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402. Genetics and neurobiology of sensorimotor gating: the gain in brain comes mainly in the strain
Saturday Abstracts
Hz repetitive transcranial magnetic stimulation (rTMS) of ⬃15 minutes duration has been shown to reduce cortical activation. We will present two studies testing the hypothesis that 1 Hz rTMS delivered to left temporoparietal cortex, a brain region critical for speech processing, reduces AHs. The first study used once daily rTMS at 80% motor threshold for 4 –16 minutes duration built up over four days. Twelve schizophrenic patients with medication-resistant AHs were randomized to active versus sham stimulation and studied using a double-blind, cross-over design. Significant improvements in AHs were detected following 12 minutes (p ⬍ .02) and 16 minutes (p ⬍ .0001) of active rTMS but not following sham stimulation. Endpoint hallucination severity following the active stimulation trial was significantly less than hallucination severity following sham stimulation trial (p ⬍ .006). Duration of symptomatic improvement ranged from 1 day to 2 months. Results of a second, double-blind trial of rTMS utilizing seven instances of rTMS at 16 minutes duration will also be presented. Data from our first nine patients suggest that this more extended trial produces robust and sustained reductions in AHs in ⬃70% of patients. Our findings emphasize the role of posterior, speech processing areas of the brain in the generation of AHs. One Hz rTMS deserves further study as a possible treatment for hallucinations and other psychotic symptoms. Supported by NIH/NCRR/GCRC Program Grant RR00125 and a NARSAD Independent Investigator Award.
Cross-Species Genetics of a Complex Phenotype: Schizophrenia-Linked Startle Gating Deficits Saturday, May 13, 2:30 PM–5:00 PM Location: Gold Coast Chair: David L. Braff
402. GENETICS AND NEUROBIOLOGY OF SENSORIMOTOR GATING: THE GAIN IN BRAIN COMES MAINLY IN THE STRAIN
BIOL PSYCHIATRY 2000;47:1S–173S
123S
pharmacologic sensitivity. Strategies are used to identify the neural substrates of strain differences, and to insure that strain differences do not reflect inherited differences in peripheral sensory systems. Ultimately, “inconsistencies” identified in PPI studies across laboratories promise to help understand the genetics of sensorimotor gating deficits in schizophrenia and other disorders.
403. MOUSE GENETIC MODELS FOR SENSORIMOTOR GATING DEFICITS R. Paylor Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 Several patient populations with neuropsychiatric disorders, including schizophrenia, have impaired sensorimotor gating as measured using the prepulse inhibition (PPI) paradigm. Several studies using various mouse genetic models to understand the genetic basis for PPI will be discussed. Evaluating the PPI response in different inbred strains of mice we found that PPI is a polygenic trait. The chromosomal regions influencing PPI in a segregating F2 mice have initially been mapped using QTL strategies. The PPI response appears to have a relatively high heritable rate, but only a few suggestive QTL loci (LOD score 2 to 2.5) have been identified. Different gene-targeted mutant mice have also been a valuable tool for studying the role of single gene mutations in PPI. Although many mutant mice appear to have normal PPI, we have identified the Dv11-deficient mouse as a potential animal model system for studying schizophreniarelated traits in mice. However, in contrast to what might have been predicted, mice deficient in the ␣7 nicotinic receptor subunit displayed normal sensorimotor gating. Most recently we found an abnormal PPI response in mice with a deletion of chromosome 16 in a region syntenic for DiGeorge syndrome. Mice with a deletion of chromosome 16 showed significantly greater levels of PPI compared to their wild-type controls, which is opposite of what we might have predicted since patients with DiGeorge syndrome often display “schizophrenic-like” behaviors. We believe that using various types of mouse genetic models systems will help to better understand the biological basis for sensorimotor gating deficits associated with neuropsychiatric disorders.
N.R. Swerdlow, Z.A. Martinez, F.M. Hanlon, M. Farid, A. Platten, P. Auerbach Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804 Sensorimotor gating of the startle reflex, measured by prepulse inhibition of startle (PPI), is impaired in humans with specific neuropsychiatric disorders, and in laboratory animals after manipulations of dopamine, serotonin or glutamate activity within specific cortico-striato-pallidopontine (CSPP) circuitries. PPI is being used widely to understand the neurobiology of “gating” disorders, and to develop novel antipsychotics based on their ability to reverse experimentally-induced PPI deficits. As PPI studies have increased exponentially in the past decade, differences in drug effects across laboratories were identified that first prompted concern regarding potential interpretative flaws, and later stimulated efforts to understand methodological contribution to these apparent inconsistencies. An awareness has emerged that “baseline” levels of PPI differ significantly across specific outbred rat strains, and within strains, across specific suppliers. Differences in PPI sensitivity to pharmacologic manipulations have also been identified across rat strains and substrains. Differences in both baseline PPI and PPI drug sensitivity may reflect genetic differences within CSPP circuitries that regulate PPI, since they exist even when rats are raised in identical environments, and are tested very early in development. Inheritance patterns are being studied by selective cross-breeding and development of inbred lines based on
404. MODULATION OF THE STARTLE RESPONSE AND STARTLE LATERALITY IN RELATIVES OF SCHIZOPHRENIC PATIENTS AND SCHIZOTYPAL SUBJECTS: EVIDENCE OF INHIBITORY DEFICITS K.S. Cadenhead, N.R. Swerdlow, K. Shafer, D.L. Braff Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804 Schizophrenic patients and schizotypal personality disordered (SPD) subjects have been shown to have deficits in sensorimotor gating when assessed in a paradigm that measures prepulse inhibition (PPI) of the startle response. The findings of reduced PPI in both schizophrenic patients and SPD subjects suggest that PPI is a potentially useful neurobiological marker for intermediate phenotypes of schizophrenia spectrum illness. The study of vulnerability markers in clinically unaffected relatives of schizophrenia patients has become increasingly important because it provides a means of assessing phenotypic traits of
Hz repetitive transcranial magnetic stimulation (rTMS) of ⬃15 minutes duration has been shown to reduce cortical activation. We will present two studies testing the hypothesis that 1 Hz rTMS delivered to left temporoparietal cortex, a brain region critical for speech processing, reduces AHs. The first study used once daily rTMS at 80% motor threshold for 4 –16 minutes duration built up over four days. Twelve schizophrenic patients with medication-resistant AHs were randomized to active versus sham stimulation and studied using a double-blind, cross-over design. Significant improvements in AHs were detected following 12 minutes (p ⬍ .02) and 16 minutes (p ⬍ .0001) of active rTMS but not following sham stimulation. Endpoint hallucination severity following the active stimulation trial was significantly less than hallucination severity following sham stimulation trial (p ⬍ .006). Duration of symptomatic improvement ranged from 1 day to 2 months. Results of a second, double-blind trial of rTMS utilizing seven instances of rTMS at 16 minutes duration will also be presented. Data from our first nine patients suggest that this more extended trial produces robust and sustained reductions in AHs in ⬃70% of patients. Our findings emphasize the role of posterior, speech processing areas of the brain in the generation of AHs. One Hz rTMS deserves further study as a possible treatment for hallucinations and other psychotic symptoms. Supported by NIH/NCRR/GCRC Program Grant RR00125 and a NARSAD Independent Investigator Award.
Cross-Species Genetics of a Complex Phenotype: Schizophrenia-Linked Startle Gating Deficits Saturday, May 13, 2:30 PM–5:00 PM Location: Gold Coast Chair: David L. Braff
402. GENETICS AND NEUROBIOLOGY OF SENSORIMOTOR GATING: THE GAIN IN BRAIN COMES MAINLY IN THE STRAIN
BIOL PSYCHIATRY 2000;47:1S–173S
123S
pharmacologic sensitivity. Strategies are used to identify the neural substrates of strain differences, and to insure that strain differences do not reflect inherited differences in peripheral sensory systems. Ultimately, “inconsistencies” identified in PPI studies across laboratories promise to help understand the genetics of sensorimotor gating deficits in schizophrenia and other disorders.
403. MOUSE GENETIC MODELS FOR SENSORIMOTOR GATING DEFICITS R. Paylor Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 Several patient populations with neuropsychiatric disorders, including schizophrenia, have impaired sensorimotor gating as measured using the prepulse inhibition (PPI) paradigm. Several studies using various mouse genetic models to understand the genetic basis for PPI will be discussed. Evaluating the PPI response in different inbred strains of mice we found that PPI is a polygenic trait. The chromosomal regions influencing PPI in a segregating F2 mice have initially been mapped using QTL strategies. The PPI response appears to have a relatively high heritable rate, but only a few suggestive QTL loci (LOD score 2 to 2.5) have been identified. Different gene-targeted mutant mice have also been a valuable tool for studying the role of single gene mutations in PPI. Although many mutant mice appear to have normal PPI, we have identified the Dv11-deficient mouse as a potential animal model system for studying schizophreniarelated traits in mice. However, in contrast to what might have been predicted, mice deficient in the ␣7 nicotinic receptor subunit displayed normal sensorimotor gating. Most recently we found an abnormal PPI response in mice with a deletion of chromosome 16 in a region syntenic for DiGeorge syndrome. Mice with a deletion of chromosome 16 showed significantly greater levels of PPI compared to their wild-type controls, which is opposite of what we might have predicted since patients with DiGeorge syndrome often display “schizophrenic-like” behaviors. We believe that using various types of mouse genetic models systems will help to better understand the biological basis for sensorimotor gating deficits associated with neuropsychiatric disorders.
N.R. Swerdlow, Z.A. Martinez, F.M. Hanlon, M. Farid, A. Platten, P. Auerbach Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804 Sensorimotor gating of the startle reflex, measured by prepulse inhibition of startle (PPI), is impaired in humans with specific neuropsychiatric disorders, and in laboratory animals after manipulations of dopamine, serotonin or glutamate activity within specific cortico-striato-pallidopontine (CSPP) circuitries. PPI is being used widely to understand the neurobiology of “gating” disorders, and to develop novel antipsychotics based on their ability to reverse experimentally-induced PPI deficits. As PPI studies have increased exponentially in the past decade, differences in drug effects across laboratories were identified that first prompted concern regarding potential interpretative flaws, and later stimulated efforts to understand methodological contribution to these apparent inconsistencies. An awareness has emerged that “baseline” levels of PPI differ significantly across specific outbred rat strains, and within strains, across specific suppliers. Differences in PPI sensitivity to pharmacologic manipulations have also been identified across rat strains and substrains. Differences in both baseline PPI and PPI drug sensitivity may reflect genetic differences within CSPP circuitries that regulate PPI, since they exist even when rats are raised in identical environments, and are tested very early in development. Inheritance patterns are being studied by selective cross-breeding and development of inbred lines based on
404. MODULATION OF THE STARTLE RESPONSE AND STARTLE LATERALITY IN RELATIVES OF SCHIZOPHRENIC PATIENTS AND SCHIZOTYPAL SUBJECTS: EVIDENCE OF INHIBITORY DEFICITS K.S. Cadenhead, N.R. Swerdlow, K. Shafer, D.L. Braff Department of Psychiatry, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804 Schizophrenic patients and schizotypal personality disordered (SPD) subjects have been shown to have deficits in sensorimotor gating when assessed in a paradigm that measures prepulse inhibition (PPI) of the startle response. The findings of reduced PPI in both schizophrenic patients and SPD subjects suggest that PPI is a potentially useful neurobiological marker for intermediate phenotypes of schizophrenia spectrum illness. The study of vulnerability markers in clinically unaffected relatives of schizophrenia patients has become increasingly important because it provides a means of assessing phenotypic traits of