The need for caution in considering the diagnostic utility of antibasal ganglia antibodies in mov... more The need for caution in considering the diagnostic utility of antibasal ganglia antibodies in movement disorders
ABSTRACTBackgroundIndividuals with Tourette syndrome (TS) often report that they express tics as ... more ABSTRACTBackgroundIndividuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS.ObjectiveThe aim of this study was to examine the contribution of brain γ‐aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS.MethodsEdited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions...
Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cau... more Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cause(s) has remained elusive. We examined a European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants (CNVs) using SNP microarrays and identified two genome-wide significant loci that confer a substantial increase in risk for TS (NRXN1, OR=20.3, 95%CI [2.6-156.2], p=6.0 × 10−6; CNTN6, OR=10.1, 95% CI [2.3-45.4], p=3.7 × 10−5). Approximately 1% of TS cases carried one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.
Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS ofte... more Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS often report difficulty with ignoring (habituating to) tactile sensations, and some patients perceive that this contributes to a “premonitory urge” to tic. While common, the physiological basis of impaired tactile processing in TS, and indeed tics themselves, remain poorly understood. It has been well established that GABAergic processing plays an important role in shaping the neurophysiological response to tactile stimulation. Furthermore, there are multiple lines of evidence suggesting that a deficit in GABAergic transmission may contribute to symptoms found in TS. In this study, GABA-edited magnetic resonance spectroscopy (MRS) was combined with a battery of vibrotactile tasks to investigate the role of GABA and atypical sensory processing in children with TS. Our results show reduced primary sensorimotor cortex (SM1) GABA concentration in children with TS compared with healthy control su...
An autoimmune etiology has been proposed for a variety of movement disorders, making the detectio... more An autoimmune etiology has been proposed for a variety of movement disorders, making the detection of autoantibodies a high investigative priority. Recognizing the existence of different methodologic approaches to identify these antibodies, we sought to investigate the effects of tissue preparation, antibody selection, and Western immunoblot detection methods on outcome. ELISA and immunoblotting studies were performed in healthy controls evaluating non-pathogenic autoantibodies. Our results indicate that enhanced data can be obtained by using fresh, rather than frozen, postmortem tissue homogenates for Western immunoblots and enzyme-linked immunosorbent assays and support the use of electrochemiluminescent detection for Western immunoblots. Molecular localization is significantly affected by the selected standard. Removal of lipids from homogenates does not affect anti-basal ganglia antibody (ABGA) results. Methodological variables should be taken into consideration when performing ...
The direct estimation of heritability from genome-wide common variant data as implemented in the ... more The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for ...
Journal of the American Academy of Child and Adolescent Psychiatry, 2014
Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental d... more Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large…
The need for caution in considering the diagnostic utility of antibasal ganglia antibodies in mov... more The need for caution in considering the diagnostic utility of antibasal ganglia antibodies in movement disorders
ABSTRACTBackgroundIndividuals with Tourette syndrome (TS) often report that they express tics as ... more ABSTRACTBackgroundIndividuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS.ObjectiveThe aim of this study was to examine the contribution of brain γ‐aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS.MethodsEdited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions...
Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cau... more Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cause(s) has remained elusive. We examined a European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants (CNVs) using SNP microarrays and identified two genome-wide significant loci that confer a substantial increase in risk for TS (NRXN1, OR=20.3, 95%CI [2.6-156.2], p=6.0 × 10−6; CNTN6, OR=10.1, 95% CI [2.3-45.4], p=3.7 × 10−5). Approximately 1% of TS cases carried one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.
Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS ofte... more Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS often report difficulty with ignoring (habituating to) tactile sensations, and some patients perceive that this contributes to a “premonitory urge” to tic. While common, the physiological basis of impaired tactile processing in TS, and indeed tics themselves, remain poorly understood. It has been well established that GABAergic processing plays an important role in shaping the neurophysiological response to tactile stimulation. Furthermore, there are multiple lines of evidence suggesting that a deficit in GABAergic transmission may contribute to symptoms found in TS. In this study, GABA-edited magnetic resonance spectroscopy (MRS) was combined with a battery of vibrotactile tasks to investigate the role of GABA and atypical sensory processing in children with TS. Our results show reduced primary sensorimotor cortex (SM1) GABA concentration in children with TS compared with healthy control su...
An autoimmune etiology has been proposed for a variety of movement disorders, making the detectio... more An autoimmune etiology has been proposed for a variety of movement disorders, making the detection of autoantibodies a high investigative priority. Recognizing the existence of different methodologic approaches to identify these antibodies, we sought to investigate the effects of tissue preparation, antibody selection, and Western immunoblot detection methods on outcome. ELISA and immunoblotting studies were performed in healthy controls evaluating non-pathogenic autoantibodies. Our results indicate that enhanced data can be obtained by using fresh, rather than frozen, postmortem tissue homogenates for Western immunoblots and enzyme-linked immunosorbent assays and support the use of electrochemiluminescent detection for Western immunoblots. Molecular localization is significantly affected by the selected standard. Removal of lipids from homogenates does not affect anti-basal ganglia antibody (ABGA) results. Methodological variables should be taken into consideration when performing ...
The direct estimation of heritability from genome-wide common variant data as implemented in the ... more The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for ...
Journal of the American Academy of Child and Adolescent Psychiatry, 2014
Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental d... more Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large…
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Papers by Harvey Singer