical/mechanical restraints were collected for each consented patient. Case conferences with two psychiatrists and the team of assessing psychologists were held for all patients. After case conferences were completed, the patients who were identified as having ASD on the ADI-R were further examined to identify differences between false positives and true positives. Results: Case conferences as well as ADI-R and CTS-PC administration are ongoing. Twenty-two percent of patients with completed ADI-R interviews definitely or are highly to likely meet criteria for an ASD. Only 50% of subjects scoring positively on the ADI-R definitely met criteria for ASD based on record review and expert clinical judgment. Chart review found that all false positives experienced some form of abuse (physical, psychological, or sexual). In addition, all of the possible cases of ASD had a history of abuse. Only 29% of cases meeting research criteria for ASD had a history of abuse. Formal analysis of other characteristics that discriminate false positives from true positives is ongoing. To date, no differences between the false positives and true positives in patterns of responses on the ADI-R have been identified. Preliminary results indicate that false positives who have experienced abuse also have a more recent history of criminal involvement and substance abuse, while those meeting research criteria for ASD do not. Conclusions: Even in an institutionalized adult population, the ADI-R is a useful tool. Our results suggest, however, the need for different cut-offs and to augment the ADI-R with other information, especially about physical, sexual and substance abuse history.
    International Meeting for Autism Research 2010; 05/2010
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    ABSTRACT: Recent studies have implicated the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) in depression vulnerability, particularly in the context of stress. Several neuroimaging studies have shown that 5-HTTLPR genotype predicts amygdala reactivity to negatively valenced stimuli, suggesting a mechanism whereby the short allele confers depression risk. The current study investigated whether 5-HTTLPR genotype similarly affects neural activity during an induced sad mood and during recovery from sad mood. Participants were 15 homozygous short (S) and 15 homozygous long (L) individuals. Regional cerebral blood flow was measured with perfusion functional magnetic resonance imaging during four scanning blocks: baseline, sad mood, mood recovery and following return to baseline. Comparing mood recovery to baseline, both whole brain analyses and template-based region-of-interest analyses revealed greater amygdala activity for the S vs the L-group. There were no significant amygdala differences found during the induced sad mood. These results demonstrate the effect of the S allele on amygdala activity during intentional mood regulation and suggest that amygdala hyperactivity during recovery from a sad mood may be one mechanism by which the S allele confers depression risk.
    Social Cognitive and Affective Neuroscience 10/2009; 5(1):1-10. · 5.04 Impact Factor
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    ABSTRACT: Genetic linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The metallophosphoesterase (MPPE1) gene maps to this region. Dysregulation of protein phosphorylation and subsequent abnormal cellular signaling has been postulated to be involved in neuropsychiatric disorders thus making MPPE1 a plausible biological candidate gene for BPD. In this study, we hypothesized that genetic variation in the MPPE1 gene contributes to BPD. We tested this hypothesis by genotyping four SNPs (rs871044; rs3974590; rs593713; rs602201) in BPD patients (n = 570) and healthy controls (n = 725). Genotypes and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs3974590 with BPD (P = 0.009; permutation corrected P = 0.046). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide evidence of an association between a polymorphism in the MPPE1 gene and BPD. Additional studies are necessary to confirm and elucidate the role of MPPE1 as a susceptibility gene for BPD on chromosome 18p.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2009; 153B(3):830-6. · 3.23 Impact Factor
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    ABSTRACT: Neuregulin-1 (NRG1) is one of susceptibility genes for schizophrenia and plays critical roles in glutamatergic, dopaminergic and GABAergic signaling. Using mutant mice heterozygous for Nrg1 (Nrg1(+/-)) we studied the effects of Nrg1 signaling on behavioral and electrophysiological measures relevant to schizophrenia. EXPERIMENTAL PROCEDURE: Behavior of Nrg1(+/-) mice and their wild type littermates was evaluated using pre-pulse inhibition, contextual fear conditioning, novel object recognition, locomotor, and social choice paradigms. Event-related potentials (ERPs) were recorded to assess auditory gating and novel stimulus detection. Gating of ERPs was unaffected in Nrg1(+/-) mice, but mismatch negativity in response to novel stimuli was attenuated. The Nrg1(+/-) mice exhibited behavioral deficits in contextual fear conditioning and social interactions, while locomotor activity, pre-pulse inhibition and novel object recognition were not impaired. Nrg1(+/-) mice had impairments in a subset of behavioral and electrophysiological tasks relevant to the negative/cognitive symptom domains of schizophrenia that are thought to be influenced by glutamatergic and dopaminergic neurotransmission. These mice are a valuable tool for studying endophenotypes of schizophrenia, but highlight that single genes cannot account for the complex pathophysiology of the disorder.
    Brain research 08/2009; 1294:116-27. · 2.46 Impact Factor

Publication Stats

1k Citations
213.74 Total Impact Points

Institutions

  • 2007–2014
    • University of Pennsylvania
      • • Department of Psychiatry
      • • Department of Radiology
      • • Department of Psychology
      Philadelphia, Pennsylvania, United States
  • 2004–2011
    • Hospital of the University of Pennsylvania
      • Department of Psychiatry
      Philadelphia, Pennsylvania, United States
  • 2002
    • Princeton University
      • Department of Molecular Biology
      Princeton, NJ, United States
  • 1996–1999
    • Yale University
      • Department of Psychiatry
      New Haven, CT, United States